EP1885702A2

EP1885702A2 - Quinazolinones

Info

Publication number: EP1885702A2
Application number: EP06753676A
Authority: EP
Inventors: Hans-Peter Buchstaller; Dirk Finsinger; Kai Schiemann; Ulrich Emde; Frank Zenke; Christiane Amendt
Original assignee: Merck Patent GmbH
Current assignee: Merck Patent GmbH
Priority date: 2005-05-25
Filing date: 2006-05-17
Publication date: 2008-02-13
Also published as: JP2008542215A; CA2609391A1; AU2006251355A1; DE102005024017A1; WO2006125555A2; AR057322A1; US20080234299A1; WO2006125555A3

Abstract

Disclosed are compounds of formula (I), wherein R, R1, R2, R3, R4, R5, R6, R7, R8, Z1, Z2, Z3, k, and Y1 have the meanings indicated in claim 1. Said compounds can be used for the treatment of tumors, among other things.

Description

quinazolinones

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

The present invention relates to compounds of the formula I and their use for the treatment and prophylaxis of diseases in which the inhibition, regulation and / or modulation of mitotic motor proteins, in particular of the mitotic motor protein Eg5 plays a role, and also pharmaceutical compositions which contain these compounds.

More particularly, the present invention relates to compounds of formula I which preferentially inhibit, regulate and / or modulate one or more mitotic motor proteins, compositions containing these compounds, and methods for their use in the treatment of diseases and conditions such as angiogenesis, cancer , Tumorigenesis, growth and spread, arteriosclerosis, eye diseases, choroidal neovascularization and diabetic retinopathy, inflammatory diseases, arthritis, neurodegeneration, restenosis,

Wound healing or graft rejection. In particular, the compounds according to the invention are suitable for the therapy or prophylaxis of cancerous diseases.

During mitosis, various kinesins regulate the formation and dynamics of the spindle apparatus responsible for correct and coordinated alignment and separation of the chromosomes. It has been observed that specific inhibition of a mitotic motor protein - Eg5 - leads to collapse of the spindle fibers. As a result, the chromosomes can no longer be correctly distributed to the daughter cells. This leads to mitotic arrest and can thus cause cell death. An upregulation of the motor protein For example, Eg5 has been described in tissues of breast, lung and colon tumors. Since Eg5 occupies a function specific to mitosis, mainly rapidly dividing cells and not fully differentiated cells are affected by Eg5 inhibition. In addition, Eg5 regulates exclusively the movement of mitotic microtubules

(Spindle apparatus) and not those of the cytoskeleton. This is crucial for the side effect profile of the compounds of the invention, e.g. Neuropathies, as observed in Taxol, do not occur or only weakened. Therefore, the inhibition of Eg5 by the compounds according to the invention is a relevant therapeutic concept for the treatment of malignant tumors.

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

It has surprisingly been found that the inventive

Connections cause a specific inhibition of mitotic Moter proteins, in particular Eg5. The compounds of the invention preferably exhibit a beneficial biological activity which is readily detectable in the assays described herein, for example. In such assays, the compounds of the invention preferably exhibit and effect an inhibitory effect, usually documented by IC ₅₀ values in a suitable range, preferably in the micromolar range, and more preferably in the nanomolar range.

As discussed herein, effects of the compound of the invention are relevant to various diseases. Accordingly, the compounds of the invention are useful in prophylaxis and / or Treatment of diseases that are influenced by inhibition of one or more mitotic motor proteins, in particular Eg5.

The present invention therefore relates to compounds according to the invention as medicaments and / or active pharmaceutical ingredients in the

Treatment and / or prophylaxis of said diseases and the use of compounds of the invention for the manufacture of a pharmaceutical for the treatment and / or prophylaxis of said diseases, as well as a method for the treatment of said diseases comprising administering one or more of the compounds of the invention to a patient in need on such administration.

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

In addition, the compounds of the invention preferably exhibit one or more advantageous or improved properties over the compounds of the prior art. These preferably include an optimized solubility behavior, a modified, in particular improved pharmacokinetic behavior, a modified, in particular improved metabolite behavior or metabolite pattern, a modified, in particular improved side effect or tolerability profile and / or a modified half life, preferably a prolonged half life.

The host or patient may be of any mammalian species, e.g. A primate species, especially humans; Rodents, including mice, rats and hamsters; Rabbits; Horses, cattle, dogs, cats, etc. Animal models are of interest for experimental studies, providing a model for the treatment of human disease. The susceptibility of a particular cell to treatment with the compounds of the invention can be determined by testing in vitro. Typically, a culture of the cell is combined with a compound of the invention at various concentrations for a period of time sufficient to allow the drugs to induce cell death or inhibit migration, usually between about one hour and one week. For testing in vitro, cultured cells from a biopsy sample can be used. The viable cells remaining after treatment are then counted.

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

The invention relates to compounds of the formula I.

wherein R ¹ , R ² , R ³ and R ^{4 are} independently H, A, Ar, Het, OR ^a , SR ^a , OAr, SAr, N (R ^a ) _2l NR ³ Ar, Hal, NO ₂ , CN, (CH ₂ ) _m COOR ^a , (CH ₂ ) _m COOAr, (CH ₂ ) mCON (R ^a ) _2> (CH ₂ ) _m CONHAr, COR ³ , COAr, S (O) _n AS (O) _m Ar, NHCOA, NHCOAr, NHSO ₂ A, NHSO ₂ Ar or SO ₂ N (R ³ ) ₂ ,

R ^{a is} H, A, Ar, Het, aralkyl or hetero-aralkyl,

R ⁵ , R ^{8 are} independently H, A, Ar, Het, aralkyl or hetero-aralkyl, and

R ⁶ , R ^{7 are} independently H, A, Ar, Het, aralkyl or heteroaryl

Aralkyl mean, or

R ⁶ and R ⁷ together with the N-atom to which they are attached form a saturated or unsaturated 5-, 6- or 7-membered heterocycle, optionally 1, 2 or 3 further heteroatoms selected from N, S and O, may contain,

Y ^{1 represents} O, S or NR ¹ ,

Z ¹ , Z ^{2 are} independently selected from (CR ⁹ R ¹⁰ ) _n and (CR ⁹ R ¹ V

(C = Y ² HCR ¹¹ R ¹² ) _{q are} selected,

Z ³ is absent or independently among those given for Z ¹ and Z ²

Meanings is selected,

A is alkyl or cycloalkyl,

Ar is aryl or heteroaryl,

Heteroaryl or heterocyclyl, HaI F, Cl, Br or I,

Y ² O, S or NR ² ,

R ⁹ , R ¹⁰ , R ¹¹ , R ¹² independently of one another are H, A, OA, Ar, Het, aralkyl or heteroaralkyl,

k is 0, 1 or 2, preferably 0 or 1,

m is 1, 2, 3 or 4, preferably 0, 1, 2 or 3,

n is 1, 2, 3, 4, 5 or 6, preferably 2, 3, 4 or 5, and

p, q are independently 0, 1, 2, 3 or 4, preferably O ₁ 1, 2 or 3

mean,

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

The invention also relates to the optically active forms, the enantiomers, the racemates, the diastereomers and the hydrates and solvates of these compounds. Solvates of the compounds are understood to mean additions of inert solvent molecules to the compounds of the formula I which form on account of their mutual attraction. Solvates are e.g. Mono or dihydrate or alcoholates.

Pharmaceutically usable derivatives are understood as meaning, for example, the salts of the compounds according to the invention as well as so-called prodrugs. Compounds or prodrug derivatives. Suitable prodrug compounds or prodrug derivatives and processes for their preparation are known in the art.

By prodrug compounds or prodrug derivatives is preferably understood with z. As alkyl or acyl groups, sugars or oligopeptides modified compounds of formula I, which are rapidly cleaved in the organism to the active compounds of the invention. These include biodegradable polymer derivatives of the compounds of the invention, as z. In Int. J. Pharm. 1J5, 61-67 (1995).

Similar compounds are e.g. in Tetrahedron Lett. 1988, 29, 5855-5858, Tetrahedron Lett. 2003, 44, 217-219, J. Org. Chem. 1997, 62, 4880-4882, J. Org. Chem. 1999, 64, 6462-6467, Chem. Lett. 1995, 423-424, J. Org. Chem. 2000, 65, 5009-5013, Chem. Lett. 2003, 32, 222-223, US2003149069A1, but are not mentioned in connection with cancer treatments and / or do not contain the features essential to the invention.

The term "effective amount" means the amount of a drug or pharmaceutical agent which elicits a biological or medical response in a tissue, system, animal or human, e.g. sought or desired by a researcher or physician. In addition, the term "therapeutically effective amount" means an amount that produces at least one of the following effects in a human or other mammal (as compared to a subject who has not received that amount):

Improvement of the curative treatment, cure, prevention or elimination of a disease, a clinical picture, a disease state, a disease, a disorder or side effects or the

Reduction of the progression of a disease, a disease or a disorder. The term "therapeutically effective amount" also includes the Amounts effective to increase or enhance normal physiological function.

In the context of the present invention, the term "herein" preferably means "in the description and / or the claims" and in particular "above and / or below in the description and / or the claims". For example, the term "as described herein" preferably has the meaning "as described in the specification and / or claims" and particularly the meaning "as described above and / or hereinafter in the specification and / or claims".

The invention also provides the use of mixtures of the compounds of formula I, e.g. Mixtures of two diastereomers, for example mixtures of two diastereomers in the ratio of about 1: 1, 1: 2, 1: 3, 1: 4, 1: 5, 1: 10, 1: 100 or about 1: 1000.

These are particularly preferably mixtures of stereoisomeric compounds.

The invention relates to the compounds of the formula I and their salts, and to a process for the preparation of compounds of the formula I according to the claims and their pharmaceutically usable derivatives, salts, solvates and stereoisomers, characterized in that a) a compound of the formula II

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , Y ¹ and Z ^{1 have} the meanings given herein, X is O is NH or S and in particular O, and LG ¹ and LG ² each represents a leaving group , cyclized leaving the leaving group LG ¹ to a compound of formula IIb;

reacting the compound of the formula IIb with a compound of the formula

wherein R ^{5 has} the meaning given herein, and L ² and L ^{3 are} independently H or a metal atom and in particular both stand for H,

and thereby obtaining a compound of formula Nc;

c) reacting the compound of the formula Nc with a compound of the formula IV,

L ^{4 is} H or a metal atom and Z ² , Z ³ , k, R ⁶ , R ⁷ and R ^{8 have} the meanings given herein,

wherein the groups LG ² and L ^{4 are} split off and a compound of the formula I is obtained; and optional

d) the resulting compound of the formula I is isolated and / or treated with an acid or a base in order to convert it into one of its salts.

Suitable leaving groups LG ¹ and LG ² for the above process are known to the person skilled in the art, for example from standard works such as Houben-Weyl, Methods of Organic Chemistry, Georg Thieme Verlag, Stuttgart.

Preferably, LG ^{1 is} a leaving group selected from H and a metal atom. LG ¹ particularly preferably stands for H, in particular when X is O.

LG ² preferably represents a leaving group selected from Hal _1, in particular Cl, Br or I, and OSO ₂ R ⁶ , where R ^{e is} preferably selected from A, in particular alkyl, such as methyl and trifluoromethyl, and Ar, in particular phenyl or substituted phenyl , LG ² particularly preferably represents Hal, particularly preferably Cl, Br or I, and in particular Br.

L ² and L ³ independently of one another preferably represent H or a metal atom, for example an alkali metal atom, such as Na or K, and particularly preferably H.

The process according to the invention is preferably carried out under reaction conditions which are known and suitable for the reactions mentioned or which are analogous to the person skilled in the art

Derive reactions in a simple manner. One can also make use of known per se, not mentioned here variants.

The starting materials for the process according to the invention are either commercially available or can be prepared by methods known per se, as described in the literature (eg in the standard works such as Houben-Weyl, Methods of Organic Chemistry, Georg Thieme Verlag, Stuttgart), under reaction conditions known and suitable for these reactions. One can also make use of known per se, not mentioned here variants.

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

It is also possible to convert a compound of the formula I into another compound of the formula I by reacting one or more radicals, for example one or more radicals selected from R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁵ , R ⁶ , R ⁷ and R ⁸ into one or more other radicals R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁵ , R ⁶ , R ⁷ and R ⁸ converted (ie, for example, a radical R ^{1 is converted} into another R ¹ radical or one R ⁵ radical is converted to another R ⁵ radical), for example by reacting nitro groups, for example by hydrogenation on Raney nickel or Pd-carbon in an inert solvent such as methanol or ethanol, reduced to amino groups and / or converts an ester group to a carboxy group and / or converts an amino group to an alkylated amine by reductive amination and / or carboxy groups by reaction with alcohols esterified.

Further, one can acylate free amino groups in the usual manner with an acid chloride or anhydride or alkylate with an unsubstituted or substituted alkyl halide, suitably in an inert solvent such as dichloromethane or THF and / or in the presence of a base such as triethylamine or pyridine at temperatures between -60 and + 30 °.

If desired, in a compound of the formula I, a functionally modified amino and / or hydroxyl group can be liberated by solvolysis or hydrogenolysis by customary methods. This can e.g. with NaOH or KOH in water, water-THF or water-dioxane at temperatures between 0 and 100 °.

Another object of the invention is a preferred method for

Preparation of compounds of the formula I according to the claims and their pharmaceutically usable derivatives, salts, solvates and

Stereoisomers, characterized in that

a) a compound of formula II '

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁹ , X, LG ¹ and Y ^{1 have} the meanings given herein, LG ^{1 is} a leaving group, with removal of the leaving group LG ¹ to a compound of formula IIb cyclized;

b) the compound of formula IIb 'by reaction with a compound of formula III

and introducing a leaving group LG ³ into a compound of formula Nc ';

d) converting the compound of the formula Nc 'by reaction with cyanide into a compound of the formula Hd';

c2) the compound of the formula Hd 'is converted under reductive conditions into a compound of the formula I', ie into a compound of the formula I in which k is 0, Z ^{1 is} -CHR ⁹ -CH ₂ - and R ⁶ and R ⁷ each represents H;

and optionally either

c3a) the compound of the formula I 'obtained in step c2) is converted by reaction with a compound FG ¹ -R ⁶ and / or FG ² -R ⁷ into a compound of the formula I ", ie a compound of the formula I in which k is the same 0 is, Z ^{1 is} -CHR ⁹ -CH ₂ - and in which R ⁶ and / or R ⁷ are different from H;

c3b) the compound of the formula I 'obtained in step c2) by reaction with a compound of the formula FG ³ -Z ² -NR ⁶ R ⁷ and optionally a compound FG ⁴ -Z ³ -R ⁸ , wherein FG ³ and FG ⁴ denote are suitable functional groups, converted into a compound of formula I '",

ie, converting a compound of formula I wherein k is 1, Z ^{1 is} -CHR ⁹ -CH ₂ -, and optionally wherein Z ³ -R ^{8 is} a group other than H;

and optional

d) the resulting compound of formula I (or formula I ', formula I "or formula I'") isolated and / or treated with an acid or a base to convert them into one of their salts.

The preferred process according to the invention is preferably carried out under reaction conditions which are known and suitable for the reactions mentioned or which are analogous to the person skilled in the art

Derive reactions in a simple manner. One can also make use of known per se, not mentioned here variants. The starting materials for the process according to the invention are either commercially available or can be prepared by methods known per se, as described in the literature. Also in this preferred process, the radicals R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , X, Z ² , Z ³ , L ² , L ³ , LG ¹ , LG ³ and Y ¹ preferably have the meanings given herein, unless explicitly stated otherwise in the individual steps.

Suitable leaving groups LG ³ for the above process are known to the person skilled in the art, for example from standard works such as Houben-Weyl, Methods of Organic Chemistry, Georg-Thieme-Verlag, Stuttgart.

Preferably, LG ^{3 is} a leaving group selected from Hal, in particular Cl, Br or I, and OSO 2 R ^e , wherein R ^{e is} preferably selected from

A, especially alkyl, such as methyl and trifluoromethyl, and

Ar, in particular phenyl or substituted phenyl.

LG ³ particularly preferably represents Hal, particularly preferably Cl ₁ Br or I, and in particular Br.

Such functional groups FG ¹ , FG ² , FG ³ and FG ⁴ suitable for the above process are known to the person skilled in the art, for example from

Standard works such as Houben-Weyl, Methods of Organic Chemistry, Georg Thieme Verlag, Stuttgart.

In the context of the process according to the invention, the term FG ¹ , FG ² , FG ³ and FG ⁴ preferably each independently represent a functional group which is suitable for the reaction with a primary amino group, ie a primary amino group in a secondary (or a convert secondary into a tertiary) amino group.

Particularly preferred are FG ¹ , FG ² , FG ³ and FG ⁴ for in

Alkylating agents, arylating agents and / or acylating agents contained functional groups, as well as functional groups that are suitable for a reductive amination.

If FG ¹ , FG ² , FG ³ and / or FG ^{4 are} the functional group of alkylating agents, arylating agents and / or acylating agents, FG ¹ , FG ² , FG ³ and / or FG ⁴ are each independently preferably Hal, in particular Cl , Br or I, and OSO ₂ R ^e , wherein R ^{e is} preferably selected from A, in particular alkyl, such as methyl and trifluoromethyl, and Ar, in particular phenyl or substituted phenyl, and particularly preferably Hal, in particular Cl and / or Br.

When FG ¹ , FG ² , FG ³ and / or FG ^{4 represent} those functional groups which are suitable for reductive amination, they are preferably independently selected as follows: when R ⁶ and / or R ^{7 have} one above a methylene group or a

Represent methine group to the nitrogen atom of the group NR ⁶ R ⁷ bonded radical, FG ¹ and / or FG ^{2 is} preferably an oxo radical, ie = O. For example, a group -NR ⁶ R ⁷ , wherein R ⁶ and R ^{7 are} H, can be prepared by reaction with a compound of the formula R ^f -C = OR ^g , wherein R ^f and R ⁹ independently of one another are preferably H, A, aryl and Het are selected, first into a group of the formula -N (= CR ^f R ⁹ ) R ⁷ and then converted under reductive conditions into a group of the formula -N (CHR ^f R ⁹ ) R ⁷ . A further reaction of a group of the formula --N (CHR ^f R ^g ) R ⁷ with a compound of the formula R ^f -C = OR ⁹ or the formula R ^h -C = OR '(wherein R ^h and Ri ⁹ independently of one another are preferably are selected from H, A, aryl and Het) leads analogously to a group of the formula N (CHR ^f R ⁹ ) ₂ or N (CHR ^f R ⁹ ) (CHR ^h R ^j ), in each case depending on the educt used. This reaction sequence is known as reductive amination and described in detail in the prior art, for example in Houben-Weyl, Methods of Organic Chemistry, Georg-Thieme-Verlag, Stuttgart. In a manner analogous to the methods described above, it is also possible if appropriate to introduce a group R ⁸ -Z ³ other than H into the compounds of the formula I (see step c3b) in the preferred process), ie a group of the formula -Z ¹ -NH- Z ² - into a group of the formula -Z ¹ -N (Z ³ -R ⁸ ) -Z ² - convert.

Preferred is such a reductive amination using compounds of the formula R ^f -C = OR ⁹ and / or or the formula R ¹ ^ -C = OR ¹ , and in particular compounds of the formula R ^f -C = OH (ie compounds of the formula R ^f -CHO) or of the formula R ^f -C = OH (ie compounds of the formula R ^f -CHO), wherein R ^f and R 'are as defined above and are in particular selected from A, aryl and Het. Conventional reducing agents, such as, for example, hydrides, preferably cyanoborohydrides and in particular NaCNBH ₃ , can advantageously be used here for the provision of reductive conditions.

For the preparation of compounds of the formula I ₁ in which k is 1 or 2 and in which R ⁶ and / or R ^{7 is} H, it may be advantageous, in the preferred process in reaction step c3b), to obtain compounds of the formula FG ³ -Z ² - Use NR ⁶ R ⁷ , wherein R ⁶ and / or R ^{7 is} an amino-protecting group to use, and then the resulting compound of formula I, wherein R ⁶ and / or R ^{7 is} an amino-protecting group, by cleavage of Amino protective group (s) subsequently to convert a compound of formula I, wherein R ⁶ and / or R ^{7 is} H. Compounds of the formula FG ³ -Z ² -NR ⁶ R ⁷ can advantageously be used for this purpose, in which R ^{7 is} the Boc protective group (Boc is tert-butoxycarbonyl) and R ^{6 is} H. Further suitable amino-protecting groups are known to the person skilled in the art, for example from Houben-Weyl, Methods of Organic Chemistry, Georg-Thieme-Verlag, Stuttgart (see, inter alia, Houben-Weyl, 15/1, 117-133, and Greene, Protective Groups in Organic Syntheses, New York: Wiley 1981). Cyanides in the context of the invention are both hydrocyanic acid (HCN) and hydrocyanic acid or cyanide anion-releasing compounds and precursors, and in particular the salts of hydrocyanic acid, very particularly preferably potassium cyanide (KCN) and sodium cyanide (NaCN).

Suitable conditions for carrying out the process steps of the process according to the invention are known to the person skilled in the art, for example from Houben-Weyl, Methods of Organic Chemistry, Georg Thieme Verlag, Stuttgart.

The process steps of the process according to the invention are preferably carried out in inert solvents under the respective reaction conditions. Suitable inert solvents in the context of the invention are e.g. Hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichlorethylene, 1, 2

Dichloroethane.Techrachlorocarbon, chloroform or dichloromethane; Alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; Ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; Glycol ethers such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); Ketones such as acetone or butanone; Amides such as acetamide, dimethylacetamide or dimethylformamide (DMF); Nitriles such as acetonitrile; Sulfoxides such as dimethyl sulfoxide (DMSO); Carbon disulphide; Carboxylic acids such as formic acid or acetic acid; Nitro compounds such as nitromethane or nitrobenzene; Esters such as ethyl acetate, water or mixtures of the solvents mentioned. In general, the process steps of the process according to the invention at reaction temperatures in the range of - 20 ° C to +200 ⁰ C, preferably in the range of ^{0 0} C to 15O ⁰ C, for example at about 0 ⁰ C, at about room temperature (25 ⁰ C ), at about 40 ^° C., at about 50 ^° C., at about 65 ^° C. or at about 130 ^° C.

In general, the reaction times for the process steps of the process according to the invention are in the range of a few minutes to a few days, preferably in the range of ten minutes to 48 hours, in particular one hour to twelve hours. Suitable reductive conditions for carrying out the process according to the invention are known to the person skilled in the art, for example from Houben-Weyl, Methods of Organic Chemistry, Georg Thieme Verlag, Stuttgart. Preferred reductive conditions in the context of the process according to the invention are the reaction with hydrides as reducing agents, for example metal or borohydrides and in particular complex hydrides, such as lithium aluminum hydride, and so-called deactivated complex hydrides, such as LiAl (OR) _x H _4- X, wherein X is 1 , 2 or 3 and R represents alkyl radicals or alkoxyalkyl radicals of 1 to 5 carbons and preferably alkyl radicals of 1 to 4 carbons or alkoxyalkyl radicals of 2 to 4 carbons. A deactivated complex hydride suitable for this reduction is commercially available under the name Vitride. A particularly preferred form for reductive conditions, in particular for the conversion of compounds of the formula Mc 'into compounds of the formula I', is the hydrogenation in a hydrogen atmosphere in the presence of suitable hydrogenation catalysts, for example a platinum metal catalyst, in particular palladium / Carbon, or a nickel metal catalyst, in particular Raney nickel (Raney Ni). Preferably, the reaction is carried out under reductive conditions in a solvent inert under the reaction conditions.

Preferably, the hydrogenation is carried out in a polar inert solvent such as methanol or THF. In many cases, hydrogenation with Raney nickel can advantageously be carried out in THF as solvent in the presence of trifluoroacetic acid (TFA) or in methanol as solvent in the presence of ammonia.

The cyclization of a compound of the formula II into a compound of the formula IIb (or a compound of the formula II 'into a compound of the formula IIb') can advantageously be carried out by heating in acetic anhydride, preferably to a temperature in the range of the boiling point of the acetic anhydride, preferably for a reaction time in the range of two to five hours.

Preferably, the mixtures of diastereomers and enantiomers of the compounds of formula I optionally obtained by the process described herein are separated by chromatography or crystallization.

Optionally, the bases and acids of formula I obtained by the process described herein are converted to their salts.

Above and below, the radicals R ¹ , R ² , R ³ , R ⁴ , R ^a , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , Y ¹ , Y have ² , Z ¹ , Z ² , Z ³ , A, Het, Ar, Hal ₁ k, m, n, p and q are the meanings given for the formula I, unless expressly stated otherwise. When multiple occurrences of individual radicals within a compound, the radicals independently of one another assume the meanings indicated.

Preferred compounds of the formula I are compounds of the formula Ia,

wherein

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , Y ¹ and Z ^{1 are} as defined herein, and their pharmaceutically usable derivatives, solvates, tautomers,

Salts and stereoisomers, including mixtures thereof in all

Conditions.

Preferred compounds of formula Ia are compounds as defined above wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and Y ¹ are as hereinbefore specified

Have meanings, and in which

Z ¹ for (CR ⁹ R ¹⁰ ) _n or (CR ⁹ R ¹⁰ ) _p - ( ^{c = γ 2} ) - ( ^{CR i i Ri 2} ) q ^is > ^{and is} preferably (CHR ¹⁰ ) _n or (CHR ¹⁰ ) _p - (C = Y ²⁾ - (CR ¹¹ H) _Q in which n is preferably 2, 3 or 4, preferably there are 2 or 3, and p and q preferably are independently 0, 1 or 2, preferably 0 or 1, preferably one of the two indices, p or q, stands for 0, and

R ⁶ , R ^{7 are} independently H, A, Ar, Het, aralkyl and

Heteroaralkyl and preferably independently of one another under H,

A, aralkyl and hetero-aralkyl are under-selected.

Preferred compounds of the formula I are compounds of the formula I,

wherein

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

Preferred compounds of the formula Iβ are compounds as defined above, wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and Y ^{1 have} the meanings given herein, and wherein

Z ^{1 is} (CR ⁹ R ¹⁰ ) _n or (CR ⁹ R ¹⁰ ) _p - (C = Y ² ) - (CR ¹¹ R ¹² ) _q , and is preferably (CHR ¹⁰ ) _n or (CHR ¹⁰ ) _p - (C = Y ² ) - (CR ¹¹ H) _q where n is preferably 1, 2 or 3, preferably 1 or 2, and p and q are preferably independently 0, 1 or 2, preferably 0 or 1 , wherein preferably one of the two indices, p or q, is 0, and

R ⁶ , R ^{7 are} independently H, A, Ar, Het, aralkyl and

Hetero-aralkyl and are preferably independently selected from H, A, aralkyl and hetero-aralkyl,

For the purposes of the invention, alkyl is preferably unbranched (linear) or branched, has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms and may be substituted. Substituted alkyl is preferably an alkyl radical as described in this section, which has 1-7, preferably 1-5 and particularly preferably 1-3 substituents, which are preferably selected from = O, = S; = NH, = N-alkyl, Hal, especially Cl and F, OH, Oalkyl, NH ₂ and N (alkyl) ₂ , wherein alkyl is as described above and is preferably unsubstituted alkyl as described above. Substituted alkyl particularly preferably denotes an alkyl radical as described above, wherein 1 - 7 H atoms are replaced by F and / or chlorine, z. B. a perchlorinated or perfluorinated alkyl radical. Such fluorine- and / or chlorine-substituted alkyl radicals preferably have 1, 2, 3, 4 or 5 C atoms. Preferred fluorine- and / or chlorine-substituted alkyl radicals are perfluorinated alkyl radicals, in particular trifluoromethyl radicals. Particular preference is given to unsubstituted or substituted alkyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1, 1- , 1, 2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1, 1, 1, 2, 1, 3, 2,2- , 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2 or 1,2,2-trimethylpropyl, more preferably trifluoromethyl. Very particular preference is given to alkyl having 1, 2, 3, 4, 5 or 6 C atoms, which may be chlorinated and / or fluorinated as described above, and is especially selected from methyl, ethyl, propyl, isopropyl, butyl, Isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl, pentafluoroethyl and 1,1,1-trifluoroethyl. In addition, alkyl is preferably an alkyl radical having 1, 2, 3, 4, 5 or 6 C atoms, particularly preferably 1, 2 or 3 C atoms, of 1 or 2, preferably 1, substituent selected from, = 0, = S; = NH and = N-alkyl, preferably below = O, = S and = NH and in particular below = 0 and = S has. Then alkyl is particularly preferably carbonyl, acetyl, propionyl or butyryl (butanoyl) and the thio derivatives thereof.

For the purposes of the invention, cycloalkyl is preferably selected from substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Substituted cycloalkyl is preferably a cycloalkyl radical as described above which has 1-7, preferably 1-5 and particularly preferably 1-3 substituents, which are preferably selected from Hal, in particular Cl and F, OH, Oalkyl, NH ₂ and N (Alkyl) ₂ , wherein alkyl is as described above and is preferably unsubstituted alkyl as described above. In the context of this invention, alkylene is preferably an unbranched or branched divalent hydrocarbon radical having 1-10 C atoms, preferably 1-4 C atoms, which may optionally have 1-7, preferably 1-5 and particularly preferably 1-3 substituents which are preferably selected below = 0, = S; = NH, = N-alkyl, Hal ₁ in particular Cl and F, OH, O-alkyl, NH2 and N (alkyl) _2, wherein alkyl is as described above and preferably as described above unsubstituted alkyl. Unsubstituted alkylene is preferably methylene, ethylene, n-propylene, isopropylene or n-butylene and in particular methylene or ethylene. Preferably, substituted alkylene is methylene, ethylene, n-propylene, isopropylene or n-butylene and in particular methylene or ethylene, which is 1 -3 substituents as described above and in particular 1 or 2 substituents selected from = O, = S; = NH and Hal, in particular Cl and F. When substituted alkylene has 1 or 2 substituents selected from among = O, SS and NHNH, it is particularly preferred for -C =O-, -CH ₂ -C =O-, -C =O-CH ₂ -, -CH ₂ -CH ₂ -C = O-, -C = O-CH ₂ -CH ₂ - or -CH ₂ -C = O-CH ₂ -, most preferably -CH ₂ -C = O-, -C = O-CH ₂ -, -CH ₂ -CH ₂ -C = O- or -C = O-CH ₂ -CH ₂ -, and the thio derivatives thereof.

For the purposes of the invention, aryl is preferably a substituted or unsubstituted benzene ring, for example a phenyl radical, or a system of benzene rings, for example anthracene, phenanthrene or naphthalene ring systems or radicals. Substituted aryl is preferably an aryl radical as described above, which has 1-7, preferably 1-5 and particularly preferably 1-3 substituents, which are preferably selected from Hal, A, OH, OA, NH ₂ , NO ₂ , CN , COOH, COOA, CONH ₂ , NHCOA, NHCONH ₂ , NHSO ₂ A, CHO, COA, SO ₂ NH ₂ , SO ₂ A, -CH ₂ -COOH and -OCH ₂ -COOH and especially under HaI, in particular Cl and F , OH, O-alkyl, NH ₂ and N (alkyl) ₂ , wherein alkyl is as described above, and is preferably unsubstituted alkyl as described above. Aryl therefore particularly preferably denotes unsubstituted or mono-, di- or trisubstituted by Hal, A, OH, OA, NH ₂ , NO ₂ , CN, COOH, COOA, CONH ₂ , NHCOA, NHCONH ₂ , NHSO ₂ A, CHO ₁ COA , SO ₂ NH ₂ , SO ₂ A, -CH ₂ -COOH and / or -OCH ₂ -COOH substituted phenyl, naphthyl or biphenyl. Aryl is very particularly preferably phenyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p-tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-methoxyphenyl, o-, m- or p-nitrophenyl, o-, m- or p- Aminophenyl, o-, m- or p- (N-methylamino) -phenyl, o-, m- or p- (N-methylaminocarbonyl) -phenyl, o-, m- or p-acetamidophenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p-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, , m- or p-fluorophenyl, o-, m- or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- or p- (methylsulfonamido) -phenyl, o-, m- or p- (Methylsulfonyl) -phenyl, more preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2 , 5-, 2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3 , 4- or 3,5-dibromophenyl, 2,4- or 2,5-dinitrophenyl, 2,5- or 3,4-dimethoxyphenyl, 3-nitro-4-chlorophenyl, 3-amino-4-chloro, 2 -Amino-3-chloro, 2-amino-4-chloro, 2-amino-5-chloro or 2-amino-6-chlorophenyl, 2-nitro-4-N, N-dimethylamino or 3-nitro 4-N, N-dimethylaminophenyl, 2,3-diaminophenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl , 2,4,6-trimethoxyphenyl, 2-hydroxy-3,5-dichlorophenyl, p-iodophenyl, 3,6-dichloro-4-aminophenyl, 4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl, 2 , 5-Difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl, 3-chloro-6-methoxyphenyl, 3-chloro-4-acetamidophenyl, 3-fluoro-4-methoxyphenyl, 3-amino-6-methylphenyl, 3 Chloro-4-acetamidophenyl or 2,5-dimethyl-4-chlorophenyl.

Heteroaryl is in the context of the invention preferably a substituted or unsubstituted monocyclic 5- to 7-membered aromatic ring or cycle, or an unsubstituted or substituted fused ring system comprising two or three such monocyclic 5- to 7-membered rings, said ring or rings containing one or more heteroatoms, preferably selected from N, S and O. A heteroaryl radical preferably contains 1 to 4 heteroatoms as described above and in particular 1 to 4 nitrogen atoms. Examples of heteroaryl radicals are furanyl,

Thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, oxo-pyridyl, thiadiazolyl, isothiazolyl, pyridyl, pyridazyl, pyrazinyl, pyrimidyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothiophenyl, indolyl, indazolyl, and substituted Derivatives thereof, preferably one, two or three times by Hal, A, OH, OA, NH ₂ , NO ₂ , CN, COOH, COOA, CONH ₂ , NHCOA, NHCONH ₂ , NHSO ₂ A, CHO, COA, SO ₂ NH ₂ , SO ₂ A, -CH ₂ -COOH or -OCH ₂ -COOH substituted derivatives thereof.

Heteroaryl preferably denotes a mono- or binuclear unsubstituted or mono-, di- or trisubstituted by Hal, A, NO ₂ , NHA, NA ₂ , OA, COOA and / or CN substituted aromatic heterocycle having one or more N-, O- and / or S atoms.

Heteroaryl particularly preferably denotes a monocyclic saturated or aromatic heterocycle having an N, S or O atom which is unsubstituted or mono-, di- or trisubstituted by Hal, A, NHA, NA ₂ , NO ₂ , COOA and / or benzyl may be substituted.

Notwithstanding further substitutions, unsubstituted heteroaryl means e.g. 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5- imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2 -, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2 -, 4-, 5- or 6-pyrimidinyl, more preferably 1, 2,3-triazole-1, -A- or -5-yl, 1, 2,4-triazole-1 -, -3- or 5 -yl, 1- or 5-tetrazolyl, 1, 2,3-

Oxadiazol-4 or -5-yl, 1, 2,4-oxadiazol-3 or -5-yl, 1, 3,4-thiadiazol-2 or -5-yl, 1, 2,4-thiadiazole 3 or 5-yl, 1, 2,3-thiadiazol-4 or 5-yl, 3 or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 4- or 5-isoindolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1 -, 3-, A-, 5-, 6- or 7- benzopyrazolyl, 2-, A-, 5-, 6- or 7-benzoxazolyl, 3-, A-, 5-, 6- or 7- benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, A-, 5-, 6- or 7- benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1, 3 oxadiazolyl, 2-, 3-, A-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, A-, 5-, 6-, 7- or 8-isoquinolyl, 3-, A, 5-, 6-, 7- or 8-cinnolinyl, 2-, A-, 5-, 6-, 7- or 8-quinazolinyl, 5- or 6-quinoxalinyl, 2-, 3-, 5- , 6-, 7- or 8-2H-benzo [1,4] oxazinyl, more preferably 1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl, 2,1,3-benzothiadiazole-4 - or -5-yl or 2,1,3-benzoxadiazol-5-yl.

Aralkyl or arylalkyl is in the context of the invention preferably an aryl radical as defined above, connected to an alkylene radical as defined above. Aralkyl may be substituted or preferably unsubstituted. Examples of preferred unsubstituted arylalkyl radicals are benzyl, phenethyl, phenylpropyl and phenylbutyl and in particular benzyl and phenethyl. Substituted arylalkyl is preferably an arylalkyl radical as described above which has 1-7, preferably 1-5 and particularly preferably 1-3 substituents, which are preferably selected from Hal, A ₁ OH, OA, NH ₂ , NO ₂ , CN , COOH, COOA, CONH ₂ , NHCOA ₁

NHCONH ₂ , NHSO ₂ A, CHO, COA, SO ₂ NH ₂ , SO ₂ A, -CH ₂ -COOH and -OCH ₂ -COOH and particularly preferably under Hal, in particular Cl and F, OH, Oalkyl, NH ₂ and N (Alkyl) ₂₎ wherein alkyl is as described above and is preferably unsubstituted alkyl as described above. In addition, alkylene in aralkyl is preferably an alkylene radical having 1, 2, 3, 4, 5 or 6 C atoms, more preferably 1, 2 or 3 C atoms, of 1 or 2, preferably 1 substituent selected from , = 0, = S; = NH and = N-alkyl, preferably below = 0, = S and = NH and in particular below = 0 and = S, having. Aralkyl then particularly preferably represents benzoyl, 2-phenylacetyl and 3-phenylpropionyl or 4-phenylbutyryl (4-phenylbutanoyl), and the thio derivatives thereof, these aralkyl radicals having 1-5 and preferably 1-5. May have 3 substituents, which are preferably selected under HaI, A, OH, OA, NH ₂ , NO ₂ , CN, COOH ₁ COOA, CONH ₂ , NHCOA ₁ NHCONH ₂ , NHSO ₂ A, CHO, COA, SO ₂ NH ₂ , SO ₂ A, -CH ₂ - COOH and -OCH ₂ - COOH and more preferably under Hal _1, in particular Cl and F, OH ₁ O alkyl, NH ₂ and N (alkyl) _{2 l} wherein alkyl is as described above and is preferably unsubstituted alkyl as described above.

Hetero-aralkyl is for the purposes of the invention preferably aralkyl as defined above, in which one or more carbon atoms, preferably 1 to 4 carbon atoms, by heteroatoms, preferably selected from N, S and O and in particular from N and S _{1 are} substituted. More preferably, hetero-aralkyl is a heteroaryl radical as defined above linked to an alkylene radical as defined above. Hetero-aralkyl may be substituted or preferably unsubstituted. Examples of preferred unsubstituted heteroarylalkyl radicals are pyridyl-2-ylmethyl, yridyl-3-ylmethyl, pyridyl-4-ylmethyl, pyridyl-2-yl-ethyl, pyridyl-3-yl-ethyl and pyridyl-4-yl-ethyl. In addition, alkylene in aralkyl is preferably an alkylene radical having 1, 2, 3, 4, 5 or 6 C atoms, more preferably 1, 2 or 3 C atoms, of 1 or 2, preferably 1 substituent selected from , = 0, = S; = NH and = N-alkyl, preferably below = 0, = S and = NH and in particular below = 0 and = S has. Aralkyl then particularly preferably represents pyridyl-2-ylcarbonyl, pyridyl-3-ylcarbonyl, pyridyl-4-ylcarbonyl, pyridyl-2-yl-acetyl, pyridyl-3-yl-acetyl or pyridyl. 4-yl-acetyl, and the thio derivatives thereof, these hetero-aralkyl radicals having 1-5 and preferably 1 -3 substituents, which are preferably selected from Hal, A, OH, OA, NH ₂ , NO ₂ , CN, COOH, COOA, CONH ₂ , NHCOA,

NHCONH ₂ , NHSO ₂ A, CHO, COA, SO ₂ NH ₂ , SO ₂ A, -CH ₂ -COOH and -OCH ₂ -COOH and particularly preferably under Hal, in particular Cl and F, OH, Oalkyl, NH ₂ and N (Alkyl) ₂ , wherein alkyl is as described above and is preferably unsubstituted alkyl as described above.

Heterocyclyl is in the context of the invention preferably an unsaturated or preferably saturated cyclic radical, preferably 1 to 6 carbon atoms and 1 to 4 heteroatoms, preferably selected from N, S and O, has. Heterocyclyl is preferably a 5-, 6- or 7-membered cycle as described above, which is unsubstituted or substituted by 1 to 5 and in particular 1 to 3 substituents, where the substituents are preferably selected from Hal, A, OH, OA, NH ₂ , NO ₂ , CN, COOH, COOA, CONH ₂ , NHCOA,

NHCONH ₂ , NHSO ₂ A, CHO, COA, SO ₂ NH ₂ , SO ₂ A, -CH ₂ -COOH, -OCH ₂ -COOH, = O, = S and = NR ^a and in particular under Hal, in particular Cl and F , OH, OAlkyl, NH ₂ , N (alkyl) ₂ , = 0 and = S are selected. Particular preference is given to heterocyclyl selected from 1-piperidyl, 4-piperidyl, 1-methylpiperidin-4-yl, 1-piperazyl, 1- (4-methyl) piperazyl, 4-methylpiperazin-1-yl amine, 1 - ( 4- (2-hydroxyethyl) -piperazyl, 4-morpholinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-pyrazolidinyl 1- (2-methyl) -pyrazolidinyl, 1-imidazolidinyl or 1- (3-methyl ) -imidazolidinyl, thiophen-2-yl, thiophen-3-yl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-thiazolyl, 4-thiazolyl and 5-thiazolyl, wherein among the radicals mentioned above, the saturated radicals are particularly are preferred. Also particularly preferred are the abovementioned radicals, in particular the abovementioned saturated radicals which have 1, 2 or 3, preferably one or two, substituents selected from A, = 0, = S, = NR ^a and / or Hal. Most preferably, heterocyclyl is a saturated radical as defined above which is either unsubstituted or monosubstituted or disubstituted by A and / or = O.

A is alkyl, preferably as described above, and more preferably is unbranched (linear) or branched, and has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms. A is preferably methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1, 1, 1, 2 or 2,2-dimethylpropyl, 1 - ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1, 1-, 1, 2-, 1, 3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2 or 1,2,2-trimethylpropyl, more preferably, for example, trifluoromethyl , A very particularly preferably denotes alkyl having 1, 2, 3, 4, 5 or 6 C atoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl , Pentafluoroethyl or 1,1,1-trifluoroethyl. A also denotes cycloalkyl. Cycloalkyl is preferably

Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, but especially cyclopentyl.

Ar is preferably aryl radicals and heteroaryl radicals as described herein, and especially aryl radicals as described herein.

Het preferably represents heteroaryl radicals and heterocyclyl radicals as described herein, and especially heterocyclyl radicals as described herein.

Preferably, R ¹ , R ² , R ³ and R ^{4 are} in each case independently selected from H, A, CF ₃ , OCF ₃ , OR ^a , SA, S (O) ₂ A, S (O) A, CH ₂ CN, COOA, CONHA, Hal, SCF, CN and Het, also under H, Cl, Br, F ₁ t-butyl, - CH (CH ₃ ) CH ₂ CH ₃ , isopropyl, ethyl and methyl. More preferably, R ^1, R ^2, R ³ and R ⁴ are in each case independently selected from H, t-butyl, isopropyl, ethyl, CF _3, methyl, Br, Cl, F, SCF _3, CH (CH ₃₎ CH ₂ CH ₃ , n-propyl, OCH ₃ , SCH ₃ , n-butyl, CH ₂ CN and Het. In particular, R ¹ , R ² , R ³ and R ^{4 are} in each case independently selected from H, Cl, Br ₁ F, t-butyl, isopropyl, ethyl or CF ₃ .

Preferably, at least one of R ¹ , R ² , R ³ and R ^{4 is} different from H. Particularly preferably, one, two or three of the radicals R ¹ , R ² , R ³ and R ^{4 are} different from H.

Therefore, at least one of the radicals R ¹ , R ² , R ³ and R ⁴ , more preferably one, two or three of the radicals R ¹ , R ² , R ³ and R ⁴ , is in each case independently selected from A, Ar , Het, OR ^a , SR ^a , OAr, SAr, N (R ^a ) ₂ , NR ³ Ar ₁ Hal, NO ₂ , CN, (CH ₂ ) _m COOR ^a , (CH ₂ ) _m COOAr, (CH ₂ ) _m CON (R ^a ) ₂ , ( CH ₂ ) _m CONHAr, COR ³ , COAr, S (O) _m A, S (O) _m Ar, NHCOA, NHCOAr, NHSO ₂ A, NHSO ₂ Ar and SO ₂ N (R ^a ) ₂ . Therefore, more preferably at least one of R ¹ , R ² , R ³ and R ^{4 is more} preferably one, two or three of R ¹ , R ² , R ³ and R ⁴ , in each case independently selected from A, CF ₃ , OCF ₃ , OR ^a , SA, S (O) ₂ A, S (O) A ₁ CH ₂ CN, COOA, CONHA, Hal, SCF, CN and Het, preferably also among H, Cl, Br, F, t-butyl, -CH (CH ₃ ) CH ₂ CH ₃ , isopropyl, ethyl and methyl, most preferably selected from t-butyl, isopropyl, ethyl, CF ₃ , methyl, Br, Cl ₁ F, SCF ₃ , CH ( CH ₃ ) CH ₂ CH ₃ , n -propyl, OCH ₃ , SCH ₃ , n-butyl, CH ₂ CN and Het, and especially selected from Cl ₁ Br, F, t-butyl, isopropyl, ethyl or CF ₃ .

Preferably, R ¹ and / or R ^{4 is} H.

Preferably, R ² and / or R ^{3 is} a radical other than H, preferably selected from the abovementioned radicals other than H.

Preferably, R ² and R ^{3 are} independently selected from H, Cl, F, CH ₃ , C (CH ₃ ) ₃ , CF ₃ and OCH ₃ , more preferably with the proviso that one or both of R ² , R ³ different from H

Preferably, R ² and / or R ^{3 is} Hal, A or OA, in particular Cl, F, CH ₃ , C (CH ₃ ) ₃ , cyclopropyl, CF ₃ or OCH ₃ .

In particularly preferred compounds according to the invention, one of the radicals R ² and R ^{3 has} the meaning H and the other radical has the meaning Cl, F, CH ₃ , C (CH ₃ ) ₃ , CF ₃ or OCH ₃ . In this case, the radical R ³ particularly preferably has the meaning H and the radical R ^{2 has} the meaning the meaning Cl, F ₁ CH ₃ , C (CH ₃ ) ₃ , CF ₃ or OCH ₃ . In further particularly preferred compounds according to the invention, both radicals R ² and R ^{3 are} independently selected from Cl, F, CH ₃ , C (CH ₃ ) ₃ , CF ₃ and OCH ₃ . In this case, R ^{3 is} particularly preferably selected from among F, Cl and CH ₃ , and the radical R ^{2 is more} preferably independently selected from Cl, F, CH ₃ , C (CH ₃ ) ₃ , CF ₃ and OCH ₃ .

In further particularly preferred compounds of the invention R ^{3 is} H and R ^{2 is} Cl or CF ₃ .

R ^a is preferably H, A, Ar, Het, aralkyl or heteroaralkyl, particularly preferably H, A, Ar, Het or aralkyl I, very particularly preferably H, A, Ar or Het and in particular H, A or Ar. When R ^{a is} A, Ar, Het, aralkyl or hetero-aralkyl, the radicals mentioned may also be substituted. Then R ^a generally has 1 to 5 and preferably 1 to 3 substituents, preferably selected from Hal, A, OH, OA,

NH ₂ , NO ₂ , CN ₁ COOH, COOA, CONH ₂ , NHCOA, NHCONH ₂ , NHSO ₂ A, CHO, COA, SO ₂ NH ₂ , SO ₂ A, -CH ₂ -COOH and -OCH ₂ -COOH and in particular under HaI, in particular Cl and F, OH, OAlkyl, NH ₂ and N (alkyl) ₂ , wherein alkyl is as described above and is preferably as described above unsubstituted alkyl.

R ⁵ is preferably H, A, Ar, Het, aralkyl or heteroaralkyl, particularly preferably A, Ar _{1 is} het, aralkyl or heteroaralkyl, very particularly preferably A, Ar, aralkyl or heteroaralkyl and in particular aralkyl or heteroaralkyl. aralkyl. In particular, R ^{5 is} benzyl, phenethyl, or

Phenylpropyl, or substituted derivatives thereof. When R ^{5 is} substituted benzyl, phenethyl, or phenylpropyl, it has 1 to 5 and preferably 1 to 3 substituents, preferably selected from Hal, A, OH, OA, NH ₂ , NO ₂ , CN, COOH, COOA, CONH ₂ , NHCOA, NHCONH ₂ , NHSO ₂ A, CHO, COA, SO ₂ NH ₂ , SO ₂ A, -CH ₂ -COOH and -OCH ₂ -COOH and especially under HaI, especially Cl and F, OH, OAlkyl, NH ₂ and N (alkyl) ₂ , wherein alkyl is as described above and preferably as above-described unsubstituted alkyl. R ⁵ particularly preferably represents substituted or unsubstituted benzyl and in particular unsubstituted benzyl. R ⁸ is preferably H, A, Ar, Het, aralkyl or hetero-aralkyl, more preferably A, Ar, Het, aralkyl or hetero-aralkyl, most preferably A, Ar, aralkyl or hetero-aralkyl and especially A or Ar. When R ⁸ is Ar, Ar is preferably unsubstituted or substituted phenyl. When R ^{8 is} substituted phenyl, it has 1 to 5 and preferably 1 to 3 substituents, preferably selected from Hal, A, OH, OA, NH ₂ , NO ₂ , CN, COOH, COOA, CONH ₂ , NHCOA, NHCONH ₂ , NHSO ₂ A, CHO, COA, SO ₂ NH ₂ , SO ₂ A, -CH ₂ -COOH and -OCH ₂ -COOH and especially under Hal, in particular Cl and F, OH, Oalkyl, NH ₂ and N (alkyl ) ₂ , wherein alkyl is as described above and is preferably unsubstituted alkyl as described above.

R ⁶ is preferably H, A, Ar, aralkyl or hetero-aralkyl, especially H, A, or aralkyl. When R ⁶ is A, A is preferably substituted or unsubstituted alkyl having 1 to 6 C atoms, and especially methyl or ethyl. When R ^{6 is} Ar, it is preferably substituted or unsubstituted phenyl. When R ⁶ is aralkyl, aralkyl is preferably selected from benzyl, phenethyl, phenylpropyl, phenylbutyl, benzoyl, 2-phenylacetyl and 3-phenylpropionyl or butyryl, and substituted derivatives thereof, in particular substituted derivatives in which the phenyl- Rest 1, 2 or 3 as defined herein substituents.

R ⁷ is preferably H, A, Ar, aralkyl or hetero-aralkyl, especially H, A, or aralkyl. When R ⁶ is A, A is preferably substituted or unsubstituted alkyl having 1 to 6 C atoms, and especially methyl or ethyl. When R ^{6 is} Ar, it is preferably substituted or unsubstituted phenyl. When R ⁶ is aralkyl, aralkyl is preferably selected from benzyl, phenethyl, phenylpropyl, phenylbutyl, benzoyl, 2-phenylacetyl and 3-phenylpropionyl or butyryl, and substituted derivatives thereof, in particular substituted derivatives, in which the phenyl radical has 1, 2 or 3 substituents as defined herein.

Alternatively, R ⁶ and R ^7, together with the N-atom to which they are attached, represent a saturated or unsaturated 5-, 6- or 7-membered heterocycle, preferably a saturated or unsaturated 5- or 6-membered heterocycle, which optionally may contain 1, 2 or 3 further heteroatoms, preferably 1 or 2 further heteroatoms, which are preferably selected from N, S and O and in particular from N and O. In this embodiment, NR ⁶ R ^{7 is} preferably 1-piperidyl, 1-piperazyl, 1- (4-methyl) -piperazyl, 4-methylpiperazin-1-ylamine, 4-morpholinyl, 1-pyrrolidinyl, 1-pyrazolidinyl 1- ( 2-methyl) -pyrazolidinyl, 1-imidazolidinyl or 1- (3-methyl) -imidazolidinyl, 4-pyridyl, oxazolyl, thiazolyl, quinolinyl, isoquinolinyl, 2- or 4-pyridazyl, 2-, 4- or 5-pyrimidyl, 2- or 3-pyrazinyl.

Y ¹ is preferably O or S and in particular O.

Y ² is preferably O or S and in particular O.

Z ¹ is preferably (CR ⁹ R ¹⁰ J _n or (CR ⁹ R ¹⁰ ) _p - (C = Y ² ) - (CR ¹¹ R ¹² ) _q , where n is preferably 2, 3 or 4, more preferably 2 or 3 and in particular 2, and in which p is preferably O, 1 or 2, particularly preferably O or 1 and in particular O, and in which q is preferably 0, 1 or 2, particularly preferably 0 or 1 and in particular 0 In (CR ⁹ R ¹⁰ ) _n , R ⁹ and R ^{10 are} independently of one another preferably selected from H, A, OA, Ar, Het, aralkyl and

Hetero-aralkyl, more preferably under H, A, Ar and aralkyl and in particular under H and A. In (CR ⁹ R ¹ V (C = Y ² ) - (CR ¹¹ R ¹² ) _q R ⁹ , R ¹⁰ ; R ¹¹ and R ¹² independently of one another preferably selected from H, A,

OA, Ar, Het, aralkyl and hetero-aralkyl, more preferably H, A, Ar and aralkyl and especially H and A. In Z ¹ , in (CR ⁹ R ¹⁰ ) _n, each group CR ⁹ R ^{10 is} in each case independently of one another preferably selected from CR ⁹ R ¹⁰ , CHA, CAA and CH ₂ . In Z ¹ , (CR ⁹ R ¹ V (C = Y ² MCR ¹¹ R ¹² ) _{q is} preferably selected from CR ⁹ R ¹⁰ - (C = Y ² ), (C = Y ² ) -CR ¹¹ R ¹² and C = Y ² , and especially under CR ⁹ R ¹⁰ - (C = O), (C = O) -CR ¹¹ R ¹² and C = O.

Thus, in Z ^1, the group (CR ⁹ R ¹⁰ ) _n preferably represents groups selected from among CR ⁹ R ¹⁰ CR ⁹ R ¹⁰ , CR ⁹ R ¹⁰ CH ₂ , CH ₂ CR ⁹ R ¹⁰ , CHACHA, CAACAA ₁ CHACH ₂ , CH ₂ CHA and CH ₂ CH ₂ .

Thus, in Z ^1, the group (CR ⁹ R ¹⁰ ) _p - (C = Y ² ) - (CR ¹¹ R ¹² ) _q preferably represents groups selected from CR ⁹ R ¹⁰ - (C = Y ² ), (C = Y ² ) -CR ¹¹ R ¹² and C = Y ² , more preferably selected from CR ⁹ R ¹⁰ - (C = O), (C = O) -CR ¹¹ R ¹² and C = O, most preferably selected from CR ⁹ R ¹⁰ - (C = O) and (C = O) -CR ¹¹ R ¹² , and especially selected from CHA- (C = O) and (C = O) -CHA.

Z ¹ particularly preferably represents CR ⁹ R ¹⁰ CH ₂ , CH ₂ CR ⁹ R ¹⁰ , CHACHA, CAACAA, CHACH ₂ , CH ₂ CHA, CR ⁹ R ¹⁰ - (C =O), (C =O) -CR ¹¹ R ¹² , CHA- (C = O) or (C = O) -CHA ₁ most particularly for and especially for CHACH ₂ , CH ₂ CHA, CHA- (C = O) or (C = O) -CHA, and especially for CHACH ₂ or CHA- (C = O).

Z ² is preferably (CR ⁹ R ¹⁰ J _n or (CR ⁹ R ¹⁰ ) _p - (C = Y ² ) - (CR ¹¹ R ¹² ) _q , where n is preferably 1, 2, 3 or 4, more preferably 1, 2 or 3 and in particular 2 or 3, wherein p is preferably 0, 1 or 2 and more preferably O or 1, and wherein q is preferably 0, 1 or 2 and more preferably O or 1. In (CR ⁹ R ¹⁰ ) _n , R ⁹ and R ^{10 are} independently of one another preferably selected from H, A _v OA, Ar, Het, aralkyl and hetero-aralkyl, more preferably H, A, Ar and

Aralkyl and especially H and A. In (CR ⁹ R ¹⁰ ) _p - (C = Y ² ) - (CR ¹¹ R ¹² ) _q R ⁹ , R ¹⁰ ; R ¹¹ and R ¹² are preferably independently selected among H, A, OA, Ar, Het, aralkyl and Hβtero-aralkyl, more preferably under H, A, Ar and aralkyl and especially under H and A.

In Z ² , (CR ⁹ R ¹⁰ ) _{n is} preferably selected from CR ⁹ R ¹⁰ , (CR ⁹ R ¹⁰ ) ₂₎ (CR ⁹ R ¹⁰ ) ₃ and (CR ⁹ R ¹⁰ ) ₄ , wherein R ⁹ and R ^{10 are} as shown are each independently selected from H and A, and more preferably selected from CHA, (CHA) ₂ , (CHA) ₃ and (CHA) ₄ , wherein each A is independently defined as hereinbefore , In Z ² , (CR ⁹ R ¹⁰ J _n is most preferably selected from CH ₂ , (CH ₂ J ₂ , (CH ₂ ) ₃ and (CH ₂ J ₄₎ in Z ² (CR ⁹ R ¹⁰ ) _p - ( C = Y ² ) - (CR ¹¹ R ¹² ) _q preferably selected from CR ⁹ R ¹⁰ - (C = Y ² ) -CR ¹¹ R ¹² , CR ⁹ R ¹⁰ - (C = Y ² ), (C = Y ² ) -CR ¹¹ R ¹² , CR ⁹ R ¹⁰ CR ⁹ R ¹⁰ - (C = Y ² ), (C = Y ² J-CR ¹¹ R ¹² CR ¹¹ R ¹² and C = Y ² , and especially under CR ⁹ R ¹⁰ - (C = O), (C = O) -CR ¹¹ R ¹² and C = O.

More preferably Z ^{2 is} selected from CR ⁹ R ¹⁰ , (CR ⁹ R ¹⁰ J ₂ , (CR ⁹ R ¹⁰ J ₃ and (CR ⁹ R ¹⁰ J ₄ wherein R ⁹ and R ^{10 are} as defined above / below and are preferred are in each case independently selected from H and A, and in particular from CH ₂ , (CH ₂ J ₂ , (CH ₂ J ₃ and (CH ₂ J ₄ .

Z ³ is preferably (CR ⁹ R ¹⁰ J _n or (CR ⁹ R ¹⁰ Jp- (C = Y ² J- (CR ¹¹ R ¹² Jq, wherein n is preferably 1, 2 or 3, more preferably 1 or 2 in particular is 1, wherein p is preferably 0, 1 or 2, more preferably O or 1 and especially O, and wherein q is preferably 0, 1 or 2, more preferably O or 1 and especially O. In (CR ⁹ R ¹⁰ Y _n R ⁹ and R ^{10 are} independently preferably selected from H, A, OA, Ar, Het, aralkyl and hetero-aralkyl, particularly preferably H, A, Ar and aralkyl, and in particular from H and A. In (CR ⁹ R ¹⁰ Jp- (C =Y ² J- (CR ¹¹ R ¹² Jq) R ⁹ , R ¹⁰ ; R ¹¹ and R ^{12 are} independently of one another preferably selected from H, A, OA, Ar, Het, aralkyl and hetero -Aralkyl, more preferably under H, A, Ar and aralkyl and especially under H and A. In Z ³ , (CR ⁹ R ¹⁰ ) _{n is} preferably selected from CR ⁹ R ¹⁰ , CHA, CAA and CH ₂ . In Z ³ , (CR ⁹ R ¹ V (C = Y ² MCR ¹¹ R ¹² ) _{q is} preferably selected from CR ⁹ R ¹⁰ - (C = Y ² ), (C = Y ² ) -CR ¹¹ R ¹² and C = Y ² , and in particular from CR ⁹ R ¹⁰ - (C = O), (C = O) -CR ¹¹ R ¹² and C = O. Z ³ is particularly preferably selected from CH ₂ , (CH ₂ ) ₂ , (CH ₂ ) ₃ and (CH ₂ ) ₄ ,

C = Y ² , C = O and C = S, most preferably under CH ₂ , C = Y ² , C = O and C = S.

In preferred compounds according to the invention, Z ^{3 may} also be absent, ie the radical R ⁸ is bonded directly to the N atom. In these cases, the group - (Z ¹ -N (-Z ³ -R ⁸ ) -Z ² ) _k - represents the group - (Z ¹ -N (-R ⁸ ) -Z ² ) _k -.

Particularly preferably, R ⁸ -Z ^{3 is} H, substituted or preferably unsubstituted methyl, ethyl, propyl or butyl, substituted or preferably unsubstituted benzyl, phenethyl, phenylpropyl, phenylbutyl, benzoyl, 2-phenyl-acetyl, 3-phenyl-propionyl or 4 phenyl-butyryl. When R ⁸ -Z ^{3 is} substituted methyl, ethyl, propyl or butyl, it has 1 to 5 and preferably 1 to 3 substituents, preferably selected from HaI ₁ A ₁ OH, OA, NH ₂ , NO ₂ , CN, COOH , COOA, CONH ₂ , NHCOA, NHCONH ₂ , NHSO ₂ A, CHO, COA, SO ₂ NH ₂ , SO ₂ A, -CH ₂ -COOH or -OCH ₂ - COOH and particularly preferably under Hal, in particular Cl and F, OH, O-alkyl, NH ₂ and N (alkyl) ₂ , wherein alkyl is as described above, and is preferably unsubstituted alkyl as described above. When R ⁸ - Z ^{3 is} substituted benzyl, phenethyl, phenylpropyl, phenylbutyl, benzoyl, 2-phenylacetyl, 3-phenylpropionyl or 4-phenylbutyryl, it has 1 to 5 and preferably 1 to 3 substituents. preferably selected from HaI, A, OH, OA ₁ NH ₂ , NO ₂ , CN, COOH, COOA, CONH ₂ , NHCOA, NHCONH ₂ , NHSO ₂ A, CHO, COA, SO ₂ NH ₂ , SO ₂ A, -CH ₂ -COOH or -OCH ₂ - COOH, and particularly preferably from Hal, in particular Cl and F, OH, O-alkyl, NH ₂ and N (alkyl) _2, wherein alkyl is as described above and preferably as described above unsubstituted alkyl. The substituents are preferably arranged on the phenyl ring. Hal preferably denotes F, Cl or Br, but also I, particularly preferably F or Cl.

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

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

Particularly preferred compounds of the formula I are the compounds of the subformulae IA to IT:

wherein

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , Y ¹ , Y ² , Z ¹ and Z ^{3 have} the meanings given herein,

is 1, 2, 3 or 4, preferably 1, 2, or 3 and especially 2 or 3,

s and t independently of one another are 0, 1 or 2 and in particular 0 or 1,

Y ^{3 is} O, S or NR ^a and in particular O or S, R ¹⁹ and R ^{20 are} independently selected from the meanings given for R ⁹ and R ¹⁰ , or together represent = O, = S or = NH,

R ^c and R ^d independently of one another are those indicated for R ¹ to R ⁴

Meanings are selected, and

u and v independently of one another are 0, 1, 2 or 3 and in particular 0, 1 or 2.

Preferably, R ^c is more preferably selected from A, CF ₃ , OCF ₃ , OR ^a , SA, S (O) ₂ A, S (O) A, CH ₂ CN, COOA, CONHA, Hal, SCF ₁ CN and Het also under H, Cl, Br, F, t-butyl, -CH (CH ₃ ) CH ₂ CH ₃ , isopropyl, ethyl and methyl, most preferably selected from t-butyl, isopropyl, ethyl, CF ₃ , methyl, Br , Cl, F, SCF ₃ , CH (CH ₃ ) CH ₂ CH ₃ , n -propyl, OCH ₃ , SCH ₃ , n-butyl, CH ₂ CN and Het, and especially selected from Cl, Br, F, t- Butyl, isopropyl, ethyl and CF ₃ .

Preferably, R ^{d is more} preferably selected from A, CF ₃ , OCF ₃ , OR ^a , SA, S (O) ₂ A, S (O) A, CH ₂ CN, COOA, CONHA, Hal, SCF, CN and Het also under H, Cl, Br, F, t-butyl, -CH (CH ₃ ) CH ₂ CH ₃ , isopropyl, ethyl and methyl, most preferably selected from t-butyl, isopropyl, ethyl, CF ₃ , methyl, Br , Cl, F, SCF ₃ , CH (CH ₃ ) CH ₂ CH ₃ , n -propyl, OCH ₃ , SCH ₃ , n-butyl, CH ₂ CN and Het, and especially selected from Cl, Br, F, t- Butyl, isopropyl, ethyl and CF ₃ .

Particular preference is given to compounds according to the invention, that is to say compounds of the formula I and preferably of the formula I ', I ", I ¹ ", Ia, Iβ, IA, IB, IC, ID, IE, IF, IG, IH, Ii, IJ, IK, IL, IM, IN, 10, IP, IR, IS and / or IT, which combine one or preferably more of the preferred embodiments described below: A preferred embodiment relates to compounds of the invention wherein

R ² A, CF ₃ , OCF ₃ , SA, SCN, CH ₂ CN, -OCOA, Hal, SCF ₃ , t -butyl, - CH (CH ₃ ) CH ₂ CH ₃ , isopropyl, ethyl or methyl.

A further preferred embodiment relates to compounds according to the invention, in which

R ^{3 is} H, A, CF ₃ , OCF ₃ , SA, SCN, CH ₂ CN, -OCOA, Hal, SCF ₃ , t-butyl,

-CH (CH ₃ ) CH ₂ CH ₃ , isopropyl, ethyl or methyl.

R ¹ and R ⁴ independently of one another are either H or are selected from A, CF ₃ , OCF ₃ , OR ^a , SA, S (O) ₂ A, S (O) A, CH ₂ CN, COOA, CONHA, Hal, SCF, CN and Het.

R ³ and R ^{4 are} independently selected from H and Cl.

R ^{5 is} selected from Ar, aralkyl and hetero-aralkyl, preferably from aralkyl and hetero-aralkyl and in particular from benzyl and phenethyl; R ⁶ , R ^{7 are} independently selected from H, A, Ar and

Aralkyl, preferably under H and A and in particular under H, methyl and ethyl; and

R ^{8 is} selected from H, A, Ar and Het, preferably from A, Ar and Het, very particularly preferably from Ar and Het and in particular from phenyl and pyridyl.

R ^{5 is} unsubstituted or substituted benzyl, and

R ^{8 is} unsubstituted or substituted phenyl.

A further preferred embodiment relates to compounds according to the invention in which R ⁶ and R ⁷ , together with the N-atom to which they are attached, form a saturated or unsaturated 5-, 6- or 7-membered heterocycle which is optionally 1, 2 or 3 further heteroatoms selected from N, S and O, and is more preferably selected from 1-piperidyl, 4-piperidyl, 1-methyl-piperidin-4-yl, 1-piperazyl, 1- (4-methyl ) -piperazyl, 4-methyl-piperazin-1-yl-amine, 1- (4- (2-hydroxyethyl) -piperazyl, 4-morpholinyl and 1-pyrrolidinyl.

Accordingly, the invention particularly relates to compounds of the invention, in particular compounds of the formula I and / or the sub-formulas thereof, in which at least one of said radicals has one of the preferred meanings given above and / or the one or more of the preferred embodiments described herein combine.

The compounds according to the invention are particularly preferably selected from the following compounds:

2- (1 - {[(2-Amino-ethyl) -benzyl-amino] -methyl} -2-methyl-propyl) -3-benzyl-7-trifluoromethyl-3H-quinazolin-4-one (MW = 522, 61; Rt = 2.59);

3-Benzyl-2- [1- (benzylamino-methyl) -2-methyl-propyl] -7-trifluoromethyl-3H-quinazolin-4-one (MW = 479.54; Rt = 2.6);

2- {1 - [(2-Amino-ethylamino) -methyl] -2-methyl-propyl} -3-benzyl-7-trifluoromethyl-3H-quinazolin-4-one (MW = 432.49, Rt = 1, 85);

N- (2-aminoethyl) -N- [2- (3-benzyl-4-oxo-7-trifluoromethyl-3,4-dihydroquinazolin-2-yl) -3-methyl-butyl] -benzamide ( MW = 536.60; Rt = 2.37);

N- [2- _{(3-benzyl-4-oxo-7-trifluoromethyl-3>} 4-dihydro-quinazolin-2-yl) -3-methyl-butyl] -benzamide (MW = 493.53; Rt = 3, 31);

N- [2- (3-Benzyl-4-oxo-7-trifluoromethyl-3,4-dihydro-quinazolin-2-yl) -3-methyl-butyl] -2-phenyl-acetamide (MW = 507.55; Rt = 3.29);

N- (2-aminoethyl) -N- [2- (3-benzyl-4-oxo-7-trifluoromethyl-3,4-dihydroquinazolin-2-yl) -3-methyl-butyl] -2- phenylacetamide (MW = 550.52, Rt = 2.43);

2- {1 - [(3-Amino-propylamino) -methyl] -2-methyl-propyl} -3-benzyl-7-trifluoromethyl-3H-quinazolin-4-one (MW = 446.51; Rt = 1, 85);

3-Benzyl-2- {1 - [(2-dimethylamino-ethylamino) -methyl] -2-methyl-propyl} -7-trifluoromethyl-3H-quinazolin-4-one (MW = 460.54, Rt = 1, 95);

3-Benzyl-2- [2-methyl-1- (phenethylamino-methyl) -propyl] -7-trifluoromethyl-3H-quinazolin-4-one (MW = 493.57; Rt = 2.65);

2- {1 - [(2-Amino-ethylamino) -methyl] -2-methyl-propyl} -3-benzyl-7-chloro-3H-quinazolin-4-one (MW = 398.94, Rt = 1, 65);

N- (2-aminoethyl) -N- [2- (3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl) -3-methyl-butyl] -2- phenylacetamide (MW = 517.07, Rt = 2.25);

2- (1 - {[(2-Amino-ethyl) -benzyl-amino] -methyl} -2-methyl-propyl) -3-benzyl-7-chloro-3H-quinazolin-4-one (MW = 489, 06, Rt = 2.42);

2- (1 - {[(2-Amino-ethyl) -phenethyl-amino] -methyl} -2-methyl-propyl) -3-benzyl-7-chloro-3H-quinazolin-4-one (MW = 503, 09, Rt = 2.39);

2- {1 - [(3-Amino-propylamino) -methyl] -2-methyl-propyl} -3-benzyl-7-chloro-3H-quinazolin-4-one (MW = 412.96, Rt = 1, 65);

N- (3-Amino-propyl) -N- [2- (3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl) -3-methyl-butyl] -2- phenyl-acetamide (MW = 531, 10, Rt = 2.29);

2- (1 - {[(3-Amino-propyl) -benzyl-amino] -methyl} -2-methyl-propyl) -3-benzyl-7-chloro-3H-quinazolin-4-one (MW = 503, 09, Rt = 1, 92);

2- (1 - {[(3-Amino-propyl) -phenethyl-amino] -methyl} -2-methyl-propyl) -3-benzyl-7-chloro-3H-quinazolin-4-one (MW = 517, 11, Rt = 1.95);

2- (1-Amino-methyl-2-methyl-propyl) -3-benzyl-6,7-dichloro-3H-quinazolin-4-one (MW = 390.32; Rt = 2.31);

2- (1-Aminomethyl-2-methyl-propyl) -3-benzyl-7-chloro-6-fluoro-3H-quinazolin-4-one (MW = 373.86; Rt = 2.17);

2- (1-Amino-methyl-2-methyl-propyl) -3-benzyl-7-chloro-6-methyl-3H-quinazolin-4-one (MW = 369.89, Rt = 2.22);

2- (3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl) -3-methyl-butyramide;

2- (1-Aminomethyl-2-methyl-propyl) -3-benzyl-3H-quinazolin-4-one (MW 321, 42; Rt = 1, 9);

2- (1-Aminomethyl-2-methyl-propyl) -3-benzyl-7-chloro-3H-quinazolin-4-one (MW = 355.87, Rt = 2.13);

2- (1-Aminomethyl-2-methyl-propyl) -3-benzyl-7-tert-butyl-3H-quinazolin-4-one (MW = 377.53, Rt = 2.33);

2- (1-Aminomethyl-2-methyl-propyl) -3-benzyl-7-trifluoromethyl-3H-quinazolin-4-one (MW = 389.42; Rt = 2.21); and the pharmaceutically acceptable derivatives, solvates, salts and stereoisomers thereof, including mixtures of the forms in all ratios, and preferably the salts and / or solvates thereof, and in particular the physiologically acceptable salts and / or solvates thereof.

With particular preference the compounds according to the invention are selected from the following compounds:

N - ^ - CS-benzyl-y-chloro-oxo-S ^ -dihydro-quinazolin ^ -yO-S-methyl-butyl] -acetamide;

N- [2- (3-benzyl-4-oxo-3,4-dihydro-quinazolin-2-yl) -3-methyl-butyl] -acetamide;

2- (3-Benzyl-4-oxo-7-trifluoromethyl-3,4-dihydro-quinazolin-2-yl) -3-methylbutyramide;

2- (3-Benzyl-7-tert-butyl-4-oxo-3,4-dihydroquinazolin-2-yl) -3-methylbutyramide;

3-Benzyl-2- [1- (benzylamino-methyl) -2-methyl-propyl] -7-trifluoromethyl-3H-quinazolin-4-one;

and the pharmaceutically acceptable derivatives, solvates, salts and stereoisomers thereof, including mixtures of the forms in all

Conditions, and preferably the salts and / or solvates thereof, and in particular the physiologically acceptable salts and / or solvates thereof.

Depending on the choice of the substituents and radicals described above, the compounds according to the invention may have one or more chiral centers, in particular one or more chiral carbon atoms. If a compound of defined composition according to the invention has one or more chiral centers, this compound of defined composition can be present in different stereoisomers. The present invention relates to all possible stereoisomers of compounds according to the invention which may be present both as individual, stereochemically uniform compounds and as mixtures of two or more stereochemically uniform compounds. In the case of mixtures of two or more stereoisomers, the individual stereoisomers may be present in different or equal proportions. For mixtures of two stereoisomers, which are present in equal proportions and represent optical antipodes, one speaks of racemic mixtures. Racemic mixtures of compounds of the formula I are likewise the subject of the present invention.

The use of a hatched wedge instead of a dash to represent a bond in a structural formula preferably indicates a three-dimensional indication of the structure of the corresponding compound or chiral center in that formula and means (in accordance with the corresponding general rules for the preparation of stereoisomers ), that the corresponding, at the wider side of the wedge arranged residue is arranged behind the plane of the paper; see for example the representation of the substructures IG and IH of the compounds according to the invention.

The compounds of formula I and also the starting materials for their preparation are otherwise prepared by methods known per se, as described in the literature (eg in the standard works such as Houben-Weyl, Methods of Organic Chemistry, Georg-Thieme-Verlag, Stuttgart) under reaction conditions which are known and suitable for the reactions mentioned. One can also make use of known per se, not mentioned here variants.

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

The process steps of the process according to the invention are generally carried out in a solvent which is inert under the respective reaction conditions, for example as listed herein, for example acetonitrile, preferably in the presence of a base, for example amines, preferably tertiary amines, hydroxides, in particular alkali metal hydroxides, such as KOH, or NaOH or in particular alkali metal or alkaline earth metal carbonates, such as Na ₂ CO ₃ and K ₂ CO ₃ . The reaction time is between a few minutes and 14 days, depending on the conditions used, the reaction temperature between about 0 ° and 180 °, usually between 0 ° and 100 °, more preferably between 15 ⁰ C and 60 ⁰ C, most preferably between 15 ° C and 35 ⁰ C, such as about 20 ⁰ C, about 25 ⁰ C or about 45 degrees Celsius.

Suitable inert solvents are, for example, hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as Trichlorethylene, 1-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; Nitriles such as acetonitrile; Carbon disulphide; Carboxylic acids such as formic acid or acetic acid; Nitro compounds such as nitromethane or nitrobenzene or mixtures of said solvents.

The reduction of an ester to the aldehyde or to the alcohol, or the reduction of a nitrile to the aldehyde or amine by methods known in the art and are described in standard works of organic chemistry.

The abovementioned compounds according to the invention can be used in their final non-salt form. On the other hand, the present invention also encompasses the use of these compounds in the form of their pharmaceutically acceptable salts, which can be derived from various organic and inorganic acids and bases according to procedures known in the art. Pharmaceutically acceptable salt forms of the compounds of formula I are for the most part prepared conventionally. If the compound of the formula I contains a carboxylic acid group, one of its suitable salts can be formed by reacting the compound with a suitable base to give the corresponding base addition salt. Such bases include, for example, alkali metal hydroxides, including potassium hydroxide, sodium hydroxide and lithium hydroxide; Alkaline earth metal hydroxides such as barium hydroxide and calcium hydroxide; Alkali metal alcoholates, eg, potassium ethanolate and sodium propanolate; and various organic bases such as piperidine, diethanolamine and N-methylglutamine. The aluminum salts of the compounds of formula I are also included. at certain compounds of formula I can acid addition salts formed by reacting these compounds with pharmaceutically acceptable organic and inorganic acids, for example hydrogen halides such as hydrogen chloride, hydrogen bromide or hydrogen iodide, other mineral acids and their corresponding salts such as sulfate, nitrate or phosphate and the like, and alkyl and Monoarylsulfonates such as ethane sulfonate, toluenesulfonate and benzenesulfonate, and other organic acids and their corresponding salts such as acetate, trifluoroacetate, tartrate, maleate, succinate, citrate, benzoate, salicylate, ascorbate and the like. Accordingly, pharmaceutically acceptable acid addition salts of the compounds of formula I include the following: acetate, adipate, alginate, arginate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate, chloride, chlorobenzoate, citrate , Cyclopentanepionate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, fumarate, galacterate (from mucic acid), galacturonate, glucoheptanoate, gluconate, glutamate, glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate , iodide, isethionate, isobutyrate, lactate, lactobionate, malate, maleate, malonate, mandelate,

Metaphosphate, methanesulfonate, methyl benzoate, monohydrogen phosphate, 2-naphthalene sulfonate, nicotinate, nitrate, oxalate, oleate, pamoate, pectinate, persulfate, phenyl acetate, 3-phenylpropionate, phosphate, phosphonate, phthalate, but this is not limiting.

Furthermore, the base salts of the compounds according to the invention include aluminum, ammonium, calcium, copper, iron (III), iron (II), lithium, magnesium, manganese (III), manganese (II), potassium , Sodium and zinc salts, but this should not be limiting. Preferred among the above salts are ammonium; the alkali metal salts sodium and

Potassium, as well as the alkaline earth metal salts calcium and magnesium. To salts of the compounds of formula I ₁ which are pharmaceutically acceptable derive salts of primary, secondary and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, eg arginine, betaine, caffeine, chloroprocaine, choline, N, N'-dibenzylethylenediamine ( Benzathine), dicyclohexylamine, diethanolamine,

Diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, iso-propylamine, lidocaine, lysine, meglumine, N-methyl-D-glucamine, morpholine, Piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethanolamine, triethylamine, trimethylamine, tripropylamine and tris (hydroxymethyl) methylamine (tromethamine), but this is not intended to be limiting.

Compounds of the present invention containing basic nitrogen-containing groups can be reacted with agents such as (C 1 -C ₄ ) alkyl halides, eg, methyl, ethyl, isopropyl, and tert-butyl chloride, bromide, and iodide; Di (C ₁ -C ₄ ) alkyl sulfates, for example dimethyl, diethyl and diamyl sulfate; (Ci ₀ - Ci ₈ ) alkyl halides, eg decyl, dodecyl, lauryl, myristyl and stearyl chloride, bromide and iodide; and quaternize aryl- (C 1 -C ₄ ) alkyl halides, eg benzyl chloride and phenethyl bromide. With such salts, both water- and oil-soluble compounds of the invention can be prepared.

The above-mentioned pharmaceutical salts which are preferred include acetate, trifluoroacetate, besylate, citrate, fumarate, gluconate,

Hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate, mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodium phosphate, stearate, sulfate, sulfosalicylate, tartrate, thiomalate, tosylate and tromethamine, but this is not intended to be limiting.

The acid addition salts of basic compounds of the formula I are prepared by reacting the free base form with a sufficient The amount of the desired acid brings into contact, which is the salt in a conventional manner. The free base can be regenerated by contacting the salt form with a base and isolating the free base in a conventional manner. The free base forms differ, in a sense, from their corresponding salt forms with respect to certain physical ones

Properties such as solubility in polar solvents; however, in the context of the invention, the salts otherwise correspond to their respective free base forms.

As mentioned, the pharmaceutically acceptable base addition salts of the compounds of formula I are formed with metals or amines such as alkali metals and alkaline earth metals or organic amines. Preferred metals are sodium, potassium, magnesium and calcium. Preferred organic amines are N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methyl-D-glucamine and procaine.

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

If a compound according to the invention contains more than one group which can form such pharmaceutically acceptable salts, the invention also encompasses multiple salts. Typical multiple salt forms include, for example, bitartrate, diacetate, difumarate, dimeglumine, diphosphate, disodium and trihydrochloride, but this is not intended to be limiting. In view of the above, it can be seen that the term "pharmaceutically acceptable salt" in the present context means an active ingredient which contains a compound of the formula I in the form of one of its salts, especially if this salt form is the active ingredient in the Imparts improved pharmacokinetic properties to the free form of the active ingredient or any other salt form of the active ingredient which has previously been used. The pharmaceutically acceptable salt form of the active substance may also first impart a desired pharmacokinetic property to this active ingredient which it has not previously possessed, and may even positively influence the pharmacodynamics of this active ingredient in terms of its therapeutic efficacy in the body.

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

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

Dose unit included, to be presented. Preferred unit dosage formulations are those containing a daily or partial dose as indicated above or a corresponding fraction thereof of an active ingredient. Furthermore, such pharmaceutical formulations can be prepared by any of the methods well known in the pharmaceutical art. Pharmaceutical formulations may be administered by any suitable route, for example, oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal). Ways, adapt. Such formulations can be prepared by any method known in the pharmaceutical art, for example, by bringing the active ingredient together with the carrier (s) or excipient (s).

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

Thus, for example, when administered orally in the form of a tablet or capsule, the active ingredient component may be admixed with an oral, non-toxic and pharmaceutically acceptable inert carrier, e.g. Ethanol, glycerin, water and the like. combine. Powders are prepared by comminuting the compound to a suitable fine size and mixing it with a similarly comminuted pharmaceutical excipient, e.g. an edible carbohydrate such as starch or mannitol. A flavor, preservative, dispersant and dye may also be present.

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

In addition, if desired or necessary, suitable bonding,

Lubricants and disintegrants as well as dyes are also incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars, e.g. Glucose or beta-lactose, corn sweeteners, natural and synthetic gums, e.g. Acacia, tragacanth or sodium alginate, carboxymethyl cellulose, polyethylene glycol, waxes, and the like. The lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. The disintegrating agents include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum and the like. The tablets are formulated by, for example, preparing a powder mixture, granulating or dry-pressing, adding a lubricant and a disintegrant, and pressing the whole into tablets. A powder mixture is prepared by treating the appropriately comminuted compound with a diluent or a base as described above, and optionally with a

Binders such as carboxymethyl cellulose, an alginate, gelatin or polyvinylpyrrolidone, a Lösungsverlangsamer such as paraffin, a absorption accelerator such as a quaternary salt and / or an absorbent, such as bentonite, kaolin or dicalcium phosphate. The powder mixture can be granulated by wetting it with a binder such as syrup, starch paste, Acadia slime or solutions of cellulosic or polymeric materials and pressing through a sieve. As an alternative to granulation, the powder mixture can be run through a tabletting machine to produce non-uniformly shaped lumps which are broken up into granules. The granules may be greased by the addition of stearic acid, a stearate salt, talc or mineral oil to prevent sticking to the tablet molds. The greased mixture is then compressed into tablets. The compounds according to the invention can also be combined with a free-flowing inert carrier and then pressed directly into tablets without carrying out the granulation or dry-pressing steps. A transparent or opaque protective layer, consisting of a

Shellac sealant, a layer of sugar or polymeric material and a glossy layer of wax may be present. Dyes can be added to these coatings in order to differentiate between different dosage units.

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

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

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

The compounds of formula I as well as the salts, solvates and physiologically functional derivatives thereof can also be delivered using monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds can also be coupled with soluble polymers as targeted drug carriers. Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol or polyethyleneoxidepolylysine substituted with palmitoyl radicals. Furthermore, the compounds can be attached to a class of biodegradable polymers suitable for the controlled release of a drug, e.g. Polylactic acid, polyepsilon-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydroxypyrans, polycyanoacrylates, and crosslinked or amphipathic block copolymers of hydrogels.

Pharmaceutical adapted to transdermal administration

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

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

For treatments of the eye or other external tissues, eg mouth and skin, the formulations are preferably used as topical ointment or Cream applied. When formulated into an ointment, the active ingredient can be used with either a paraffinic or water miscible cream base. Alternatively, the active ingredient can be formulated into a cream with an oil-in-water cream base or a water-in-oil base.

The pharmaceutical formulations adapted for topical application to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.

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

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

Pharmaceutical formulations adapted for nasal administration in which the vehicle is a solid contain a coarse powder having a particle size, for example, in the range of 20-500 microns, which is administered in the manner in which snuff is received, i. by rapid inhalation via the nasal passages from a container held close to the nose with the powder. Suitable formulations for administration as a nasal spray or nasal drops with a liquid carrier include drug solutions in water or oil.

Pharmaceutical formulations adapted for administration by inhalation include fine particulate dusts or mists which may be generated by various types of pressurized dosing dispensers with aerosols, nebulizers or insufflators. Pharmaceutical formulations adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.

Among the adapted for parenteral administration pharmaceutical

Formulations include aqueous and non-aqueous sterile injection solutions containing anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the recipient to be treated; and aqueous and non-aqueous sterile suspensions which may contain suspending agents and thickeners. The formulations may be administered in single or multiple dose containers, e.g. sealed vials and vials, and stored in the freeze-dried (lyophilized) state so that only the addition of the sterile carrier liquid, e.g. Water for injections, needed immediately before use. Injection solutions and suspensions prepared by formulation can be prepared from sterile powders, granules and tablets.

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

A therapeutically effective amount of a compound of formula I depends on a number of factors, including, for example, the age and weight of the human or animal, the exact disease state requiring treatment, as well as its severity, the nature of the formulation, and the route of administration. and is ultimately determined by the attending physician or veterinarian. However, an effective amount of a compound of the invention for the treatment of neoplastic growth, eg colon or breast carcinoma, is general in the range of 0.1 to 100 mg / kg body weight of the recipient (mammal) per day and more typically in the range of 1 to 10 mg / kg body weight per day. Thus, for a 70 kg adult mammal, the actual amount per day would usually be between 70 and 700 mg, this amount as a single dose per day or more commonly in a number of divided doses (such as two, three, four, five or six) per Day can be given so that the total daily dose is the same. An effective amount of a salt or solvate or a physiologically functional derivative thereof can be determined as a proportion of the effective amount of the compound of the invention per se. It can be assumed that similar dosages are suitable for the treatment of the other, above-mentioned disease states.

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

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

(a) an effective amount of a compound of formula I and / or its pharmaceutically acceptable derivatives, solvates and stereoisomers, including mixtures thereof in all proportions, and (b) an effective amount of another active pharmaceutical ingredient.

The kit contains suitable containers, such as boxes or boxes, individual bottles, bags or ampoules. The set may e.g. containing separate ampoules, in each of which an effective amount of a compound of formula I and / or its pharmaceutically acceptable

Derivatives, solvates and stereoisomers, including mixtures thereof in all ratios, and an effective amount of another drug ingredient is dissolved or in lyophilized form.

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

Table 1.

Alkylating agent Cyclophosphamide Lomustine

Busulfan procarbazine

Ifosfamide altretamine

Melphalan estramustin phosphate

Hexamethylmelamine mechlorethamine

Thiotepa streptozocin

Chlorambucil Temozolomide

Dacarbazine Semustin

carmustine

Platinum agent cisplatin carboplatin

Oxaliplatin ZD-0473 (AnorMED)

Spiroplatin Lobaplatin (Aetema)

Carboxyphthalatoplatinum Satraplatin (Johnson

Tetraplatinum Matthey)

Ormiplatin BBR-3464 (Hoffmann-La

Iproplatin Roche)

SM-11355 (Sumitomo)

AP-5280 (Access)

Antimetabolite azacytidine Tomudex

Gemcitabine trimetrexate

Capecitabine deoxycoformycin 5-fluorouracil fludarabine

Floxuridine pentostatin

2-chlorodeoxyadenosine Raltitrexed

6-mercaptopurine hydroxyurea

6-thioguanine decitabine (SuperGen)

Cytarabine Clofarabine (Bioenvision)

2-Fluorodeoxycytidine Irofulvene (MGI Pharma)

Methotrexate DMDC (Hoffmann-La

Idatrexate Roche)

Ethinylcytidine (Taiho)

Topoisomerase Amsacrine Rubitecane (SuperGen)

Inhibitors Epirubicin Exatecan Mesylate (Daiichi)

Etoposide Quinamed (ChemGenex)

Teniposide or Mitoxantrone Gimatecan (Sigma-Tau)

Irinotecan (CPT-11) diflomotecan (Beaufour

7-ethyl-10-Ipsen) hydroxycamptothecin TAS-103 (Taiho)

Topotecan Elsamitrucin (Spectrum)

Dexrazoxanet (TopoTarget) J-107088 (Merck & Co)

Pixantron (Novuspharrna) BNP-1350 (BioNumerik)

Rebeccamycin analog CKD-602 (Chong Kun

(Exelixis) Dang)

BBR-3576 (Novuspharrna) KW-2170 (Kyowa Hakko)

Antitumor Dactinomycin (Actinomycin Amonafide

Antibiotics D) Azonafide

Doxorubicin (adriamycin) anthrapyrazole

Deoxyrubicin Oxantrazole

Valrubicin losoxantrone

Daunorubicin (daunomycin) bleomycin sulfate

Epirubicin (blenoxane) Therarubicin bleomycinic acid

Idarubicin bleomycin A

Rubidazone bleomycin B

Plicamycin mitomycin C

Porfiromycin MEN-10755 (Menarini)

Cyanomorpholinodoxorubici GPX-100 (Gem n Pharmaceuticals)

Mitoxantrone (Novantrone)

Antimitotic Paclitaxel SB 408075

Agent Docetaxel (GlaxoSmithKline)

Colchicine E7010 (Abbott).

Vinblastine PG-TXL (Cell

Vincristin Therapeutics)

Vinorelbine IDN 5109 (Bayer)

Vindesin A 105972 (Abbott)

Dolastatin 10 (NCI) A 204197 (Abbott)

Rhizoxin (Fujisawa) LU 223651 (BASF)

Mivobulin (Warner-Lambert) D 24851 (ASTA Medica)

Cemadotin (BASF) ER-86526 (Eisai)

RPR 109881A (Aventis) Combretastatin A4 (BMS)

TXD 258 (Aventis) isohomohalichondrin-B

Epothilone B (Novartis) (PharmaMar)

T 900607 (Tularik) ZD 6126 (AstraZeneca)

T 138067 (Tularik) PEG-paclitaxel (Enzon)

Cryptophycin 52 (Eli Lilly) AZ10992 (Asahi)

Vinflunin (Fabre)! DN-5109 (lndena)

Auristatin PE (Teikoku AVLB (Prescient

Hormones) NeuroPharma)

BMS 247550 (BMS) azaepothilone B (BMS)

BMS 184476 (BMS) BNP-7787 (BioNumerik)

BMS 188797 (BMS) CA-4 prodrug (OXiGENE) Taxoprexin (Protarga) Dolastatin-10 (NrH)

CA-4 (OXiGENE)

Aromatase-aminoglutethimide exemestane

Inhibitors Letrozole Atamestane (BioMedicines)

Anastrazole YM-511 (Yamanouchi)

formestane

Thymidylate synthem pemetrexed (EIi Lilly) Nolatrexed (Eximias) thase inhibitors ZD-9331 (BTG) CoFactor ™ (BioKeys)

DNA Trabectedin (PharmaMar) Mafosfamide (Baxter

Antagonists glufosfamide (Baxter International)

International) Apaziquon (Spectrum

Albumin + 32P (Isotope Pharmaceuticals)

Solutions) O6-Benzylguanine

Thymectacin (NewBiotics) (Paligent)

Edotreotide (Novartis)

Farnesyltransfer Arglabin (NuOncology Tipifamib (Johnson & Inhibitors Labs) Johnson) lonafarnib (Schering Perillyl Alcohol (DOR

Plow) BioPharma)

BAY-43-9006 (Bayer)

Pump CBT-1 (CBA Pharma) Zosuquidar

Inhibitors Tariquidar (Xenova) Trihydrochloride (EIi Lilly)

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

Histone acetyl trans-Tacedinalin (Pfizer) pivaloyloxymethyl butyrate ferase SAHA (Aton Pharma) (titanium) Inhibitors MS-275 (Schering AG) Depsipeptide (Fujisawa)

Metalloproteinase Neovastat (Aeterna CMT -3 (CollaGenex) Inhibitors Laboratories) BMS-275291 (Celltech)

Ribonucleoside Marimastat (British Biotech) Tezacitabine (Aventis) Reductase Gallium Maltolate (Titanium) Didox (Molecules for

Inhibitors Triapine (Vion) Health)

TNF-alpha-virulizine (Lorus Revimid (Celgene)

Agonists / anti-therapeutics) gonisten CDC-394 (Celgene)

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

Receptor ZD-4054 (AstraZeneca)

antagonists

Retinoic acid fenretinide (Johnson & alitretinoin (ligand) zeptor agonist Johnson)

LGD-1550 (ligand)

Immunomodula Interferon Dexosome Therapy oncophage (Antigenics) (Anosys)

GMK (Progenics) Pentrix (Australian Cancer

Adenocarcinoma Vaccine Technology)

(Biomira) JSF-154 (Carrying)

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

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

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

Synchrovax Vaccines (CTL MGV (Progenics)

Immuno)! 3-Alethine (Dovetail)

Melanoma vaccine (CTL CLL-Thera (Vasogen) Immuno) p21 RAS vaccine

(GemVax)

Hormonal and estrogenic prednisone antihormonal conjugated estrogens methylprednisolone

Agent ethinyl estradiol prednisolone

Chlorotrienes Aminoglutethimide

Idenestrol Leuprolide

Hydroxyprogesterone caproate goserelin

Medroxyprogesterone Leuporelin

Testosterone Bicalutamide

Testosterone Propionate Flutamide

Fluoxymesterone octreotide

Methyltestosterone Nilutamide

Diethylstilbestrol Mitotane

Megestrol P-04 (Novogen)

Tamoxifen 2-methoxyestradiol

Toremofin (EntreMed)

Dexamethasone Arzoxifen (EIi Lilly)

Photodynamic Talaporfin (Light Sciences) Pd-Bacteriopheophorbide

Central Theralux (Yeda)

(Theratechnologies) Lutetium Texaphyrin

Motexafin Gadolinium (Pharmacyclics)

(Pharmacyclics) Hypericin

Tyrosine kinase imatinib (Novartis) Kahalid F (PharmaMar)

Inhibitors Leflunomide CEP-701 (Cephalon)

(Sugen / Pharmacia) CEP-751 (Cephalon)

ZDI839 (AstraZeneca) MLN518 (Millenium) Erlotinib (Oncogene PKC412 (Novartis)

Science) phenoxodiol O

Canertjnib (Pfizer) Trastuzumab (Genentech)

Squalamine (Genaera) C225 (ImCIone)

SU5416 (Pharmacia) rhu-Mab (Genentech)

SU6668 (Pharmacia) MDX-H210 (Medarex)

ZD4190 (AstraZeneca) 2C4 (Genentech)

ZD6474 (AstraZeneca) MDX-447 (Medarex)

Vatalanib (Novartis) ABX-EGF (Abgenix)

PKI166 (Novartis) IMC-1 C11 (ImCIone)

GW2016 (GlaxoSmithKline)

EKB-509 (Wyeth)

EKB-569 (Wyeth)

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

Sanofi-Synthelabo) BioCryst)

Tocladesin (cyclic Ranpimase

AMP agonist, Ribapharm) (ribonuclease stimulant,

Alvocidib (CDK inhibitor, Alfacell)

Aventis) galarubicin (RNA

CV-247 (COX-2 inhibitor, synthesis inhibitor, dendritic

Ivy Medical) A)

P54 (COX-2 inhibitor, tirapazamine

Phytopharm) (reducing agent, SRI

CapCell ™ (CYP450-International)

Stimulant, Bavarian Nordic) N-acetylcysteine

GCS-IOO (gal3 antagonist, (reducing agent,

GlycoGenesys) Zambon)

G17DT immunogen R-flurbiprofen (NF-

(Gastrin inhibitor, Aphton) kappaB inhibitor, Encore)

Efaproxiral (oxygenator, 3CPA (NF-kappaB-

Allos Therapeutics) Inhibitor, Active Biotech)

PI-88 (heparanase-seocalcitol (vitamin D Inhibitor, progens) receptor agonist, Leo)

Tesmilifen (histamine 131-I-TM-601 (DNA

Antagonist, YM antagonist,

BioSciences) TransMolecular)

Histamine (histamine H2-eflomithine (ODC inhibitor,

Receptor agonist, Maxim) ILEX Oncology)

Tiazofurin (IMPDH inhibitor, minodronic acid

Ribapharm) (osteoclast inhibitor,

Cilengitide (Integrin Yamanouchi)

10 antagonist, Merck KGaA) indisulam (p53 stimulant,

SR-31747 (I L-1 antagonist, Eisai)

Sanofi-Synthelabo) Aplidine (PPT inhibitor,

CCI-779 (mTOR kinase PharmaMar)

Inhibitor, Wyeth) rituximab (CD20-

15 Exisulind (PDE V inhibitor, antibody, Genentech)

Cell Pathways) gemtuzumab (CD33-

CP-461 (PDE V inhibitor, antibody, Wyeth Ayerst)

Cell Pathways) PG2 (hematopoietic

AG-2037 (GART inhibitor, amplifier,

20 Pfizer) Pharmagenesis)

WX-UK1 Immunol ™ (triclosan

(Plasminogen Activator Oral Irrigation, Endo)

Inhibitor, Wilex) triacetyluridine (uridine

PBI-1402 (PMN stimulant, prodrug, Wellstat)

25 ProMetic LifeSciences) SN-4071 (sarcoma agent,

Bortezomib (Proteasome Signature BioScience)

Inhibitor, Millennium) TransMID-107 ™

SRL-172 (T cell stimulant, (immunotoxin, KS

SR Pharma) Biomedix)

30 TLK-286 (glutathione-S-PCK-3145 (apoptosis

Transferase inhibitor, Telik promoter, Procyon)

PT-100 (growth factor doranidazole (apoptosis Agonist, point promoter, PoIa)

Therapeutics) CHS-828 (cytotoxic

Midostaurin (PKC inhibitor, agent, Leo)

Novartis) trans-retinoic acid

Bryostatin-1 (PKC (differentiator, NIH)

Stimulant, GPC Biotech) MX6 (apoptosis promoter,

CDA-II (apoptosis promoter, MAXIA)

Everlifθ) apomin (apoptosis

SDX-101 (apoptosis promoter, ILEX Oncology)

Promoter, salmedix) urocidin (apoptosis

Ceflatonin (Apoptosis promoter, Bioniche)

Conveyor, ChemGenex) Ro-31-7453 (apoptosis

Promoter, La Roche)

Brostallicin (Apoptosis

Promoter, Pharmacia)

Preferably, the compounds of the formula I are combined with those with known anticancer agents:

These known anticancer agents include the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic agents, antiproliferative agents, prenyl protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors and other angiogenesis inhibitors. The present compounds are particularly suitable for co-administration with radiotherapy. The synergistic effects of inhibiting VEGF in combination with radiotherapy have been described in the art (see WO 00/61186). "Estrogen receptor modulators" refers to compounds that interfere with or inhibit the binding of estrogen to the receptor, regardless of how this occurs. "Estrogen receptor modulators include, for example, tamoxifen, raloxifene, idoxifen, LY353381, LY 117081," Toremifene, fulvestrant, 4- [7- (2,2-dimethyl-1-oxopropoxy-4-methyl-2- [4- [2- (1-piperidinyl) ethoxy] phenyl] -2H-1-benzopyran-3 yl] phenyl-2,2-dimethyl-propanoate, 4,4'-dihydroxybenzophenone-2,4-dinitrophenylhydrazone and SH646, but this is not intended to be limiting. "Androgen receptor modulators" refers to compounds that inhibit the binding of androgens to the receptor Regardless of how this happens, androgen receptor modulators include, for example, finasteride and other 5α-reductase inhibitors, nilutamide, flutamide, bicalutamide, liarozole, and abiraterone acetate.

"Retinoid receptor modulators" refers to compounds that interfere with or inhibit the binding of retinoids to the receptor, regardless of how this occurs Such retinoid receptor modulators include, for example, bexarotene, tretinoin, 13-cis-retinoic acid, 9-cis Retinoic acid, α-difluoromethylmuthine, ILX23-7553, trans-N- (4'-hydroxyphenyl) -retinamide, and N-4-carboxyphenylretinamide. "Cytotoxic agents" refers to compounds that cause cell death primarily by direct action on cell function or inhibit cell myosis, including alkylating agents, tumor necrosis factors, intercalators, microtubulin inhibitors, and topoisomerase inhibitors.

The cytotoxic agents include, for example, tirapazimine, Sertenef, cachectin, ifosfamide, tasonermine, lonidamine, carboplatin, altretamine, prednimustine, dibromodulcite, ranimustine, fotemustine, nedaplatin, oxaliplatin, temozolomide, heptaplatin, estramustine, improvisulfan-tosylate, trofosfamide, nimustine, dibrosylamine. pidium chloride, Pumitepa, Lobaplatin, Satraplatin, Profiromycin, Cisplatin, Irofulvene, Dexifosfamide, cis-Amine dichloro (2-methylpyridine) platinum, Benzylguanine, Glufosfamide, GPX100, (trans, trans, trans) -bis-mu (hexane -1, 6-diamine) -mu- [diamine-platinum (II)] bis [diamine (chloro) platinum (II)] tetrachloride, diarizidinylspermine, arsenic trioxide, 1- (11-dodecylamino-10-hydroxyundecyl) -3, 7-dimethylxanthine, zorubicin, idarubicin, daunorubicin, bisantrene, mitoxantrone, pirarubicin, pinafid, valrubicin, amrubicin, antineoplaston, 3'-desamino-3'-morpholino 13-desoxo-10-hydroxycarminomycin, annamycin, galarubicin, elinafide, MEN 10755 and 4-desmethoxy-3-desamino-3-aziridinyl-4-methylsulfonyl-daunorubicin (see WO 00/50032), but this is not intended to be limiting. The microtubulin inhibitors include, for example, paclitaxel, vindesine sulfate, 3 ', 4'-didehydro-4'-deoxy-8'-norvincaleukoblastin, docetaxol, rhizoxin, dolastatin, mivobulinisethionate, auristatin, cemadotin, RPR109881, BMS184476, Vinflunine, Cryptophycin, 2,3,4,5,6-pentafluoro-N- (3-fluoro-4-methoxyphenyl) benzenesulfonamide, anhydrovinblastine, N, N-dimethyl-L-valyl-L-valyl-N-methyl-L -valyl-L-prolyl-L-proline t-butylamide, TDX258 and BMS188797.

Topoisomerase inhibitors are, for example, topotecan, hycaptamine, irinotecan, rubitecan, 6-ethoxypropionyl-3 ', 4'-O-exo-benzylidene-chartreusine, 9-methoxy-N, N-dimethyl-5-nitropyrazolo [3,4, 5-kl] acridine-2- (6H) propanamine, 1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H, 12H-benzo [de] -pyrano Indolizino [1,2b] quinoline-10,13 (9H, 15H) -dione, lurtotecan, 7- [2- (N-isopropylamino) ethyl] - (20S) camptothecin, BNP1350, BNPM 100, BN80915, BN80942, etoposide-phosphate, teniposide, sobuzoxan, 2 ¹ -dimethylamino-2'-deoxy-etoposide, GL331, N- [2- (dimethylamino) ethyl] -9-hydroxy-5,6-dimethyl 6H-pyrido [4,3-b] carbazole-1-carboxamide, asulacrine,

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

Antiproliferative agents include antisense RNA and DNA oligonucleotides such as G3139, ODN698, RVASKRAS ₁ GEM231 and INX3001, and antimetabolites such as enocitabine, carmofur, tegafur, pentostatin, doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine, cytarabine ocfosfate, fosteabin sodium hydrate, raltitrexed, paltitrexide, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed, nelzarabine, 2'- Deoxy-2'-methylidenecytidine, 2'-fluoromethylene-2'-deoxycytidine, N- [5- (2,3-

Dihydrobenzofuryl) sulfonyl] -N '- (3,4-dichlorophenyl) urea, N6- [4-deoxy-4- [N 2 - [2 (E), 4 (E) -tetradecadienoyl] -glycylamino] -L-glycero-BL -manno-heptopyranosyl] adenine, aplidine, ecteinascidin, troxacitabine, 4- [2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimidino [5 ₍ 4-b] [1, 4 ] thiazine-6-yl- (S) -ethyl] -2,5-thienoyl-L-glutamic acid, aminopterin, 5-fluorouracil, alanosine, 11-acetyl-8-

(carbamoyloxymethyl) O -formyl-β-methoxy-oxa-1H-diazatetracyclo (7.4.1.0.0) -tetradeca-2,4,6-trien-9-ylacetic acid ester, swainsonine, lometrexol, dexrazoxane, methioninase, 2 ' -cyan-2'-deoxy-N4-palmitoyl-1-B-D-arabinofuranosylcytosine and 3-aminopyridine-2-carboxaldehyde-thiosemicarbazone The "antiproliferative agents" also include other monoclonal antibodies to growth factors than those already described under "angiogenesis Inhibitors, such as trastuzumab, as well as tumor suppressor genes, such as p53, which can be delivered via recombinant virus-mediated gene transfer (see, eg, US Pat. No. 6,069,134).

Particularly preferred is the use of the compound according to the invention for the treatment and prophylaxis of tumor diseases.

The tumor is preferably selected from the group of squamous cell tumors, bladder, stomach, kidney, head and neck, esophagus, cervix, thyroid, intestine, liver, brain, prostate, genitourinary tract , the lymphatic system, the stomach, the larynx and / or the lungs. The tumor is furthermore preferably selected from the group lung adenocarcinoma, small cell lung carcinomas, pancreatic cancer, glioblastomas, colon carcinoma and breast carcinoma.

Further preferred is the use for the treatment of a tumor of the

Blood and immune system, preferably for the treatment of a tumor selected from the group of acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia and / or chronic lymphocytic leukemia.

The invention also includes a method of treating a patient having a neoplasm, such as a cancer, by administration

a) one or more of the compounds of the formula I:

b) and one or more of the compounds of the formula VI or their acid addition salts, in particular hydrochlorides:

wherein Y 'and Z' are each independently O or N, R ⁹ and R ^{10 are} each independently H, OH, halogen, OC 1-10 alkyl, OCF ₃ , NO ₂ or NH ₂ , n is an integer between 2 and 6, each inclusive, and R ⁸ and R ^{11 are} each independently preferably at the meta or para position and selected from the group:

wherein the first and second compounds are administered simultaneously or within 14 days of each other in amounts sufficient to inhibit the growth of the neoplasm.

The combination of the compounds of the formula I with the compounds of the formula VI and other pentamedin analogues leads to a synergistic effect in the inhibition of neoplasms. Combinations containing the compounds of formula VI are e.g. mentioned in WO 02058684.

The mechanism of action of pentamidine or its derivatives is currently unclear: pentamidine or its derivatives appear to have pleiotropic effects as it leads to a decrease in DNA, RNA and protein synthesis. Pentamidine has recently been described as a potent inhibitor of PRL1, -2 and 3 phosphatases (Pathak et al., 2002) and tyrosine phosphatases, and its overexpression is associated with human neoplastic malignant tumors. On the other hand, it has been described that pentamidine is a drug that binds to the small DNA groove (Puckowska et al., 2004) and that can exert its effect via the disruption of gene expression and / or DNA synthesis.

Experiments show that:

- Both pentamidine and preferably the compounds of the formula I cells in the G2 / M cell cycle stop. the combination of pentamidine and compounds of formula I preferably have additive to synergistic effects on cell proliferation.

Other suitable pentamidine analogs include stilbamidine (G-1) and

Hydroxystilbamidine (G-2) and its indole analogs (e.g., G-3):

(G-1)

(G-2) and

(G-3)

Each amidine unit can be independently replaced by one of the units defined above for R ⁸ and R ¹¹ . As in the case of benzimidazoles and pentamidines, salts of stilbamidine, hydroxystilbamidine and their indole derivatives are also suitable for the process according to the invention. Preferred salts include, for example, dihydrochloride and methanesulfonate salts. Still other analogs are those falling within a formula disclosed in any of U.S. Patent Nos. 5,428,051, 5,521,189, 5,602,172, 5,643,935, 5,723,495, 5,843,980, 6,172,104 and 6,326,395, or US Patent Application Publ. US 2002/0019437 A1, each of which is incorporated by reference in its entirety. Exemplary analogs include 1, 5-bis (4 '- (N-hydroxyamidino) phenoxy) pentane, 1, 3-bis (4' - (N-hydroxyamidino) phenoxy) propane, 1, 3-bis (2 '-methoxy-4' - (N-hydroxyamidino) phenoxy) propane, 1,4-bis (4 '- (N-hydroxyamidino) phenoxy) butane, 1, 5-bis- (4' - (N-) hydroxyamidino) phenoxy) pentane, 1,4-bis (4 '- (N-hydroxyamidino) phenoxy) butane, 1, 3-bis- (4' - (4-hydroxyamidino) phenoxy) propane, 1, 3-bis - (2'-methoxy-4 '- (N-hydroxyamidino) phenoxy) propane, 2,5-bis [4-amidinophenyl] furan, 2,5-bis [4-amidinophenyl] furan-bis-amidoxime, 2.5 Bis- [4-amidinophenyl] furan-bis-O-methylamidoxime, 2,5-bis [4-amidinophenyl] furan-bis-O-ethylamidoxime, 2,8-diamidinodibenzothiophene, 2,8-bis- (N- isopropylamidino) carbazole, 2,8-bis (N-hydroxyamidino) carbazole, 2,8-bis (2-imidazolinyl) dibenzothiophene, 2,8-bis (2-imidazolinyl) -5,5-dioxodibenzothiophene, 3, 7-diamidinodibenzothiophene, 3,7-BiS- (N-isopropylamidino) dibenzothiophene, 3,7-bis- (N-hydroxyamidino) -dibenzothiophene, 3,7-diaminodibenzothiophene, 3,7-dibromodibenzothiophene, 3,7 -

Dicyanodibenzothiophene, 2,8-diamidinodibenzofuran, 2,8-di- (2-imidazolinyl) -dibenzofuran, 2,8-di (N-isopropylamidino) dibenzofuran, 2, 8-di (N-hydroxylamidino) dibenzofuran, 3, 7-di (2-imidazolinyl) dibenzofuran, 3,7-di- (isopropylamidino) dibenzofuran, 3,7-di (A-hydroxylamidino) dibenzofuran, 2,8-dicyanodibenzofuran, 4,4'-dibromo-2, 2'-dinitrobiphenyl, 2-methoxy-2'-nitro-4,4'-dibromobiphenyl, 2-methoxy-2'-amino-4,4'-dibromobiphenyl, 3,7-dibromodibenzofuran, 3,7-dicyanodibenzofuran, 2 , 5-Bis (5-amidino-2-benzimidazolyl) pyrrole, 2,5-bis [5- (2-imidazolinyl) -2-benzimidazolyl] pyrrole, 2,6-bis [5- (2-imidazolinyl ) -2-benzimidazolyl] pyridine, 1-methyl-2,5-bis (5-amidino-2-benzimidazolyl) pyrrole, 1-methyl-2,5-bis [5- (2-imidazolyl) -2- benzimidazolyl] pyrrole, 1-methyl-2,5-bis [5- (1, 4,5,6-tetrahydro-2-pyrimidinyl) -2-benzimidazolyl] pyrrole, 2,6-bis (5-amidino) 2-benzimidazoyl) pyhdine, 2,6-bis- [5- (1, 4,5,6-tetrahydro-2-pyrimidinyl) -2-benzimidazolyl] pyriclin, 2,5-bis (5-amidino-2-benzimidazolyl) furan, 2,5-bis- [5 - (2-imidazolinyl) -2-benzimidazolyl] furan, 2,5-bis (5-N-isopropylamidino-2-benzimidazolyl) furan, 2,5-bis (4-guanylphenyl) furan, 2,5-bis (4-guanylphenyl) -3,4-dimethylfuran, 2,5-di-p- [2- _(3,4,5> 6-tetrahydropyrimidyl) phenyl] furan, 2,5-bis [4- (2- imidazolinyl) phenyl] furan, 2,5- [bis {4- (2-tetrahydropyrimidinyl)} phenyl] -p- (tolyloxy) furan, 2,5- [bis (4- (2-imidazolinyl)} - phenyl ] -3-p- (tolyloxy) furan, 2,5-bis {4- [5- (N-2-aminoethylamido) benzimidazol-2-yl] phenyl} furan, 2,5-bis- [4- (2-bis) 3a, 4,5,6,7,7a-hexahydro-1H-benzimidazol-2-yl) phenyl] furan, 2,5-bis- [4- (4,5,6,7-tetrahydro-1H- 1,3-diazepin-2-yl) phenyl] furan, 2,5-bis- (4-N, N-dimethylcarboxhydrazidophenyl) furan, 2,5-bis- {4- [2- (N-2-hydroxyethyl) imidazolinyl] phenyl} furan, 2,5-bis [4- (N-isopropylaminidino) phenyl] furan, 2,5-bis {4- [3- (dimethylaminopropyl) amidino] phenyl} furan, 2, 5-bis {4- [N- (3-aminopropyl) amidino] phenyl} furan, 2.5-Bi s- [2- (imidazolinyl) phenyl] -3,4-bis (methoxymethyl) furan, 2,5-bis [4-N- (dimethylaminoethyl) guanyl] phenylfuran, 2.5-bis- { 4 - [(N-2-hydroxyethyl) guanyl] phenyl} furan, 2,5-bis [4-N- (cyclopropylguanyl) phenyl] furan, 2,5-bis [4- (N, N -diethylaminopropyl ) guanyl] phenylfuran, 2,5-bis {4- [2- (N-ethylimidazolinyl)] phenyljfuran, 2,5-bis {4- [N- (3-pentylguanyl)]} phenylfuran, 2, 5-Bis- [4- (2-imidazolinyl) phenyl] -3-methoxyfuran, 2,5-bis [4- (N -isopropylamidino) phenyl] -3-methylfuran, bis [5-amidino-2-benzimidazolyl ] methane, bis [5- (2-imidazolyl) -2-benzimidazolyl] methane, 1, 2-bis [5-amidino-2-benzimidazolyl] ethane, 1, 2-bis- [5- (2-imidazolyl ) -2-benzimidazolyl] ethane, 1, 3-bis [5-amidino-2-benzimidazolyl] propane, 1, 3-bis [5- (2-imidazolyl) -2-benzimidazolyl] propane, 1, 4- Bis [5-amidino-2-benzimidazolyl] propane, 1,4-bis [5- (2-imidazolyl) -2-benzimidazolyl] butane, 1,8-bis- [5-amidino-2-benzimidazolyl] octane , trans-1, 2-bis [5-amidino-2-benzimidazolyl] θthene, 1, 4-bis [5- (2-imidazolyl) -2-benzimidazolyl] -1-bu 1, 4-bis- [5- (2-imidazolyl) -2-benzimidazolyl] -2-butene, 1,4-bis- [5- (2-imidazolyl) -2-benzimidazolyl] -1-methylbutane, 1, 4-Bis- [5- (2-imidazolyl) -2-benzimidazolyl] -2-ethylbutane, 1,4-bis- [5- (2-imidazolyl) -2-benzimidazolyl] -1-methyl-1 - butene, 1,4-bis [5- (2-imidazolyl) -2-benzimidazolyl] -2,3-diethyl-2-butene, 1,4-bis [5- (2-imidazolyl) -2-benzimidazolyl ] -1, 3-butadiene, 1, 4-Bis- [5- (2-imidazolyl) -2-benzimidazolyl] -2-methyl-1,3-butadiene, bis [5- (2-pyrimidyl) -2-benzimidazolyl] methane, 1,2 Bis- [5- (2-pyrimidyl) -2-benzimidazolyl] ethane, 1,3-bis [5-amidino-2-benzimidazolyl] piOpane, 1, 3-bis- [5- (2-pyrimidyl) - 2-benzimidazolyl] propane, 1,4-bis [5- (2-pyrimidyl) -2-benzimidazolyl] butane, 1,4-bis [5- (2-pyrimidyl) -2-benzimidazolyl] -1-butene , 1, 4-

Bis- [5- (2-pyrimidyl) -2-benzimidazolyl] -2-butene, 1,4-bis [5- (2-pyrimidyl) -2-benzimidazolyl] -1-methylbutane, 1,4-bis- [5- (2-pyrimidyl) -2-benzimidazolyl] -2-ethylbutane, 1,4-bis [5- (2-pyrimidyl) -2-benzimidazolyl] -1-methyl-1-butene, 1, 4- Bis [5- (2-pyrimidyl) -2-benzimidazolyl] -2,3-diethyl-2-butene, 1,4-bis [5- (2-pyrimidyl) -2-benzimidazolyl] -1,3 butadiene and 1,4-bis [5- (2-pyrimidyl) -2-benzimidazolyl] -2-methyl-1,3-butadiene, 2,4-bis (4-guanylphenyl) pyrimidine, 2,4-bis - (4-imidazolin-2-yl) pyrimidine, 2,4-bis - [(tetrahydropyrimidinyl-2-yl) phenyl] pyrimidine, 2- (4- [Ni-propylguanyl] phenyl) -4- (2-methoxy- 4- [N-propylguanyl] phenyl) pyrimidine, 4- (N-cyclopentylamidino) -1, 2-phenylenediamine, 2,5-bis- [2- (5-amidino) benzimidazoyl] furan, 2,5-bis- [ 2- {5- (2-imidazolino)} benzimidazoyl] furan, 2,5-bis [2- (5-N-isopropylamidino) benzimidazoyl] furan, 2,5-bis- [2- (5-N-) cyclopentylamidino) benzimidazoyl] furan, 2,5-bis [2- (5-amidino) benzimidazoyl] pyrrole, 2,5-bis [2- {5- (2-imidazolino)} benzimidazoyl] pyrrole, 2, 5-bis [2- (5-N-isopropylamidino) benzimidazoyl] pyrrole, 2,5-bis [2- (5-N-cyclopentylamidino) benzimidazoyl] pyrrole, 1-methyl-2,5-bis- [2- (5-amidino) benzimidazoyl] pyrrole, 2,5-bis [2- {5- (2-imidazolino)} benzimidazoyl] -1-methylpyrrole, 2,5-bis [2- (5-N-cyclopentylamidino) benzimidazoyl] -1-methylpyrrole, 2,5-bis [2- (5-N-isopropylamidino) benzimidazoyl] thiophene, 2,6-bis [2- {5- (2-imidazolino)} benzimidazoyl] pyridine, 2 , 6-Bis- [2- (5-amidino) benzimidazoyl] pyridine, 4,4'-bis [2- (5-N-isopropylamidino) benzimidazoyl] -1,2-diphenylethane, 4,4'-bis [2- (5-N-cyclopentylamidino) benzimidazoyl] -2,5-diphenylfuran, 2,5-bis [2- (5-amidino) benzimidazoyl] benzo [b] furan, 2,5-bis- [2- (5-N-cyclopentylamidino) benzimidazoyl] benzo [b] furan, 2,7-bis [2- (5-N-isopropylaminidino) benzimidazoyl] fluoro, 2,5-bis- [4 - (3- (N-morpholinopropyl) carbamoyl) phenyl] furan, 2,5-bis [4- (2-N, N-dimethylaminoethylcarbamoyl) phenyl] furan, 2,5-bis- [4- (3- N, N-dimethylaminopropylcarbamoyl) phenyl] furan, 2,5-bis- [4- (3- N-methyl-3-N-phenylaminopropylcarbamoyl) phenyl] furan, 2,5-bis [4- (3-N, N8, N11-trimethylaminopropylcarbamoyl) phenyl] furan, 2,5-bis [3-amidinophenyl] furan , 2,5-bis [3- (N-isopropylamidino) amidinophenyl] furan, 2,5-bis [3 - [(N- (2-dimethylaminoethyl) amidino] phenylfuran, 2,5-bis- [4- (N-2,2,2-trichloroethoxycarbonyl) amidinophenyl] furan, 2,5-bis [4- (N-thioethylcarbonyl) amidinophenyl] furan, 2,5-bis [4- (N-benzyloxycarbonyl) amidinophenyl] furan , 2,5-bis [4- (N-phenoxycarbonyl) amidinophenyl] furan, 2,5-bis [4- (N- (4-fluoro) phenoxycarbonyl) amidino-phenyl] furan, 2,5-bis - [4- (N- (4-methoxy) phenoxycarbonyl) amidinophenyl] furan, 2,5-bis [4- (1-acetoxyethoxycarbonyl) amidinophenyl] furan and 2,5-bis- [4- (N- (3 Methods for preparing any of the above compounds are described in U.S. Patent Nos. 5,428,051, 5,521, 189, 5,602,172, 5,643,935, 5,723,495, 5,843,980, 6,172,104 and 6,326,395, or U.S. Patent Application Publication No. Hei. US 2002/0019437 A1 be wrote.

Pentamidine metabolites are also useful in the antiproliferative combination of this invention. Pentamidine is rapidly metabolized in the body to at least seven primary metabolites. Some of these metabolites have one or more effects in common with pentamidine. Pentamidine metabolites have antiproliferative activity when combined with a benzimidazole or analogue thereof.

Seven pentamidine analogs are shown below.

The combinations of compounds of the formula I and formula VI or their analogues and their metabolites according to the invention are suitable for the treatment of neoplasms. Combination therapy may be performed alone or in conjunction with another therapy (eg surgery, radiation, chemotherapy, biological therapy). In addition, a person whose risk of developing a neoplasm is greater (eg, someone who is genetically predisposed or someone who previously had a neoplasm) may be given prophylactic treatment to inhibit or delay neoplasm formation. The combination of the kinesin ATPase Eg5 / KSP with the compounds of the formula VI, pentamidine, its analogues and / or its metabolites is likewise an object of the invention.

The dosage and frequency of administration of each compound of the combination can be independently controlled. For example, a compound may be administered orally three times a day while the second compound may be administered intramuscularly once a day. The compounds may also be formulated together such that administration will deliver both compounds.

The antiproliferative combinations of the invention may also be provided as components of a pharmaceutical package. The two drugs may be formulated together or separately and in single dosage amounts.

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

The following examples are intended to assist those skilled in the art to better understand the present invention with reference to the experiments specifically set forth below and to the results of these experiments. However, the examples are not intended to limit the present invention and the scope of protection defined by the claims. The characteristics, features, properties, advantages and / or uses of the compounds mentioned in the examples can also be applied to other compounds, uses, and others not mentioned in the examples Articles are transferred, which are covered by the claims.

Above and below all temperatures are given in ⁰ C. In the following examples, "usual workup" means adding water if necessary, adjusting to pH values between 2 and 10, if necessary, depending on the constitution of the final product, extracted with ethyl acetate or dichloromethane, separating, drying organic phase over sodium sulfate, evaporated and purified by chromatography on silica gel and / or by crystallization Rf values on silica gel, mobile phase: ethyl acetate / methanol 9: 1.

Mass spectrometry (MS): El (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) ⁺

Examples

10 g (42.53 mmol) of 2-nitro-4-trifluoromethylbenzoic acid are hydrogenated with Pd-C (5%) in ethanol at room temperature until complete reaction. The reaction solution is filtered through kieselguhr, washed with EtOH and then the filtrate is concentrated. The residue is recrystallized from ethanol. Yield: 8.5 g (97%) 1b, pale yellow crystals

To produce the nitrating acid, while cooling with ice, 4.4 ml of fuming nitric acid are dissolved in 3.6 ml of ice-water. Subsequently, 12 ml of concentrated sulfuric acid are added in portions so that the temperature between 5 and 10 ° C can be maintained.

12 ml (70 mmol) of 4-tert-butyltoluene are introduced, cooled with an ice bath and the still cold nitrating acid is added dropwise in portions with vigorous stirring. The temperature is kept between 5 and 10 ⁰ C. After completion of the addition, the reaction mixture is stirred for a further 1 h at room temperature, then poured onto ice and extracted 4 times with diethyl ether. The combined organic phases are washed neutral with water, dried with Na ₂ SO ₄ , filtered and evaporated. The residue is purified by chromatography (400 g of silica gel, eluent: petroleum ether / DCM 9: 1). Yield: 9.53 g (71%) of 2-nitro-4-tert-butyltoluene, light yellow oil

4 g (21 mmol) of 2-nitro-4-tert-butyltoluene are suspended in 50 ml of pyridine / water - 1/1 and heated to boiling temperature (98 ⁰ C). Then 33 g (209 mmol) of potassium permanganate are added in several small portions and the reaction mixture is stirred for a further 3 hours under reflux. The reaction mixture is cooled to room temperature, treated with 10 ml of ethanol and 20 ml of 1 N NaOH are added. The solid is filtered off with suction and washed with water. The filtrate is extracted twice with ethyl acetate. The aqueous phase is then acidified (pH 5) and extracted with ethyl acetate. The combined organic phases are washed neutral with water, with Na ₂ SO ₄ dried, filtered and evaporated. The yellow oily residue crystallizes on standing.

Yield: 4.4 g (94%) of 2-nitro-4-tert.-butylbenzoic acid, yellow solid

8.6 g (38.14 mmol) of 2-nitro-4-tert-butylbenzoic acid are hydrogenated with Pd-C (5%) in ethanol at room temperature until complete reaction. The reaction solution is filtered through kieselguhr, washed with EtOH and the filtrate is then concentrated. Yield: 6.35 g (80%) 1c, brown solid 0

To a solution of 50 g (0:29 mol) of 2-amino-4-chlorobenzoic acid 1a in 160 o ml of dimethylformamide is added a solution of 39 ml (0:32 moles) isovaleric acid chloride in 40 ml DMF were added dropwise so that the temperature does not exceed 40 ⁰ C is rising. The reaction mixture is stirred for 2 h at room temperature and then stirred into about 1.5 L of water. The precipitated product is filtered off, washed with water and dried in vacuo. 5 Yield: 49.7 g (67%) 2a, pale yellow crystals

To a solution of 5 g (24.37 mmol) of 2-amino-4-trifluoromethyl-benzoic acid 1 b in 30 ml of dimethylformamide is added dropwise a solution of 3.3 ml (26.81 mol) of isovaleryl chloride in 5 ml of DMF so that the temperature does not exceed 40 ° C is rising. The reaction mixture is stirred for a further 2 hours at room temperature and then stirred into about 120 ml of water. The precipitated product is filtered off with suction, taken up in ethyl acetate and washed with NaHCO ₃ solution, water and saturated NaCl solution, dried with sodium sulfate, filtered and evaporated. Yield: 4.1 1 g (58%) 2b, yellow-brown oil

To a solution of 3.73 g (19.29 mmol) of 2-amino-4-tert-butylbenzoic acid 1c and 2.94 ml (21 .22 mmol) of triethylamine in 23 ml of dimethylformamide at 0-5 ° C, a solution of 2.6 ml (21.22 mol) Isovaleriansäurechlorid added dropwise in 3 ml of DMF and then the reaction mixture warmed to room temperature. After addition of a further 0.78 ml (6.37 mmol) of isovaleryl chloride, stirring is continued for 1 h at room temperature, then the reaction mixture is stirred into about 120 ml of water and extracted with ethyl acetate. The combined organic phases are washed with NaHCO ₃ solution, water and saturated NaCl solution, dried with sodium sulfate, filtered and evaporated. Yield: 1 .9 g (36%) of 2c, brown oil

49 g (0.19 mol) of 2a are suspended in 170 ml of acetic anhydride and heated to give a clear solution. The formed acetic acid is distilled off from the reaction mixture during the reaction. After 2 h, the reaction mixture is cooled to room temperature and concentrated on a rotary evaporator to the residue. The oily residue crystallizes on standing in the refrigerator. The crystals are triturated with petroleum ether, filtered off with suction and dried. Yield: 39.1 g (86%) 3a, light brown crystals

4.1 g (14.06 mol) of 2b are suspended in 20 ml of acetic anhydride and heated. The formed acetic acid is distilled off from the reaction mixture during the reaction. After 1.5 h, the reaction mixture is cooled to room temperature and concentrated to the residue on a rotary evaporator. The pulpy residue is taken up in ethyl acetate, washed with NaHCO ₃ solution, water and saturated NaCl solution, dried with sodium sulfate, filtered and evaporated. Yield: 3.44 g (76%) 3b, yellow-brown oil

1.9 g (6.85 mol) of 2c are suspended in 32 ml of acetic anhydride and heated. The formed acetic acid is distilled off from the reaction mixture during the reaction. After 3.5 h, the reaction mixture is cooled to room temperature and concentrated on a rotary evaporator to the residue. The residue is taken up in ethyl acetate, washed with NaHCO ₃ solution, water and saturated NaCl solution, dried with sodium sulfate, filtered and evaporated. Yield: 1.73 g (97%) 3c, light brown solid

39.1 g (0.165 mol) of 3a are dissolved in 250 ml of THF, mixed with 21.7 ml (0.198 mol) of benzylamine and stirred at 65 ⁰ C for 2 h. The reaction mixture is evaporated to dryness, taken up with 140 ml of ethylene glycol, admixed with 0.66 g (0.017 mol) of NaOH and stirred at 135 ° C. for 1.5 h. The reaction mixture is cooled to room temperature, treated with about 150 ml of water and neutralized with 1 M HCl (pH 7-8). That oiled Product slowly and crystallized after a short time. The crystals are filtered off, washed with water, sucked dry and dried. Yield: 53.6 g (100%) 4a, pale yellow crystals

2.8 g (10.34 mmol) of 3b are dissolved in 20 ml of THF, treated with 1.4 ml (12.8 mmol) of benzylamine and stirred at 65 ⁰ C for 2 h. The reaction mixture is evaporated to dryness, taken up with 12 ml of ethylene glycol, admixed with 285 mg (7.13 mmol) of NaOH and stirred at 135 ^° C. for 2 h. The reaction mixture is cooled to room temperature, mixed with about 15 ml of water and neutralized with 1 M HCl (pH 7-8). The product slowly oiled out. The supernatant phase is decanted off, the oily residue taken up in ethyl acetate, washed with water, dried with Na ₂ SO ₄ , filtered and evaporated. The residue is purified by chromatography (120 g of silica gel, eluent: petroleum ether / MTB ether - 9: 1). Yield: 3.68 g (99%) 4b, light brown solid

2.18 g (8.41 mmol) of 3c are dissolved in 20 ml of THF, treated with 1.09 ml (10.33 mmol) of benzylamine and stirred at 65 ⁰ C for 1.5 h. The reaction mixture is concentrated to the residue, taken up with 15 ml of ethylene glycol, treated with 238 mg (5.96 mmol) of NaOH and stirred at 135 ⁰ C for 3.5 h. The reaction mixture is cooled to room temperature, treated with about 20 ml of water and neutralized with 1 M HCl (pH 7-8). The product slowly oiled out. The supernatant phase is decanted off, the oily residue taken up in ethyl acetate, washed with water, dried with Na ₂ SO ₄ , filtered and evaporated. The residue is purified by chromatography (120 g of silica gel, eluent: petroleum ether / MTB ether - 9: 1). Yield: 2.63 g (90%) 4c, light brown oil

To a solution of 53 g (0.162 mol) 4 and 17.3 g (0.211 mol) of sodium ml in 250 of glacial acetic acid a solution of 9.1 ml of bromine (0.178 mol) is slowly added dropwise in 25 ml of glacial acetic acid at 40 ⁰ C while keeping the temperature at 40 -42 ⁰ C held. After 1 h stirring at 40 ⁰ C, the reaction mixture is cooled to room temperature and stirred into about 2 L of water. The product failed as sticky-tough mass. The supernatant is decanted off and the residue is dissolved in ethyl acetate. The solution is washed with saturated NaHCO ₃ solution, water and saturated NaCl solution, dried over Na ₂ SO ₄ , filtered and evaporated. Yield: 65 g (99%) 5a, yellow oil

To a solution of 3.68 g (10.2 mmol) of 4b and 1.09 g (13.26 mmol) of sodium acetate in 15 ml of glacial acetic acid is slowly added dropwise at 40 ° C, a solution of 0.58 ml of bromine (11.22 mmol) in 5 ml of glacial acetic acid while the temperature at 40 -42 ⁰ C held. After 4.5 h stirring at 40 ⁰ C, the reaction mixture is cooled to room temperature, stirred into about 200 ml of water and stirred for about 1 h. The precipitate is filtered off, dissolved in ethyl acetate and washed with saturated NaHC0 ₃ solution, water and saturated NaCl solution, dried over Na ₂ SO ₄ , filtered and evaporated. Yield: 4.39 g (98%) 5b, pale yellow crystals

To a solution of 2.18 g (6.27 mmol) 4c, and 669 mg (8.15 mmol) of sodium ml in 10 of glacial acetic acid a solution of 0.42 ml of bromine (28.8 mmol) is slowly added dropwise in 5 ml of glacial acetic acid at 40 ⁰ C while keeping the temperature at 40 -42 ⁰ C held. After 3 h stirring at 40 ⁰ C, the reaction mixture is cooled to room temperature and stirred into about 200 ml of water. The precipitate is filtered off, dissolved in ethyl acetate and washed with Washed with saturated NaHCO ₃ solution, water and saturated NaCl solution, dried over Na ₂ SO ₄ , filtered and evaporated. The residue is purified by chromatography (120 g silica gel, eluent: petroleum ether / MTB ether - 9: 1). Yield: 2.55 g (95%) 5c, light brown oil

1 g (2.47 mmol) of 5a is dissolved in 20 ml of dimethyl sulfoxide, mixed with 177 mg (2.71 mmol) of potassium cyanide and stirred at 50 ⁰ C for 2 h. The solution is poured into 400 ml of water and extracted several times with ethyl acetate. The combined organic phases are washed with water and saturated NaCl solution, dried with Na ₂ SO ₄ , filtered and evaporated. The oily residue is mixed with a little diethyl ether and rubbed on the flask wall until onset of crystallization with a spatula. The crystals are filtered off with suction and washed with a little ether. From the filtrate by chromatography (12 g silica gel, eluent: DCM / petroleum ether - 92: 5) further product recovered. Yield: 546 mg (63%) 6a

4:35 g (9.89 mmol) 5b is dissolved in 50 ml of dimethyl sulphoxide, treated with 709 mg (10.88 mmol) of potassium cyanide and stirred for 4.5 h at 50 ⁰ C. The solution is poured into 600 ml of water and extracted several times with ethyl acetate. The combined organic phases are washed with water and saturated NaCl solution, dried with Na ₂ SO ₄ , filtered and evaporated. The residue is purified by chromatography (120 g of silica gel, eluent: petroleum ether / MTB ether - 9: 1). The product thus obtained is crystallized by digestion with diethyl ether, the crystals are filtered off with suction, washed with a little ether and then dried in vacuo. Yield: 2.1 g (55%) 6b, pale yellow crystals

3.08 g (7.22 mmol) of 5c is dissolved in 40 ml of dimethyl sulfoxide, treated with 517 mg (7.94 mmol) of potassium cyanide and stirred at 50 ⁰ C for 2.5 h. The solution is poured into 500 ml of water and extracted several times with ethyl acetate. The combined organic phases are washed with water and saturated NaCl. Washed solution, dried with Na ₂ SO ₄ , filtered and evaporated. The residue is purified by chromatography (120 g silica gel, eluent: DCM / petroleum ether - 8: 2). Yield: 1.66 g (61%) 6c

146 mg (0.41 mmol) 6a are hydrogenated with Raney nickel in THF at 40 ⁰ C and 3 bar in the presence of trifluoroacetic acid until complete reaction. The reaction solution is filtered through kieselguhr, the filtrate is diluted with ethyl acetate and washed 2 × with water and saturated NaHCO ₃ solution. The organic phase is dried over Na ₂ SO ₄ , filtered and evaporated. The residue is purified by chromatography (12 g silica gel, eluent: DCM, later DCM / MeOH - 9: 1). Yield: 118 mg (80%) 7a, yellow oil

0.5 g (1.3 mmol) 6b are hydrogenated with Raney nickel in methanolic ammonia solution at 50 ⁰ C and 5 bar until complete reaction. The Reaction solution is filtered through kieselguhr and then the filtrate is concentrated.

Yield: 0.5 g (99%) 7b, yellow oil

465 mg (1.25 mmol) 6c are hydrogenated with Raney nickel in methanolic ammonia solution at 50 ⁰ C and 5 bar until complete reaction. The reaction solution is filtered through kieselguhr and then the filtrate is concentrated. Yield: 448 mg (95%) 7c, brown oil

Compound 7a or 7b (1 equiv.) Is dissolved in methanol together with an aldehyde (1 equiv; R ² -CHO), treated with sodium cyanoborohydride (0.7 equiv.) And stirred at room temperature overnight. The reaction mixture is evaporated, the residue dissolved in ethyl acetate and washed with saturated NaHCO ₃ solution and saturated NaCl solution, with Na ₂ SO ₄ dried, filtered and evaporated. The residue is purified by flash chromatography.

8a: R ¹ = CF ₃ , R ² = (CH ₂ ) ₂ NH-Boc; Purification: 4 g of silica gel, eluent: dichloromethane / methanol (100: 0 - 90:10 in 40 min); Yield: 40%

8b: R ¹ = CF ₃ , R ² = (CH ₂ ) ₃ NH-Boc; Purification: 4 g of silica gel, eluent: dichloromethane / methanol (100: 0 - 90:10 in 40 min); Yield: 26% 8c: R ¹ = CF ₃ , R ² = (CH ₂ ) ₂ NH (CH ₃ ) ₂ ; Purification: 4 g of silica gel, eluent: dichloromethane / methanol + 1% NH ₃ 100: 0 - 90:10 in 40 min); Yield: 38% 8d: R ¹ = CF ₃ , R ² = CH ₂ Ph; Purification: 4 g of silica gel, eluent: petroleum ether / ethyl acetate (8: 2-4: 6 in 40 min); Yield: 31% 8e: R ¹ = CF ₃ , R ² = (CH ₂ ) ₂ Ph; Purification: 4 g of silica gel, eluent: dichloromethane / methanol (100: 0 - 95: 5 in 40 min); Yield: 30% 8f: R ¹ = Cl, R ² = (CH ₂ ) ₂ NH-Boc; Purification: 12 g of silica gel, eluent: dichloromethane / methanol (100: 0 - 96: 4); Yield: 56%

8g: R ¹ = Cl, R ² = (CH ₂ ) ₃ NH-Boc; Purification: 12 g of silica gel, eluent: dichloromethane / methanol (100: 0 - 96: 4); Yield: 46% Compound 7b (1 equiv.) Is dissolved in dichloromethane together with N-ethyldiisopropylamine (1.5 equiv.), Treated with an acid chloride (1.1 equiv; R-COCl) and stirred for 2 hours at room temperature. The reaction mixture was diluted with dichloromethane, washed twice with water and with saturated NaCl solution, dried with Na ₂ SO ₄ , filtered and evaporated. The residue is freeze-dried.

8h: R = COPh; Yield: 99%

8i: R = COCH ₂ Ph; Yield: 99%

For cleavage of the protecting group 8a or 8b are stirred in DCM / TFA - 2/1 at room temperature until complete reaction. The reaction mixture is evaporated and the oily residue is freeze-dried overnight. 9a: R = CF ₃ , n = 2, yield: 98% 9b: R = CF ₃ , n = 3, yield: 99% 9c: R = Cl, n = 2, yield: 95% 9d: R = Cl, n = 3, yield: 99%

8a is initially charged at room temperature in acetonitrile, admixed with cesium carbonate (1.1 equiv.) And then benzyl bromide (1 equiv.) Is slowly added dropwise. The reaction mixture is stirred at room temperature overnight, diluted with ethyl acetate and washed 2x with water. The organic phase is dried with Na ₂ SO ₄ , filtered and evaporated. The residue is flash-chromatographed (4 g silica gel, eluent: petroleum ether / ethyl acetate 98: 2 - 90:10 in 45 min). Yield: 63%

Cleavage of the Boc protecting group analogous to 9a-d; Yield: 87%

8f, g are reacted and worked up analogously to the preparation of 9e. 9f: n = 2, Stufel, Yield: 62%; Cleavage of the Boc-protecting group, yield: 96%

9g: n = 3, Stufel, Yield: 53%; Cleavage of the Boc-protecting group, yield: 99%

9h: 8a is reacted and worked up analogously to the preparation of 8 h.

Yield: 99%

Cleavage of the Boc protective group analogous to 9a, b; Yield: 84%

9i: 8a is reacted and worked up analogously to the preparation of 8i.

Yield: 98%

Cleavage of the Boc protective group analogous to 9a, b; Yield: 100%

Reaction of 8f, g analogously to the preparation of 8i.

9j: n = 2, step, yield: 50%; Splitting off the Boc-protecting group,

Yield: 80%

9k: n = 3, Stufel, Yield: 93%; Splitting off the Boc-protecting group,

Yield: 86%

Compound 8f or 8g (1 equiv.) Is dissolved in methanol along with phenylacetaldehyde (1.1 equiv.), Treated with sodium cyanoborohydride (0.7 equiv.) And stirred at room temperature overnight. The reaction mixture is evaporated, the residue dissolved in ethyl acetate and washed with saturated NaHCO ₃ solution and saturated NaCl solution, dried with Na ₂ SO ₄ , filtered and evaporated. The residue is purified by flash chromatography.

200 mg (0.57 mmol) of potassium carbonate 6a and 393 mg (2.84 mmol) are suspended in 10 ml of methanol, admixed at room temperature with 0.141 ml (1.99 mmol) of dimethyl sulfoxide and 0.291 ml (2.84 mmol) of hydrogen peroxide and stirred for 30 min. The suspension is filtered off with suction and washed with a little MeOH and water. The crystals are dissolved in ethyl acetate and DCM, dried (Na ₂ SO ₄ ), filtered and evaporated (80 mg). The aqueous filtrate is extracted three times with ethyl acetate, the combined organic phases are washed with water, dried and evaporated. It is triturated with MeOH, filtered off with suction and washed with a little MeOH (40 mg). Yield: 120 mg (57%) 17, colorless crystals

Analogously, further compounds according to the invention are obtained using the corresponding precursors.

For example, starting from precursors 18a-c, the following compounds (19-22) are advantageously obtained according to the following reaction schemes:

18a: R = Cl; 18b: R = CF ₃ ; 18c: R = C (CH ₃ ) ₃ ;

The compounds 19 and 20 obtained according to the above reaction scheme can be separated and characterized by HPLC chromatography (column: Chromolith SpeedROD RP18e 50-4.6; gradient 5.5 min./flow: 2.75 ml (90:10 - 0: 100) H ₂ O + 0.01 vol% TFA: CH ₃ CN + 0.01 vol% TFA)), wavelength 220 nm, 19: Rt (retention time) = 2.79 min, 20: Rt = 2.41 min ).

The compound 21 obtained according to the above reaction scheme can be characterized by HPLC chromatography ^* (Rt = 2.91 min) and by mass spectroscopy (ESI-MS: M + 1 = 404.2).

The compound 22 obtained according to the above reaction scheme can be characterized by HPLC chromatography ^* (Rt = 3.05 min).

The compound 24 obtained according to the above reaction scheme can be characterized by HPLC chromatography ^* (Rt = 2.60 min) and by mass spectroscopy (ESI-MS: M + 1 = 480.15).

^* : HPLC chromatography according to the following method: Column: Chromolith SpeedROD RP18e 50-4.6; Gradient 5.5 min./flow: 2.75 ml (90:10 - 0: 100 (H ₂ O + 0.01 vol.% TFA: CH ₃ CN + 0.01 vol.% TFA)); Wave length 220 nm.

Example A: Assay I

The determination of the effectiveness of the compounds of the invention may, for. B. via the Eg5-ATPase activity, which is measured via an enzymatic regeneration of the product ADP to ATP by pyruvate kinase (PK) and subsequent coupling to an NADH-dependent lactate dehydrogenase (LDH) reaction, take place. By coupling to the NADH-dependent LDH, the reaction can be monitored by changing the absorbance at 340 nm. The regeneration of the ATP simultaneously ensures that the substrate concentration remains constant. The absorbance changes per unit time are analyzed graphically and linear regression is performed in the visually linear region of the reaction.

Example B: Assay II

The combination of the antiprotozoic pentamidine and the inhibitors of kinesin ATPase Eg5 / KSP leads to increased inhibitory effects in cell proliferation tests with the colon carcinoma cell line HCT116. Eg5 inhibitors interfere with ATPase activity and inhibit the progression of the cell cycle due to a spindle pole separation error.

The determination of the activity of the compounds of the formula I according to the invention in combination with compounds of the formula VI and / or medicaments of the table I can be shown in combination assays as follows:

10 ³ to 10 ⁴ cells of a defined cell line (HCT116, CoIo 205, MDA-MB 231, etc.) are seeded per well in a 96-well microtiter plate and cultured overnight under standard conditions. For the substances of the combination to be tested, 10-50 mM stock solutions in DMSO were prepared. Dilution series (usually 3-fold dilution steps) of the individual substances were combined in the form of a pipetting scheme (see scheme below) while maintaining a final DMSO concentration of 0.5% (v / v). The cells were taken the next morning with the

Substituted mixtures and incubated for a further 48 hours under culture conditions. At the end of the cultivation, a crystal violet staining of the cells was performed. After extracting the crystal violet from the fixed cells, absorbance at 550 nm was measured spectrophotometrically. It can be used as a quantitative measure of the existing adherent cells.

scheme

Compounds of the formula I

1 2 4 5 6 7 8 9 10 11 12

The following examples relate to drugs:

Example C: Injection glasses

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

Example D: Suppositories

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

Example E: Solution

A solution of 1 g of an active compound of the formula I, 9.38 g of NaH ₂ PO ₄ • 2H ₂ O, 28.48 g of Na ₂ HPO ₄ • 12H ₂ O and 0.1 g of benzalkonium chloride in 940 is prepared ml of double distilled water. Adjust to pH 6.8, make up to 1 liter and sterilize by irradiation. This solution can be used in the form of eye drops.

Example F: ointment

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

Example G: Tablets

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

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

Example I: Capsules

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

Example J: Ampoules

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

Claims

claims

1. Compounds of the formula I

wherein

R ¹ , R ² , R ³ and R ⁴ independently of one another are H ₁ A ₁ Ar, Het, OR ^a , SR ^a , OAr, SAr, N (R ^a ) ₂ , NR ³ Ar, Hal, NO ₂ , CN, ( CH ₂ ) m COOR ^a , (CH ₂ ) _m COOAr, (CH ₂ ) _m CON (R ^a ) ₂₎ (CH ₂ ) _m CONHAr, COR ³ , COAr, S (O) _1n A ₁ S (O) _m Ar , NHCOA, NHCOAr, NHSO ₂ A,

NHSO ₂ Ar or SO ₂ N (R ^a ) ₂ ,

R ^{a is} H, A, Ar, Het, aralkyl or hetero-aralkyl,

R ⁵ , R ^{8 are} independently H, A, Ar, Het, aralkyl or

Hetero-aralkyl, and

R ⁶ , R ^{7 are} independently H, A, Ar, Het, aralkyl or

Hetero-aralkyl, or

Y ^{1 represents} O, S or NR ¹ , Z ¹ , Z ^{2 are} independently of one another (CR ⁹ R ¹⁰ ) _n and (CR ⁹ R ¹⁰ ) _p -

(C = Y ² ) - (CR ¹¹ R ¹² ) _{q are} selected,

Z ³ is absent or independently selected from the meanings given for Z ¹ and Z ² ,

A is alkyl or cycloalkyl,

Ar is aryl or heteroaryl,

Heteroaryl or heterocyclyl,

HaI F, Cl, Br or I,

Y ² O, S or NR ² ,

k is 0, 1 or 2, preferably 0 or 1,

m is 1, 2, 3 or 4, preferably 0, 1, 2 or 3

n is 1, 2, 3, 4, 5 or 6, and

p, q are independently 0, 1, 2, 3 or 4,

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

2. Compounds according to claim 1, selected from compounds of the formula Ia,

wherein

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , Y ¹ and Z ^{1 have} the meanings given in claim 1;

and compounds of the formula

wherein

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , Y ¹ , Z ¹ , Z ² and Z ^{3 have} the meanings given in claim 1; and their pharmaceutically usable derivatives, solvates, tautomers, salts and stereoisomers, including mixtures thereof in all ratios.

3. Compounds according to claim 1 or 2, wherein

R ² A, CF ₃ , OCF ₃ , SA, SCN, CH ₂ CN, -OCOA, Hal, SCF ₃ , t-

Butyl, -CH (CH ₃ ) CH ₂ CH ₃ , isopropyl, ethyl or methyl

means; and

R ³ A, CF ₃ , OCF ₃ , SA, SCN, CH ₂ CN, -OCOA, Hal, SCF ₃ , t-

Butyl, -CH (CH ₃ ) CH ₂ CH ₃ , isopropyl, ethyl or methyl.

4. Compounds according to any one of claims 1 to 3, wherein

R ¹ and R ⁴ independently of one another are either H or are selected from A, CF ₃ , OCF ₃ , OR ^a , SA, S (O) ₂ A,

S (O) A, CH ₂ CN, COOA, CONHA, Hal, SCF ₁ CN and Het.

5. Compounds according to any one of claims 1 to 4, wherein

R ^{5 is} selected from Ar, aralkyl and hetero-aralkyl,

R ⁶ , R ^{7 are} independently selected from H, A, Ar and aralkyl, and R ^{8 is} selected from H, A, Ar and Het.

6. Compounds according to any one of claims 1 to 5, wherein

R ^{5 is} unsubstituted or substituted benzyl, and

R ^{8 is} unsubstituted or substituted phenyl.

7. Compounds according to one of claims 1 to 6, selected from the subformulae IA to IR:

20

30

wherein have the meanings given in any one of claims 1 to 6,

is 1, 2, 3 or 4, s and t are independently 0, 1 or 2,

Y ^{3 is} O, S or NR ^a ,

R ^c and R ^{d are} independently selected from the meanings given for R ¹ to R ⁴ , and

u and v independently of one another are O, 1, 2 or 3,

and their pharmaceutically usable derivatives, solvates,

Tautomers, salts and stereoisomers, including mixtures thereof in all ratios.

8. Compounds according to one of claims 1 to 7, selected from: 2- (1 - {[(2-aminoethyl) benzylamino] methyl} -2-methyl-propyl) -3-benzyl-

7-trifluoromethyl-3H-quinazolin-4-one;

3-benzyl-2- [1- (benzylamino-methyl) -2-methyl-propyl] -7-trifluoromethyl-

3H-quinazolin-4-one;

2- {1 - [(2-Amino-ethylamino) -methyl] -2-methyl-propyl} -3-benzyl-7-trifluoromethyl-3H-quinazolin-4-one;

N- (2-aminoethyl) -N- [2- (3-benzyl-4-oxo-7-fluoromethyl-3,4-dihydroquinazolin-2-yl) -3-methyl-butyl] -benzamide;

N- [2- (3-Benzyl-4-oxo-7-trifluoromethyl-3,4-dihydro-quinazolin-2-yl) -3-methyl-butyl] -benzamide; N- [2- (3-benzyl-4-oxo-7-trifluoromethyl-3,4-dihydro-quinazolin-2-yl) -3-methylbutyl] -2-phenylacetamide;

N- (2-aminoethyl) -N- [2- (3-benzyl-4-oxo-7-fluoromethyl-3,4-dihydroquinazolin-2-yl) -3-methyl-butyl] -2- phenyl-acetamide;

2- {1 - [(3-Amino-propylamino) -methyl] -2-methyl-propyl} -3-benzyl-7-trifluoromethyl-3H-quinazolin-4-one;

3-benzyl-2- {1 - [(2-dimethylamino-ethylamino) -methyl] -2-methyl-propyl} -

7-trifluoromethyl-3H-quinazolin-4-one; 3-Benzyl-2- [2-methyl-1- (phenethylamino-methyl) -propyl] -7-trifluoromethyl-3H-quinazolin-4-one;

2- {1 - [(2-Amino-thylamino) -methyl] -2-methyl-propyl} -3-benzyl-7-chloro

3H-quinazolin-4-one; N- (2-Amino-ethyl) -N- [2- (3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazoline

2-yl) -3-methyl-butyl] -2-phenyl-acetamide;

2- (1 - {[(2-Amino-ethyl) -benzyl-amino] -methyl} -2-methyl-propyl) -3-benzyl

7-chloro-3H-quinazolin-4-one;

2- (1 - {[(2-Amino-ethyl) -phenethyl-amino] -methyl} -2-methyl-propyl) -3-benzyl-7-chloro-3H-quinazolin-4-one;

2- {1 - [(3-Amino-propylamino) -methyl] -2-methyl-propyl} -3-benzyl-7-chloro

3H-quinazolin-4-one;

N- (3-Amino-propyl) -N- [2- (3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazoline

2-yl) -3-methyl-butyl] -2-phenyl-acetamide; 2- (1 - {[(3-Amino-propyl) -benzyl-amino] -methyl} -2-methyl-propyl) -3-benzyl-7-chloro-3H-quinazolin-4-one;

2- (1 - {[(3-Amino-propyl) -phenethyl-amino] -methyl} -2-methyl-propyl) -3-benzyl-7-chloro-3H-quinazolin-4-one;

2- (1-Aminomethyl-2-methyl-propyl) -3-benzyl-6,7-dichloro-3H-quinazolin-4-one;

2- (1-Amino-methyl-2-methyl-propyl) -3-benzyl-7-chloro-6-fluoro-3H-quinazolin-4-one;

2- (1-Amino-methyl-2-methyl-propyl) -3-benzyl-7-chloro-6-methyl-3H-quinazolin-4-one; 2- (3-Benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl) -3-methylbutyramide;

2- (1-Aminomethyl-2-methyl-propyl) -3-benzyl-3H-quinazolin-4-one;

2- (1-Amino-methyl-2-methyl-propyl) -3-benzyl-7-chloro-3H-quinazolin-4-one; 2- (1-Aminomethyl-2-methyl-propyl) -3-benzyl-7-tert-butyl-3H-quinazoline

4-one; 2- (1-aminomethyl-2-methyl-propyl) -3-benzyl-7-trifluoromethyl-3H-quinazolin-4-one;

N- [2- (3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl) -3-methyl-butyl] -acetamide; N- [2- (3-Benzyl-4-oxo-3,4-dihydro-quinazolin-2-yl) -3-methyl-butyl] -acetamide;

3-benzyl-2- [1- (benzylamino-methyl) -2-methyl-propyl] -7-trifluoromethyl-

3H-quinazolin-4-one; and the pharmaceutically acceptable derivatives, solvates, salts and

Stereoisomers thereof, including mixtures of the forms in all ratios, and preferably the salts and / or solvates thereof, and in particular the physiologically acceptable salts and / or solvates thereof.

9. A process for the preparation of compounds of the formula I according to claims 1 to 8 and their pharmaceutically acceptable

Derivatives, salts, solvates, tautomers and stereoisomers, characterized in that

a) a compound of formula II

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , Y ¹ and Z ^{1 have} the meanings given in any one of claims 1 to 4, X is O is NH or S, and LG ¹ and LG ^{2 are} each one Leaving group is, while removing the leaving group LG ¹ cyclized to a compound of formula IIb;

b) reacting the compound of the formula IIb with a compound of the formula

wherein R ^{5 has} the meaning given in any one of claims 1 to 4, and L ² and L ^{3 are} independently H or a metal atom,

and thereby obtaining a compound of the formula Hc;

c) reacting the compound of the formula Hc with a compound of the formula IV,

wherein L ^{4 is} H or a metal atom and Z ² , Z ³ , k, R ⁶ , R ⁷ and R ^{8 have} the meanings given in any one of claims 1 to 4,

d) isolating the resulting compound of formula I and / or with a

Acid or a base treated to convert them into one of their salts.

10. A process for the preparation of compounds according to any one of claims 1 to 8 and their pharmaceutically acceptable

a) a compound of formula II '

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁹ , X and Y ¹ have the meanings given in any one of claims 1 to 4 and 9 have meanings, LG ^{1 is} a leaving group, with removal of the leaving group LG ¹ cyclized to a compound of formula IIb;

b) the compound of formula IIb 'by reaction with a compound of formula III

and introducing a leaving group LG v3 into a compound of formula Hc ';

c1) converting the compound of the formula Mc 'by reaction with cyanide into a compound of the formula Nd';

c2) converting the compound of formula Md 'under reductive conditions into a compound of formula I';

and optional either

c3a) the compound of the formula I 'obtained in step c2)

Reaction with a compound FG ¹ -R ⁶ and / or FG ² -R ⁷ in a compound of formula I ", ie a compound of formula I, wherein k is 0, Z ^{1 is} -CHR ⁹ -CH ₂ - and wherein R ⁶ and / or R ⁷ are different from H; or

c3b) the compound of the formula I 'obtained in step c2)

Reaction with a compound of the formula FG ³ -Z ² -NR ⁶ R ⁷ and optionally a compound FG ⁴ -Z ³ -R ⁸ , wherein FG ³ and FG ^{4 are} each a functional group, converted into a compound of formula I '";

and optional

d) the compound obtained in step c2), C3a) or c3b) isolated according to any one of claims 1 to 8 and / or treated with an acid or a base to convert them into one of its salts.

11. A pharmaceutical composition comprising at least one compound of the formula I according to claim 1 to 8 and / or pharmaceutically usable derivatives thereof,

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

12. Mixture comprising one or more compounds of the formula I and also one or more compounds of the formula VI, their analogues and / or their metabolites,

Wonn

Y 'and Z' each independently represents O or N, R ⁹ and R ¹⁰ are each, independently of one 5 H, OH, halogen, OCI-10-alkyl,

OCF ₃ , NO ₂ or NH ₂ , n is an integer between 2 and 6 inclusive, and R ⁸ and R ^{11 are} each independently at the meta or para position and from the group: 10

are selected.

20

13. Use according to claim 12, wherein pentamidine or its salts are used as the compound of formula VI.

14. Use of compounds according to claim 1 to 8 and their pharmaceutically usable derivatives, salts, solvates, tautomers and stereoisomers, including mixtures thereof in all proportions or the mixture according to claim 12, for the manufacture of a medicament for the treatment of diseases.

of]

15. Use according to claim 14, characterized in that the diseases can be influenced by the inhibition, regulation and / or modulation of the mitotic motor protein Eg5.

16. Use of compound according to claim 1 to 8 or the mixture according to claim 12, for the manufacture of a medicament for the treatment and prophylaxis of cancer diseases.

17. Use according to any one of claims 14 to 16, wherein the cancerous diseases with a tumor from the group of tumors of the squamous epithelium, the bladder, the stomach, the kidneys, the head and neck, the esophagus, the cervix, the thyroid, the intestine , liver, brain, prostate, genitourinary tract, lymphatic system, stomach, larynx and / or lungs.

Use according to claim 17, wherein the tumor is selected from the group monocytic leukemia, lung adenocarcinoma, small cell

Lung cancer, pancreatic cancer, glioblastoma and breast carcinoma and colorectal carcinoma.

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

The use of claim 19, wherein the tumor is from the group of acute myeloid leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia and / or chronic lymphocytic leukemia.

21. Use of compounds of the formula I according to claim 1 to 12 and / or their physiologically acceptable salts and solvates for the manufacture of a medicament for the treatment of tumors in combination with a therapeutically effective amount of one or more compounds of formula VI, their analogs and / or its metabolites,

wherein

Y 'and Z' are each independently O or N, R ⁹ and R ^{10 are} each independently of another H, OH, halogen, OC 1-10 alkyl, OCF ₃ , NQ ₂ or NH ₂ , n is an integer between 2 and 6, each inclusive, and R ⁸ and R ^{11 are} each independently at the meta or para position and from the group:

are selected, wherein

the compounds of formula I and the compounds of formula VI, their analogues and / or their metabolites are administered simultaneously or within 14 days of each other in amounts sufficient to inhibit the growth of a tumor or other hyperproliferative cells.

22. Use according to claim 21, wherein pentamidine or its salts are used as the compound of formula VI.

23. Use of compounds of the formula I according to claim 1 to 8 and / or their physiologically acceptable salts and solvates

Preparation of a medicament for the treatment of tumors wherein a therapeutically effective amount of a compound of formula I in combination with radiotherapy and a compound from the group 1) estrogen receptor modulator, 2) androgen receptor modulator, 3) retinoid receptor modulator, 4) cytotoxic agent, 5) antiproliferative agent,

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