WO2004030671A2 - Use of 4-amino-quinazolines as anti cancer agents - Google Patents

Abstract

Use of Quinazolines of the formula (I) in which R, R1, R2, R3, R4 and Y have the meaning indicated in claim 1, and their salts or solvates as PKB inhibitors for the treatment of hyperproliferative disorders.

Description

Use of 4-amino-quinazolines as anti cancer agents

FIELD OF THE INVENTION ^"

The present invention provides compositions and methods for modulating the activity of PKB. In particular, this invention relates to 4-amino- quinazolines and there salts or solvates, that specifically bind with the human PKB protein. Such compounds have been shown to inhibit the activity of PKB.

BACKGROUND OF THE INVENTION

One of the principal mechanisms by which cellular regulation is effected is through the transduction of extracellular signals across the membrane that in turn modulate biochemical pathways within the cell. Protein phosphorylation represents one course by which intracellular signals are propagated from molecule to molecule resulting finally in a cellular response. These signal transduction cascades are highly regulated and often overlapping as evidenced by the existence of many protein kinases as well as phosphatases. Phosphorylation of proteins occurs predominantly at serine, threonine, or tyrosine residues and protein kinases have therefore been classified by their specificity of phosphorylation site i.e. serine/threonine kinases and tyrosine kinases. Because phosphorylation is such a ubiquitous process within cells and because cellular phenotypes are largely influenced by the activity of these pathways, it is currently believed that a number of disease states and/or disorders are a result of either aberrant activation or functional mutations in the molecular components of kinase cascades. Consequently, considerable attention has been devoted to the characterization of these proteins and compounds that are able to modulate there activity ( for a review see: Weinstein-Oppenheimer et al. Pharma. &. Therap., 2000, 88, 229-279).

The protein kinase PKB (also known as AKT and RAC-PK ) is a member of the AKT/PKB family of serine/threonine kinases and has been shown to be involved in a diverse set of signaling pathways in human malignancy (Nicholson et al., Cell. Signal., 2002, 14, 381-395. PKB, like other members of the AKT/PKB family is located in the cytosol of unstimulated cells and translocates to the cell membrane following stimulation. PKB translocation can be activated by several ligands including platelet derived growth factor, epidermal growth factor, basic fibroblast growth factor, cellular stress such as heat shock and hyperosmolarity as well as insulin (Bos, Trends Biochem. Sci., 1995, 20, 441-442) and other studies have shown that this activation is through PI3 kinase which is wortmannin sensitive (Franke et al., Science, 1997, 275, 665-668). Once localized to the plasma membrane, PKB has been shown to mediate several functions within the cell including apoptosis, the metabolic effects of insulin, induction of differentiation and/or proliferation, protein synthesis and stress responses (Alessi and Cohen, Curr. Opin. Genet. Dev., 1998, 8, 55-62; Downward, Curr. Opin. Cell Biol., 1998, 10, 262-267).

PKB was cloned independently in 1991 by three groups (Bellacosa et al., Science, 1991 , 254, 274-277; Coffer and Woodgett, Eur. J. Biochem., 1991, 201 , 475-481 ; Jones et al., Cell Regul., 1991 , 2, 1001- 1009) but its association with primary human gastric carcinoma was recognized as early as 1987 (Staal et al., Proc. Natl. Acad. Sci. U S A, 1987, 84, 5034-5037). Sequencing of PKBα revealed homology within the kinase domains to the PKA (-68%) and PKC isozymes (-73%) (Jones et al., Proc. Natl. Acad. Sci. U.S.A., 1991 , 88, 4171-5) a fact that lent to its renaming as PKB. There are three cellular isoforms of PKB and two splice variants (PKBα, β, γ, βt, γ-^*; Brazil, et al. Trends in Bio Sci, 2001 , 26, 657-663). PKBct was found to be amplified or overexpressed in gastric adenocarcinomas and in a breast cancer cell line (Staal et al., Proc. Natl. Acad. Sci. U.S.A., 1887, 84, 5034-7. ;Jones et al., Cell Regul., 1991 , 2, 1001-9). PKBβ is amplified or overexpressed in 3% of breast (Bellacosa etal., Int. J. Cancer, 1995 64, 280-5), 12% of pancreatic (Cheng et al., Proc. Natl. Acad. Sci. U.S.A., 1996, 93, 3636-41 ), and 15% of ovarian cancers (Bellacosa et al., Int. J. Cancer, 1995, 64, 280-5; Cheng et al., Proc. Natl. Acad. Sci. U.S.A., 1992, 89, 9267-71 ).

PKB7 is overexpressed in estrogen receptor-deficient breast cancer and in androgen-independent prostate cell lines (Nakatani et al., J. Biol. Chem. 1999, 274, 21528-32).

PKB has been proposed to be a gene involved in chromosomal rearrangement at chromosome band 14q32. This locus is known to undergo rearrangement in human T-cell malignancies such as prolymphocytic leukemias, and mixed lineage childhood leukemias (Staal et al., Genomics, 1988, 2, 96-98).

PKB also plays a role in the prevention of "programmed cell death" or apoptosis by inhibitory phoshorylation of ASK-1 , Bad, Caspase9 and FKHR (for review see Nickolson et al., Cell Signaling 2001 , 14, 281-395). It has been demonstrated that PKB provides a survival signal (for review see Lawlor et al., J. of Cell Science 2001 , 114, 2903-2910) to cells protecting them from a number of agents including UV radiation (Dudek et al., Science, 1997, 275, 661-665), withdrawal of IGF1 from neuronal cells, detachment from the extracellular matrix, stress and heat shock (Alessi and Cohen, Curr. Opin. Genet. Dev., 1998, 8, 55-62).

The dual specific phosphatase PTEN ( phosphatase and tensin homologue deleted on chromosome ten) increases the Ptdlns(3, 4, 5)P₃ level in the cell by dephosphorylation of Ptdlns(3, 4, 5)P₃. Ptdlns(3, 4, 5)P₃ binds to the PH domain ( Pleckstrin homology domain) of PKB. This binding is an essential step for membrane translocation and activation of PKB. PTEN is a tumor suppressor gene mutated in a large fraction of glioblastoma and melanoma cell lines, advances prostate cancers and endometrial cancers. Furthermore it is deleted in >80 % of patients with inherited conditions such as Cowden disease, Lhermitte-Duclose disease and Bannayan Zonana Syndrome. The patients display several similar features, including multiple benign tumors (harmatomas), and an increased susceptibility to breast and thyroid malignancies (Di Cristofano et al. Cell, 2000, 100, 387-390).

Cell lines derived from mice heterocygous for PTEN^+/" (heterocygous PTEN^"/_ mice are not viable) show increased Ptdlns(3, 4, 5)P₃ levels paralleled by increased PKB activity, with a concomitant decreased sensitivity to apoptosis (Di Christofano et al. Nat. Genet. 1998, 19, 348- 355; Stambolic et al., Cell, 1998, 95, 29-39, Myers et al., Proc. Natl. Acad. Si. U.S.A., 1998, 96 13513-13518).

PKB is also able to promote cell cycle progression by inhibiting p21 cell cycle inhibitor (Zhou et al.; Nat. Cell Biol., 2002,3, 245-252).

The identification of signal transduction pathway and the detection of cross talks can be performed by methods known in the art, for example cell line or transgenic animal models, for example according methods described therein.

The susceptibility of a particular cell to treatment with the subject compounds may be determined by in vitro testing. Typically a culture of the cell is combined with a subject compound at varying concentrations for a period of time sufficient to allow the active agents to induce cell death or inhibit migration, usually between about one hour and one week. For in vitro testing, cultured cells from a biopsy sample may be used. The viable cells left after treatment are then counted. Another test cell line would be a PTEN deficient cell line that shows enhanced PKB activity, concomitant by increase resistance to apoptotic inducers as e.g. cisplatin. A treatment with the subject compound would be overcome this apoptose resistance. For the identification of a signal transduction pathway and the detection of cross talks with other signaling pathways, cell culture ( e.g. Khwaja et al., EMBO, 1997, 16, 2783-93) models or transgenic animal models (White et al., Oncogene, 2001 , 20, 7064-7072) were generated by various scientists. For the examintion of particular steps in the signal transduction cascade, interfering compounds ( Stephens et al., Biochemical J., 2000, 351 , 95- 105) were used for signal modulation.

For the identification of kinase inhibitors various assay systems are available. In scintillation proximity assay ( Sorg et al., J. of. Biomolecular Screening, 2002, 7, 11-19) and flashplate assay the radioactive phosphorylation of a protein or peptide as substrate with γATP will be measured. In the presents of an inhibitory compound no or decreased radioactive signal is detectable. Furthermore homogeneous time-resolved fluorescence resonance energy transfer (HTR-FRET), and fluorescence polarization (FP) technologies are useful for assay methods (Sills et al., J. of Biomolecular Screening, 2002, 191-214).

Other non-radioactive ELISA based assay methods use specific phospho- antibodies (AB). The phospho-AB binds only the phosphorylated substrate. These binding is detectable with a second peroxidase conjugated anti sheep antibody by chemiluminescence (eet al., 2002, Biochem. J., immediate publication, manuscript BJ20020786).

These findings may explain the overexpression of PKB seen in cancer cells which allows preferential survival and proliferation of the carcinoma by avoiding the normal progression to apoptosis.

Currently, there are no known therapeutic agents which effectively inhibit the activity of PKB. Consequently, there remains a long felt need for additional agents capable of effectively inhibiting PKB function for the activation of pro apoptotic proteins in all kind of cancers as a chemotherapeutic agents. DESCRIPTION OF THE INVENTION

The invention relates to the use of substituted 4-amino-quinazolines of the formula I

in which R and R¹ are independently of each other H, A, OH, OA, Hal, N(R )₂, NO₂, CN, C(O)R², CON(R⁵)₂, COOR⁵, allyl, CH=CH-COOR⁵, CH=CHCON(R⁵)₂, SO₂A or phenyl, which is unsubstituted or mono-, di- or trisubstituted by A,

R² and R³ are independently of each other H, A, cycloalkyl, -Het³, -(CH₂)₀-OR⁵, -(CH₂)₀-OR⁶, -(CH₂)o-Het¹, -(CH₂)₀-NR⁵-Het¹, -(CHA)p-(CH₂)₀-N(R⁵)₂, -(CH₂)_p-(CHA)p-(CH₂)_m-Ar, -(CH₂)₀-Z-(CH₂)_q-N(R⁵)₂,

provided that R² and R³ together are not H, or NR²R³ together form a saturated monocyclic heterocyclic radical having 5 to 6 ring members, where 1 or 2 N atoms are present and the heterocyclic radical can be mono- or disubstituted by OH, Ar, OAr or arylalkyl, R⁴ is Ar or Het¹,

R⁵ is H or A,

R⁶ is benzo[1 ,3]dioxol-5-yl, Q is O or S,

Y is (CH=CH)_n,

Z is phenylene, cyclohexylene, -NR⁵-, O, -CH(OH)-, -CA₂- or

A is unbranched or branched alkyl having 1 to 6 carbon atoms,

Ar is phenyl, naphthyl or biphenyl, which is unsubstituted or mono-, di- or trisubstituted by A, OH, OA, cycloalkyloxy, ₀ O-(CH₂)_p-Ph, CF₃, OCF₃, Hal, CN, CHO, COA, COOR⁵,

N(R⁵)₂, NR⁵-COA, NO₂, SO₂N(R⁵)₂, mor, SO₂-mor, 5-methyl- 3-oxo-2,4-dihydropyrazol-2-yl, naphthyl or Het², Het¹ is a saturated, partially or completely unsaturated mono- or bicyclic heterocyclic radical having 5 to 10 ring members, _c where 1 or 2 N and/or 1 or 2 S or O atoms can be present and the heterocyclic radical can be mono- or disubstituted by A, Hal, OH, OA, CF₃, OCF₃, N(R⁵)₂, carbonyl oxygen, COOR⁵, Het², benzyl or phenyl which is unsubstituted or mono-, di- or trisubstituted by A, OH, OA, CF₃, OCF₃, Hal, CN, COOR⁵, 0 N(R⁵)₂, NO₂ or SO₂N(R⁵)₂,

Het² is a unsaturated mono- or bicyclic heterocyclic radical having

5 to 10 ring members, where 1 or 2 N and/or 1 or 2 S or O atoms can be present and the heterocyclic radical can be mono- or disubstituted by A, Hal, OH, OA, CF₃, OCF₃, N(R⁵)_{2 5} or COOR⁵,

Het³ is a partially or completely unsaturated mono- or bicyclic heterocyclic radical having 5 to 10 ring members, where 1 or 2 N atoms are present and the heterocyclic radical can be mono- or disubstituted by A, Hal, OH, OA, CF_3l OCF₃, N(R⁵)₂, Q SO₂A or COOR⁵ provided that the heterocyclic radical is not bondend via an N atom, Hal is F, CI, Br or I, mor is morpholin-4-yl,

Ph is phenyl, n is 1 or 2, m is 0, 1 , 2, 3, 4, 5 or 6, o is 1 , 2, 3, 4, 5, 6 or 7, p is 0, 1 , 2, 3 or 4, q is 1 , 2, 3 or 4, and their pharmaceutically tolerable salts and solvates for the preparation of a medicament for the treatment of hyperproliferative disorders.

Furthermore, the invention relates to the use of the substituted 4-amino- quinazolines of the formula I for the induction of anti proliferative and pro apoptotic proteins.

Compounds of formula I are described in WO 02/24666 A2.

Similar 4-amino substituted quinazolines are disclosed in WO 99/09986, Mastafanova, LI et al, Khim.-Farm.Zh. 1982, 16, 938-42 or DE 2135172.

The invention is based on the object of finding novel PKB inhibitors which can be used for the production of medicaments.

The invention is based on the object of finding novel compounds having valuable properties, in particular those which can be used for the production of medicaments.

It has been found that the compounds of the formula I and their salts or solvates have very valuable pharmacological properties together with good tolerability.

They act especially as PKB inhibitors, in particular competing with ATP. The bonding of ATP is a prerequisite for the phosphate transfer mediated by PKB. This action can be demonstrated, for example, by a method which is described by Alessi et al. EMBO L. 1996, 15, 6541-6551 can also be blocked by the compounds mentioned.

The invention relates furthermore to the use of compounds of the formula I and their salts or solvates, especially of compounds relating to group la to lc, for the preparation of a medicament for the treatment of hyperproliferative disorders.

The process for the preparation of these compounds and their salts or solvates, is characterized in that a) a compound of the formula I according to claims 1 to 4 is liberated from one of its functional derivatives by treating with a solvolysing or hydrogenolysing agent, or b) in stage 1 ) a compound of the formula 11

in which

R and R¹ have the meaning as given in Claims 1 to 4, is reacted with a compound of the formula III

in which R⁴ has the meaning indicated in Claims 1 to 4 and s is 0 or 1 , to give a compound of formula IV

in which R, R¹ and R⁴ have the meaning indicated in Claims 1 to 4 and s is O or 1 , in stage 2) a compound of formula IV as indicated above is reacted with a chlorinating agent to give a compound of formula V

in which R, R¹ and R⁴ have the meaning indicated in Claims 1 to 4 and s is 0 or 1 , and in stage 3) a compound of formula V as indicated above is reacted with a compound of formula VI

in which R² and R³ or NR²R³ have the meaning indicated in Claims 1 to 4, or in stage 1 ) a compound of the formula II

in which

R and R¹ have the meaning as given in Claims 1 to 4, is reacted with a chlorinating agent to give a compound of formula VII

in which

R and R¹ have the meaning as given in Claims 1 to 4, in stage 2) a compound of formula VII as indicated above is reacted with a compound of formula VI

in which R² and R³ or NR²R³ have the meaning indicated in Claims 1 to 4 to give a compound of formula VIII

in which R, R¹, R², R³ and NR²R³ have the meaning indicated in Claims

1 to 4 and in stage 3) a compound of formula VIII as indicated above is reacted with a compound of formula III

in which R⁴ has the meaning indicated in Claims 1 to 4 and s is 0 or 1 or a radical R, R¹, R², R³ and/or R⁴ is converted into another radical R, R¹, R², R³ and/or R⁴ by, for example reducing a nitro group, sulfonyl group or sulfoxyl group, etherifying an OH group or subjecting an OA group to ether cleavage, alkylating a primary or secondary amino group, partially or completely hydrolysing a CN group, - cleaving an ester group or esterifying a carboxylic acid radical, reacting an aryl bromide, aryl iodide, heteroaryl bromide or heteroaryliodide to give the corresponding coupling products by ^■ means of a Suzuki coupling with boronic acids, reacting a iodoquinazoline or bromoquinazoline to give the corresponding coupling products by means of a Stille coupling with allyltributyltin, reacting a iodoquinazoline or bromoquinazoline to give the corresponding coupling products by means of a Heck coupling with acrylates, - or carrying out a nucleophilic or electrophilic substitution, and/or a base or acid of the formula I is converted into one of its salts or solvates.

The compounds of the formula I can have a chiral center and therefore occur in a number of stereoisomeric forms. All these forms (e.g. R and S forms) and their mixtures (e.g. the RS forms) are included in the formula I.

The compounds according to the invention also include so-called prodrug derivatives, i.e. compounds of the formula I modified with, for example, alkyl or acyl groups, sugars or oligopeptides and which are rapidly cleaved in the body to give the active compounds according to the invention.

Furthermore, free amino groups as substituents of compounds of the formula I can be provided with appropriate conventional protective groups. Solvates of the compounds of the formula I are understood as meaning adducts of inert solvent molecules to the compounds of the formula I which are formed on account of their mutual power of attraction. Solvates are, for example, mono- or dihydrates or alcoholates.

The abbreviations used have the following meanings:

Ac acetyl,

Bu n-butyl,

DBU 1 ,8-diazabicyclo[5.4.0]undec-7-ene,

DMA dimethylacetamide,

DMF dimethylformamide, dppf 1 ,1'-bis(diphenylphosphino)ferrocene,

Et ethyl,

Me methyl,

Ph phenyl,

TEA triethylamine,

TFA trifluoroacetic acid.

In the above formulae, A is alkyl and has 1 to 6, preferably 1 , 2, 3 or 4 C atoms. Alkyl is preferably methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, additionally 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. A is preferentially methyl, ethyl, propyl, isopropyl, butyl or pentyl.

Ar is phenyl, naphthyl or biphenyl, which is unsubstituted or mono-, di- or trisubstituted by A, OH, OA, cycloalkyloxy, O-(CH₂)_p-Ph, CF₃, OCF₃, Hal, CN, CHO, COA, COOR⁵, N(R⁵)₂, NR⁵-COA, NO₂, SO₂N(R⁵)₂, mor, SO₂- mor, 5-methyl-3-oxo-2,4-dihydropyrazol-2-yl, naphthyl or Het².

Ar is preferentially phenyl, preferably - as indicated - mono- di- or trisubstituted phenyl, specifically preferentially phenyl, 2-, 3- or 4-methylphenyl, 2-, 3- or 4-ethylphenyl, 2-, 3- or 4-propylphenyl, 2-, 3- or 4-isopropylphenyl, 2-, 3- or 4-butylphenyl, 2-, 3- or 4-tert-butylphenyl, 2-, 3- or 4-aminophenyl, 2-, 3- or 4-N,N-dimethylaminophenyl, 2-, 3- or 4-sulfamoylphenyl, 2-, 3- or 4-nitrophenyl, 2-, 3- or 4-hydroxyphenyl, 2-, 3- or 4-methoxyphenyl, 2-, 3- or 4-ethoxyphenyl, 2-, 3- or 4-pentoxyphenyl, 2-,

3- or 4-phenoxyphenyl, 2-, 3- or 4-phenylmethoxyphenyl, 2-, 3- or 4- trifluoromethylphenyl, 2-, 3- or 4-trifluoromethoxyphenyl, 2-, 3- or 4- cyclopentyloxyphenyl, 2-, 3- or 4-carboxyphenyl, 2-, 3- or 4-(N,N- diethyl)sulfamoylphenyl, 2-, 3- or 4-cyanophenyl, 2-, 3- or 4-fluorophenyl, 2-, 3- or 4-chlorophenyl, 2-, 3- or 4-bromophenyl, 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, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dimethoxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-di(trifIuoromethyl)phenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5- di(phenylmethoxy)phenyl, 2-chloro-6-methylphenyl, 2-chloro-4- fluorophenyl, 3-bromo-6-fluorophenyl, 3,4,5-thmethoxyphenyl, 4-

(morpholin-4-yl)phenyl, 4-(morpholin-4-yl-sulfonyl)phenyl, 4-(5-methyl-3- oxo-2,4-dihydropyrazol-2-yl)phenyl, 4-(4,6-dimethoxy-pyrimidin-2-yl)phenyl, 3-(4,6-dimethoxy-pyrimidin-2-yl)phenyl, 4-(pyrid-3-yl)phenyl, 3-(pyrid-3- yl)phenyl, 4-(thiophen-2-yl)phenyl, 3-(thiophen-2-yl)phenyl, 4- (benzo[c]thiophen-2-yl)phenyl or 4-(naphthalen-1 -yl)phenyl.

Furthermore, however, Ar is also preferentially unsubstituted naphthyl or biphenyl - as indicated - or alternatively mono-, di- or trisubstituted biphenyl, specifically preferentially biphenyi-4-yl or biphenyl-3-yl, 2'-methylbiphenyl-4-yl, 3'-methylbiphenyl-4-yl, 4'-methylbiphenyl-4-yl, 2'-methylbiphenyl-3-yl, 3'-methylbiphenyl-3-yl, 4'-methylbiphenyl-3-yl, 2-methylbiphenyl-4-yl, 3-methylbiphenyl-4-yl, 2-methylbiphenyl-3-yl, 4-methylbiphenyl-3-yl, 2'-tert-butylbiphenyl-4-yl, 3'-tert-butylbiphenyl-4-yl, 4'-tert-butylbiphenyl-4-yl, 2'-tert-butylbiphenyl-3-yl, 3'-tert-butylbiphenyl-3-yl, 4'-tert-butylbiphenyl-3-yl, 2-tert-butylbiphenyl-4-yl, 3-tert-butylbiphenyl-4-yl, 2-tertbutylbiphenyl-3-yl, 4-tert-butylbiphenyl-3-yl, 2'-isopropylbiphenyl-4-yl, 3'-isopropylbiphenyl-4-yl, 4'-isopropylbiphenyl-4-yl, 2'-isopropylbiphenyl-3- yl, 3'-isopropylbiphenyl-3-yl, 4'-isopropylbiphenyl-3-yl, 2-isopropylbiphenyl- 4-yl, 3-isopropylbiphenyl-4-yl, 2-isopropylbiphenyl), 4-isopropylbiphenyl-3- yl, 2'-fluorobiphenyl-4-yl, 3'-fluorobiphenyl-4-yl, 4'-fluorobiphenyl-4-yl, 2'-fluorobiphenyl-3-yl, 3'-fluorobiphenyl-3-yl, 4'-fluorobiphenyl-3-yl,

2-fluorobiphenyl-4-yl, 3-fluorobiphenyl-4-yl, 2-fluorobiphenyl-3-yl, 4-fluoro- biphenyl-3-yl, 2'-chlorobiphenyl-4-yl, 3'-chlorobiphenyl-4-yl, 4'-chloro- biphenyl-4-yl, 2'-chlorobiphenyl-3-yl, 3'-chlorobiphenyl-3-yl, 4'-chlorobiphenyl-3-yl, 2-chlorobiphenyl-4-yl, 3-chlorobiphenyl-4-yl, 2-chlorobiphenyl-3-yl, 4-chlorobiphenyl-3-yl, 2'-methoxybiphenyl-4-yl, 3'-methoxybiphenyl-4-yl, 4'-methoxybiphenyl-4-yl, 2'-methoxybiphenyl-3-yl, 3'-methoxybiphenyl-3-yl, 4'-methoxybiphenyl-3-yl, 2-methoxybiphenyl-4-yl, 3-methoxybiphenyl-4-yl, 2-methoxybiphenyl-3-yl, 4-methoxybiphenyl-3-yl, 2'-nitrobiphenyl-4-yl, 3'-nitrobiphenyl-4-yl, 4'-nitrobiphenyl-4-yl, 2'-nitro- biphenyl-3-yl, 3'-nitrobiphenyl-3-yl, 4'-nitrobiphenyl-3-yl, 2-nitrobiphenyl-4-yl, 3-nitrobiphenyl-4-yl, 2-nitrobiphenyl-3-yl, 4-nitrobiphenyl-3-yl, 2'-trifluoromethylbiphenyl-4-yl, 3'-trifluoromethylbiphenyl-4-yl, 4'-tri- fluoromethyl-biphenyl-4-yl, 2'-trifluoromethylbiphenyl-3-yl, 3'-trifluoromethylbiphenyl-3-yl, 4'-trifluoromethylbiphenyl-3-yl, 2-trifluoromethylbiphenyl-4-yl, 3-trifluoromethylbiphenyl-4-yl, 2-trifluoromethylbiphenyl-3-yl, 4-trifluoromethylbiphenyl-3-yl, 2'-trifluoromethoxybiphenyl-4-yl, 3'-trifluoromethoxybiphenyl-4-yl, 4'-tri- fluoromethoxybiphenyl-4-yl, 2'-trifluoromethoxybiphenyl-3-yl, 3'-trifluoromethoxybiphenyl-3-yl, 4'-trifluoromethoxybiphenyl-3-yl, 2-trifluoromethoxybiphenyl-4-yl, 3-trifluoromethoxybiphenyl-4-yl,

2-trifluoromethoxybiphenyl-3-yl, 4-trifluoromethoxybiphenyl-3-yl, 3'- acetylbiphenyl-4-yl, 3'-acetylaminobiphenyl-4-yl, 3'-aminobiphenyl-4-yl, furthermore preferentially disubstituted biphenyls, such as 2'-methyl-3'- nitrobiphenyl-4-yl, 2'-methyl-4'-nitrobiphenyl-4-yl, 2'-methyl-5'-nitrobiphenyl- 4-yl, 2^,-methyl-6'-nitrobiphenyl-4-yl, 3'-methyl-2^*-nitrobiphenyl-4-yl, 3'- methyl-4'-nitrobiphenyl-4-yl, 3'-methyl-5'-nitrobiphenyl-4-yl, 3'-methyl-6'- nitrobiphenyl-4-yl, 4'-methyl-2'-nitrobiphenyl-4-yl, 4'-methyl-3'-nitrobiphenyl- 4-yl, 2'-methyl-3'-nitrobiphenyl-3-yl, 2'-methyI-4'-nitrobiphenyl-3-yl, 2'-methyl-5'-nitrobiphenyl-3-yl, 2'-methyl-6'-nitrobiphenyl-3-yl, 3'-methyl-2'- nitrobiphenyl-3-yl, 3'-methyl-4'-nitrobiphenyl-3-yl, 3'-methyl-5'-nitrobiphenyl- 3-yl, 3'-methyl-6'-nitrobiphenyl-3-yl, 4'-methyl-2'-nitrobiphenyl-3-yl, 4'-methyl-3'-nitrobiphenyl-3-yl, 2'-methoxy-2-methylbiphenyl-4-yl,

3'-methoxy-2-methylbiphenyl-4-yl, 4'-methoxy-2-methylbiphenyl-4-yl, 4'-methoxy-3-nitrobiphenyl-4-yl, 2'-chloro-3'-fluorobiphenyl-4-yl, 2'-chloro-4'- fluorobiphenyl-4-yl, 2'-chloro-5'-fluorobiphenyl-4-yl, 2'-chloro-6'- fluorobiphenyl-4-yl, 3'-chloro-2'-fluorobiphenyl-4-yl, 3'-chloro-4'-fluoro- biphenyl-4-yl, 3'-chloro-5'-fluorobiphenyl-4-yl, 3'-chloro-6'-fluorobiphenyl-4- yl, 4^,-chloro-2'-fluorobiphenyl-4-yl, 4^,-chloro-3'-fluorobiphenyl-4-yl, 2'-chloro-3'-fluorobiphenyl-3-yl, 2'-chloro-4'-fluorobiphenyl-3-yl, 2'-chloro-5'- fluorobiphenyl-3-yl, 2'-chloro-6'-fluorobiphenyl-3-yl, 3'-chloro-2'- fluorobiphenyl-3-yl, 3'-chloro-4'-fluorobiphenyl-3-yl, 3'-chloro-5'- fluorobiphenyl-3-yl, 3'-chloro-6'-fluorobiphenyl-3-yl, 4'-chloro-2'-fluoro- biphenyl-3-yl, 4'-chloro-3'- fluorobiphenyl-3-yi, (2,3'-diethyl)biphenyl-4-yl, (3,3'-diethyl)biphenyl-4-yl), (2,2'-diethyl)biphenyl-4-yl, (2,4^,-diethyl)biphenyl- 4-yl, (2',3'-dimethoxy)biphenyl-4-yl, (2',4'-dimethoxy)biphenyl-4-yl, (2',5'-dimethoxy)biphenyl-4-yl, (2',6'-dimethoxy)-biphenyl-4-yl, (3',4'-dimethoxy)biphenyl-4-yl, (3',5'-dimethoxy)biphenyl-4-yl,

(2',3'-dimethoxy)-biphenyl-3-yl, (2^,,4'-dimethoxy)biphenyl-3-yl, (2^,,5'-dimethoxy)biphenyl-3-yl, (2',6'-dimethoxy)-biphenyl-3-yl, (3',4'-dimethoxy)biphenyl)-3-yl, (3',5'-dimethoxy)biphenyl-3-yl, (3',5'-dichloro)biphenyl-4-yl, (S'.δ'-dichloroJbiphenyl-S-yl, ( ^'-dichlorc biphenyM-yl, (S'^'.δ'-trimethoxyJbiphenyM-yl,

(2^,,3'-di(trifluoromethyl))biphenyl-4-yl, (2',4^,-di(thfluoromethyl))biphenyl-4-yl, (2',5'-di(trifluoromethyl))biphenyl-4-yl, (2',6^,-di(trifluoromethyl))biphenyl-4-yl, (3\4'-di(trifluoromethyl))biphenyl-4-yl, (3\5'-di(trifluoromethyl))biphenyl-4-yi, (2^,,3'-di(trifluoromethyl))biphenyl-3-yl, (2^,,4^,-di(trifluoromethyl))biphenyl-3-yl, (2',5^,-di(trifluoromethyl))biphenyl-3-yl, (2^,,6^,-di(trifluoromethyl))biphenyl-3-yl, (S'^'-d trifluoromethyOJbiphenyl-S-yl, (3',5'-di(trifluoromethyl)biphenyl-3-yl, (2,2'-dimethyl)biphenyl-4-yl, (2,'3-dimethyl)biphenyl-4-yl, (2,4'-dimethyl)biphenyl-4-yl, (2,2'-dimethyl)biphenyl-3-yl, (2,3'-dimethyl)biphenyl-3-yl or (2,4'-dimethyl)biphenyl-3-yl.

Phenyl, 2-, 3- or4-fluorophenyl, 3- or4-chlorophenyl, 4-bromophenyl, 2,4- or 3,4-dichlorophenyl, 2,3-dimethoxyphenyl, 4-aminophenyl, 4- dimethylaminophenyl, 2-, 3- or 4-methylphenyl, 2-, 3- or 4-methoxyphenyl, 4-propylphenyl, 4-isopropylphenyl, 4-butylphenyl, 2-, 3- or 4-nitrophenyl, 2-, 3- or 4-pentoxyphenyl, 2-, 3- or 4-phenoxyphenyl, 2-, or 4-phenylmethoxyphenyl, 2-, 3- or 4-trifluoromethylphenyl, 2-, 3- or 4- trifluoromethoxyphenyl, 2- or 4-cyclopentyloxyphenyl, 3- or 4- carboxyphenyl, 2-, 3- or 4-(N,N-diethyl)sulfamoylphenyl, 3,4- di(phenylmethoxy)phenyl, 2-chloro-6-methylphenyl, 2-chloro-4- fluorophenyl, 5-bromo-2-fluorophenyl, 3,4,5-trimethoxyphenyl, 4- (morpholin-4-yl)phenyl, 4-(morpholin-4-yl-sulfonyl)phenyl, 4-(5-methyl-3- oxo-2,4-dihydropyrazol-2-yl)phenyl, 4-(4,6-dimethoxy-pyrimidin-2-yl)phenyl, 3-(4,6-dimethoxy-pyrimidin-2-yl)phenyl, 4-(pyrid-3-yl)phenyl, 3-(pyrid-3- yl)phenyl, 4-(thiophen-2-yl)phenyl, 3-(thiophen-2-yl)phenyl, 4- (benzo[c]thiophen-2-yl)phenyl, 4-(naphthalen-1-yl)phenyl, naphthyl, biphenyl-4-yl, 2'-fluorobiphenyl-4-yl, 4'-fluorobiphenyl-4-yl, 4'-fluorobiphenyl- 3-yl, 4'-chlorobiphenyl-4-yl, 4'-chlorobiphenyl-3-yl, 4'-methoxybiphenyl-4-yl, 4'-methoxybiphenyl-3-yl, 3'-nitrobiphenyl-4-yl, 3'-acetylbiphenyl-4-yl, 3'- acetylaminobiphenyl-4-yl, 3'-aminobiphenyl-4-yl, (2,3'-diethyl)biphenyl-4-yl, (S'.δ'-dichloroJbiphenyl-S-yl, (2^,,4'-dichloro)biphenyl-4-yl, (S'^'.δ¹- trimethoxy)biphenyl-4-yl, (3\5'-di(trifluoromethyl))biphenyl-4-yl is particularly preferred for Ar.

Arylalkyl is preferentially benzyl.

O-(CH₂)_p-Ph is phenylalkyloxy, in which p can be 0, 1 , 2, 3 or 4. Benzyloxy or phenyloxy is particularly preferred.

Cycloalkyl preferably has 3-7 C atoms and is preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and further also cyclopentyl methyl, cyclopentylethyl or cyclohexylmethyl; cyclopentyl, cyclohexylmethyl or cyclohexyl are particularly preferred.

Hal is preferably F, CI, Br or I.

Het¹ is a saturated, partially or completely unsaturated mono- or bicyclic heterocyclic radical having 5 to 10 ring members, where 1 or 2 N and/or 1 or 2 S or O atoms can be present and the heterocyclic radical can be mono- or disubstituted by A, Hal, OH, OA, CF₃, OCF₃, N(R⁵)₂, carbonyl oxygen, COOR⁵, Het², benzyl or phenyl which is unsubstituted or mono-, di- or trisubstituted by A, OH, OA, CF₃, OCF₃, Hal, CN, COOR⁵, N(R⁵)₂, NO₂, SO₂N(R⁵)₂.

Het¹ is preferably unsubstituted 2- or 3-furyl, 2- or 3-thiophenyl, 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, furthermore preferably 1 ,2,3-triazol-1-, -4- or -5-yl, 1 ,2,4-triazoM-, -4- or -5-yl, 1- or 5-tetrazolyl, 1 ,2,3-oxadiazol-4- or -5-yl, 1 ,2,4-oxadiazol-3- or -5-yl, 1 ,3,4-thiadiazol-2- or -5-yl, 1 ,2,4-thiadiazol-3- or -5-yl,

1 ,2,3-thiadiazol-4- or -5-yl, 2-, 3-, 4-, 5- or 6-2H-thiopyranyl, 2-, 3- or 4-4H-thiopyranyl, 3- or 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5-, 6- or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 7-benzothiophenyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-1H-indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1 ,3-oxadiazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolinyl, 1-, 2-, 3-, 4- or 9-carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl. The heterocyclic radicals can also be partially or completely hydrogenated. Het can thus also be 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or -5-furyl, tetrahydro-2- or -3-furyl, 1 ,3-dioxolan-4-yI, tetrahydro-2- or -3-thiophenyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or -3-pyrrolyl, tetrahydro-1-, -2- or 4-imidazolyl, 2,3-dihydro-1 -, -2-, -3-, -4-, -5-, -6-, -7-1 H-indolyl,

2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1 ,4-dihydro-1-, -2-, -3- or -4-pyridyl, 1 ,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1 ,2,3,6-tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 1-, 2-, 3- or 4-azepanyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or -4-pyranyl, 1 ,4-dioxanyl, 1 ,3-dioxan-2-, -4- or -5-yl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1 ,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-quinolinyl, 1 ,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-isoquinolinyl which can be substituted as indicated above or particularly substituted by A, OA, carbonyl oxygen, NO₂, Het² or phenyl which is substituted by Hal, CN or OA.

Thiophen-2-yl, tetrahydro-furan-2-yl, 1 -methyl-octahydro-indol-3-yl, benzo[1 ,3]dioxol-5-yl, piperazin-1-yl, 4-methyl-piperazin-1-yl, piperidin-1-yl, piperidin-4-yl, 4-benzyl-piperidin-1-yl, 2-methyl-piperidin-1-yl, 1-ethyl- pyrrolidin-2-yl, 1-methyl-pyrrolidin-2-yl, 2-oxo-pyrrolidin-1-yl, pyridin-2-yl, pyhdin-4-yl, 5-nitro-pyridin-2-yl, imidazol-1-yl, morpholin-4-yl, 5-methoxy- 1 H-indol-2-yl, 5-(3-chlorophenyl)-furan-2-yl, 5-(4-fluorophenyl)-thiophen-2- y|, 5-(2-methoxyphenyl)-thiophen-2-yl, 5-(2-cyanophenyl)-thiophen-2-yl, 5- (2,5-dimethoxyphenyl)-thiophen-2-yl, 2-[2,2']bithiophenyl-5-yl, 5-(pyridin-4- yl)-thiophen-2-yl, 5-(1 H-indol-5-yl)-thiophen-2-yl, 5-quinolin-8-yl-thiophen-2- yl or 5-(benzo[b]thiophen-2-yl)-thiophen-2-yl is particularly preferred for Het¹.

Het² is a unsaturated mono- or bicyclic heterocyclic radical having 5 to 10 ring members, where 1 or 2 N and/or 1 or 2 S or O atoms can be present and the heterocyclic radical can be mono- or disubstituted by A, Hal, OH, OA, CF₃, OCF₃, N(R⁵)₂ or COOR⁵.

Thiophen-2-yl, pyridin-3-yl, pyridin-2-yl, pyridin-4-yl, indol-5-yl, quinolin-8-yl, 4,6-dimethoxy-pyrimidin-2-yl or benzo[b]thiophen-2-yl is particularly preferred for Het².

Het³ is a partially or completely unsaturated mono- or bicyclic heterocyclic radical having 5 to 10 ring members, where 1 or 2 N atoms are present and the heterocyclic radical can be mono- or disubstituted by A, Hal, OH, OA, CF₃, OCF₃, N(R⁵)₂, SO₂A or COOR⁵ provided that the heterocyclic radical is not bondend via an N atom.

Quinolin-5-yl and 1-methanesulfonyl-2,3-dihydro-1 H-indol-5-yl is particularly preferred for Het³.

(CH₂)o-Het¹ is preferentially thiophen-2-yl-ethyl, tetrahydro-furan-2-yl- methyl, 1-methyl-octahydro-indol-3-yl-methyl, 1-methyl-octahydro-indol-3- yl-ethyl benzo[1 ,3]dioxol-5-yl-methyl, benzo[1 ,3]dioxol-5-yl-ethyl, piperazin- 1-yl-ethyl, 4-methyl-piperazin-1-yl-propyl, piperidin-1-yl-ethyl, piperidin-4-yl- methyl, 1 -methyl-piperidin-3-yl-ethyl, 4-benzyl-piperidin-1-yl-ethyl, 2-methyl- piperidin-1 -yl-propyl, 1 -ethyl-pyrrolidin-2-yl-methyl, 1 -methyl-pyrrolidin-2-yl- methyl, 2-oxo-pyrrolidin-1 -yl-propyl, pyridin-2-yl-ethyl, pyridin-4-yl-methyl, pyridin-4-yl-ethyl, imidazol-1 -yl-propyl, morpholin-4-yl-propyl or morpholin- 4-yl-ethyl.

Piperidin-4-yl-methyl, 2-oxo-pyrrolidin-1 -yl-propyl, pyridin-4-yl-methyl, imidazol-1 -yl-propyl or morpholin-4-yl-propyl is particularly preferred for (CH₂)₀-Het¹.

(CH₂)₀-OR⁵ is preferentially (CH₂)₂-OCH₃, (CH₂)₃-OCH₃ or (CH₂)₃-O(iPr). (CH₂)o-OR⁶ is preferentially

(CH₂)₀-Z-(CH₂)q-N(R⁵)₂ is preferentially

CH, H

(CH₂)₃— N— (CH₂)₃-NH₂ (CH₂)₂— N— (CH₂)₂-NEt₂

(CH₂)₃— N N— (CH₂)₃-NH₂

or -(CH₂)₃-O-(CH₂)3-NH₂.

particularly preferred for (CH₂)o-Z-(CH₂)q-N(R⁵)2.

(CH₂)_p-(CHA)p-(CH₂)m-Ar is preferentially phenyl,

H₂

CH,

is particularly preferred for (CH₂)_p-(CHA)_p-(CH₂)_m-Ar.

R and R¹ are independently of each other H, A, OH, OA, Hal, N(R⁵)₂, NO₂, CN, C(O)R², CON(R⁵)₂, COOR⁵, allyl, CH=CH-COOR⁵, CH=CHCON(R⁵)₂, SO₂A or phenyl, which is unsubstituted or mono-, di- or trisubstituted by A, where A and Hal have a preferred meaning indicated beforehand and R⁵ have a preferred meaning indicated in the following. R is preferentially H.

R¹ is preferentially H, Hal, allyl, CH=CH-COOR⁵, CH=CHCON(R⁵)₂ or phenyl, which is unsubstituted or monosubstituted by A. H, CI, Br, I, CH=CH-COOEt, 4-methylphenyl, allyl or CH=CH-CONMe₂ is particularly preferred for R¹.

The preferred position of R¹ is the 6- or 7-position of the quinazoline ring system.

R² and R³ are independently of each other H, A, cycloalkyl, -Het³, -(CH₂)₀- OR⁵, -(CH₂)₀-OR⁶, -(CH₂)₀-Het¹, -(CH₂)₀-NR⁵-Het¹, -(CHA)_P-(CH₂)₀-N(R⁵)2, - (CH₂)_p-(CHA)p-(CH2)m-Ar, -(CH2)o-Z-(CH₂)q-N(R⁵)2,

provided that R² and R³ together are not H, where A, Ar, cycloalkyl, Het¹ or

Het³ have a preferred meaning indicated beforehand and R⁵, R⁶, Q and Z have a preferred meaning indicated in the following.

R² is preferentially H or A.

R³ is preferentially A, cycloalkyl, -Het³, -(CH₂)₀-OR⁵, -(CH₂)₀-OR⁶, -(CH₂)₀- Het¹, -(CH₂)₀-NR⁵-Het¹, -(CHA)_p-(CH₂)o-N(R⁵)₂₎ -(CH₂)_p-(CHA)_p-(CH₂)_m-Ar,

-(CH₂)o-Z-(CH₂)q-N(R⁵)2,

Furthermore NR²R³ together form a saturated monocyclic heterocyclic radical having 5 to 6 ring members, where 1 or 2 N atoms are present and the heterocyclic radical can be mono- or disubstituted by OH, Ar, OAr or arylalkyl, where Ar or arylalkyl have a preferred meaning indicated beforehand. Preferred saturated monocyclic heterocyclic radicals can be piperidine or piperazine.

are particularly preferred for NR²R³.

R⁴ is Ar or Het¹, where Ar or Het¹ have a preferred meaning indicated beforehand.

R⁵ is H or A, where A has a preferred meaning indicated beforehand.

Q is O or S, preferentially O.

Y is (CH=CH)_n, where n can be 1 or 2.

Z is phenylene, cyclohexylene, -NR⁵-, O, -CH(OH)-, -CA₂- or

, where R⁵ and A have a preferred meaning indicated beforehand. Phenylene and/or cyclohexylene are particularly bonded in 1 ,4- or 1,3-position.

m is 0, 1 , 2, 3, 4, 5 or 6, preferentially 0, 1 or 2. o is 1 , 2, 3, 4, 5, 6 or 7, preferentially 1 , 2, 3 or 7. p is 0, 1 , 2, 3 or 4, preferentially 0, 1 or 2. q is 1 , 2, 3 or 4, preferentially 1 , 2 or 3.

Some preferred groups of compounds of formula I can be expressed by the following groups or subformulae la to Ic, which correspond to the formula I and in which the radicals not designated in greater detail have the meaning indicated in formula I according to Claim 1 , but

I. for the group la in which in la-1

R and R¹ are independently of each other H, A, OH, OA, Hal, N(R⁵)₂, NO₂, CN, C(O)R², CON(R⁵)₂, COOR⁵, allyl, CH=CH-COOR⁵,

CH=CHCON(R⁵)₂, SO₂A or phenyl, which is unsubstituted or mono-, di- or trisubstituted by A,

R² is H,

R³ is -(CH₂)o-Z-(CH₂)_q-N(R⁵)2, R⁴ is Ar,

R⁵ is H or A,

Y is (CH=CH)_n,

Z is phenylene, cyclohexylene, -NR⁵-, O, -CH(OH)-, -CA₂- or

A is unbranched or branched alkyl having 1 to 6 carbon atoms,

Ar is phenyl or naphthyl, which is unsubstituted or mono-, di- or trisubstituted by A, OH, OA, CF₃, OCF₃, Hal, CN, CHO, COA, COOR⁵, N(R⁵)₂, NO₂ or SO₂N(R⁵)₂,

Hal is F, CI, Br or l, n is 1 or 2,

0 is 1 , 2, 3, 4, 5, 6 or 7 and q is 1 , 2, 3 or 4;

in la-2

R and R¹ are independently of eacl R' is H, R³ is -(CH₂)₀-Z-(CH₂)_q-N(R⁵)₂, R⁴ is Ar, R⁵ is H or A, Y is (CH=CH)_n, z is phenylene, cyclohexylene, -NR⁵-, O, -CH(OH)-, -CA₂- or

A is unbranched or branched alkyl having 1 to 6 carbon atoms, Ar is phenyl or naphthyl, which is unsubstituted or mono-, di- or trisubstituted by A, OH, OA, Hal, COOR⁵, N(R⁵)₂ or NO₂,

Hal is F, CI, Br or l, n is 1 or 2, o is 1 , 2 or 3 and q is 1 , 2 or 3;

in la-3

R and R¹ are independently of each other H or Hal,

R is H,

R^J is -(CH₂)₀-Z-(CH₂)_q-N(R⁵)₂,

-(CH₂)o-Z-(CH₂)_q-N(R^s)₂ is

R⁴ is Ar,

R⁵ is H or A,

Y is (CH=CH)_n,

A is unbranched or branched alkyl having 1 to 6 carbon atoms,

Ar is phenyl or naphthyl, which is unsubstituted or mono-, di- or trisubstituted by A, OH, OA, Hal, COOR⁵, N(R⁵)₂ or NO₂,

Hal is F, CI, Br or I and n is 1 or 2; II. for the group lb in which in lb-1

R and R¹ are independently of each other H, A, OH, OA, Hal, N(R⁵)₂, NO₂, CN, C(O)R², CON(R⁵)₂, COOR⁵, allyl, CH=CH-COOR⁵,

CH=CHCON(R⁵)₂, SO₂A or phenyl, which is unsubstituted or mono-, di- or trisubstituted by A, R² and R³ are independently of each other H, A, cycloalkyl, -Het³,

-(CH₂)₀-OR⁵, -(CH₂)₀-OR⁶, -(CH₂)₀-Het¹, -(CH₂)₀-NR⁵-Het¹, -(CHA)_p-(CH₂)o-N(R⁵)2, -(CH₂)p-(CHA)p-(CH₂)_m-Ar or

-(CH₂)o-Z-(CH₂)_q-N(R⁵)₂, provided that R² and R³ together are not H, R⁴ is Ar,

R⁵ is H or A, R⁶ is benzo[1 ,3]dioxol-5-yl,

Y is (CH=CH)_n,

Z is phenylene, cyclohexylene, -NR⁵-, O, -CH(OH)-, -CA₂- or

_*

A is unbranched or branched alkyl having 1 to 6 carbon atoms,

Ar is phenyl, which is mono-, di- or trisubstituted by O-(CH₂)_p-Ph, naphthyl or Het², or biphenyl, which is unsubstituted or mono-, di- or trisubstituted by A, OH, OA, CF₃, OCF₃, Hal, CN, CHO, COA, COOR⁵, N(R⁵)₂, NR⁵-COA, NO₂, SO₂N(R⁵)₂, naphthyl or

Het², Het¹ is a saturated, partially or completely unsaturated mono- or bicyclic heterocyclic radical having 5 to 10 ring members, where 1 or 2 N and/or 1 or 2 S or O atoms can be present and the heterocyclic radical can be mono- or disubstituted by A,

Hal, OH, OA, CF₃, OCF₃, N(R⁵)₂, carbonyl oxygen, COOR⁵, Het², benzyl or phenyl which is unsubstituted or mono-, di- or trisubstituted by A, OH, OA, CF₃, OCF₃, Hal, CN, COOR⁵,

N(R⁵)₂, NO₂ or SO₂N(R⁵)₂, Het² is a unsaturated mono- or bicyclic heterocyclic radical having

5 to 10 ring members, where 1 or 2 N and/or 1 or 2 S or O atoms can be present and the heterocyclic radical can be mono- or disubstituted by A, Hal, OH, OA, CF₃, OCF₃, N(R⁵)₂ or COOR⁵, Het³ is a partially or completely unsaturated mono- or bicyclic heterocyclic radical having 5 to 10 ring members, where 1 or 2 N atoms are present and the heterocyclic radical can be mono- or disubstituted by A, Hal, OH, OA, CF₃, OCF₃, N(R⁵)₂,

SO₂A or COOR⁵ provided that the heterocyclic radical is not bondend via an N atom,

Hal is F, CI, Br or l,

Ph is phenyl, n is 1 or 2, m is O, 1 , 2, 3, 4, 5 or 6,

0 is 1, 2, 3, 4, 5, 6 or 7,

P is O, 1 , 2, 3 or 4 and q is 1, 2, 3 or 4;

in which in lb-2

R and R¹ are independently of eac

CH=CHCON(R⁵)₂ or phenyl, which is unsubstituted or mono-, di- or trisubstituted by A,

R² and R³ are independently of each other H, cycloalkyl, -(CH2)₀-Het¹, -(CHA)_p-(CH₂)o-N(R⁵)₂, -(CH₂)_P-(CHA)_p-(CH₂)m-Ar or -(CH₂)o-Z-(CH₂)_q-N(R⁵)₂, provided that R² and R³ together are not H,

R⁴ is Ar,

R⁵ is H or A,

Y is (CH=CH)_n, Z is phenylene, cyclohexylene, -NR⁵-, O, -CH(OH)-, -CA₂- or

A is unbranched or branched alkyl having 1 to 6 carbon atoms,

Ar is phenyl, which is mono-, di- or trisubstituted by O-(CH₂)_p-Ph, naphthyl or Het², or biphenyl, which is unsubstituted or mono-, di- or trisubstituted by A, OH, OA, CF₃, OCF₃, Hal, CN, CHO, COA, COOR⁵, N(R⁵)₂, NR⁵-COA, NO₂, SO₂N(R⁵)₂, naphthyl or Het²,

Het¹ is a saturated, partially or completely unsaturated mono- or bicyclic heterocyclic radical having 5 to 10 ring members, where 1 or 2 N and/or 1 or 2 S or O atoms can be present and the heterocyclic radical can be mono- or disubstituted by A, Hal, OH, OA, CF₃, OCF₃, N(R⁵)₂, carbonyl oxygen, COOR⁵,

Het², benzyl or phenyl which is unsubstituted or mono-, di- or trisubstituted by A, OH, OA, CF₃, OCF₃, Hal, CN, COOR⁵, N(R⁵)₂, NO₂ or SO₂N(R⁵)₂, Het² is a unsaturated mono- or bicyclic heterocyclic radical having 5 to 10 ring members, where 1 or 2 N and/or 1 or 2 S or

O atoms can be present and the heterocyclic radical can be mono- or disubstituted by A, Hal, OH, OA, CF₃, OCF₃, N(R⁵)₂ or COOR⁵,

Hal is F. CI, Br or l,

Ph is phenyl, n is 1 or 2, m is O, 1 or 2,

0 is 1 , 2, 3 or 7,

P is 0 or 1 and q is 1 , 2 or 3;

in which in lb-3 R and R¹ are independently of each other H, Hal, allyl, CH=CH-COOR⁵, CH=CHCON(R⁵)₂ or phenyl, which is unsubstituted or mono-, di- or trisubstituted by A,

R² and R³ are independently of each other H, cycloalkyl, -(CH₂)₀-Het¹ , -(CHA)p-(CH₂)o-N(R⁵)₂, -(CH₂)_p-(CHA)_p-(CH₂)_m-Ar or

-(CH₂)₀-Z-(CH₂)_q-N(R⁵)₂, provided that R² and R³ together are not H,

R⁴ is Ar,

R⁵ is H or A, Y is (CH=CH)_n,

Z is phenylene, cyclohexylene, -NR⁵-, O, -CH(OH)-, -CA₂- or

A is unbranched or branched alkyl having 1 to 6 carbon atoms,

Ar is phenyl, which is mono-, di- or trisubstituted by O-(CH₂)_p-Ph, naphthyl or Het², or biphenyl, which is unsubstituted or mono-, di- or trisubstituted by A, OH, OA, CF₃, Hal, COA, N(R⁵)₂, NO₂, NR⁵-COA or Het², Het¹ is thiophen-2-yl, tetrahydro-furan-2-yl, 1-methyl-octahydro- indol-3-yl, benzo[1,3]dioxol-5-yl, piperazin-1-yl, 4-methyl- piperazin-1-yl, piperidin-1-yl, piperidin-4-yl, 4-benzyl-piperidin- 1-yl, 2-methyl-piperidin-1-yl, 1 -ethyl-pyrrolidin-2-yl, 1-methyl- pyrrolidin-2-yl, 2-oxo-pyrrolidin-1-yl, pyridin-2-yl, pyridin-4-yl, 5- n itro-py rid in-2-y I , imidazol-1 -yl, morpholin-4-yl, 5-methoxy-

1 H-indol-2-yl, 5-(3-chlorophenyl)-furan-2-yl, 5-(4- fluorophenyl)-thiophen-2-yl, 5-(2-methoxyphenyl)-thiophen-2- yl, 5-(2-cyanophenyl)-thiophen-2-yl, 5-(2,5-dimethoxyphenyl)- thiophen-2-yl, 2-[2,2']bithiophenyl-5-yl, 2-(5-pyridin-4-yl- thiophen-2-yl, 5-(1 H-indol-5-yl)-thiophen-2-yl, 5-quinolin-8-yl- thiophen-2-yl or 5-(benzo[b]thiophen-2-yl)-thiophen-2-yl, Het² is thiophen-2-yl, pyridin-3-yl, pyridin-2-yl, pyridin-4-yl, indol-5- yl, quinolin-8-yl, 4,6-dimethoxy-pyrimidin-2-yl or benzo[b]thiophen-2-yl,

Hal is F. CI, Br or l, Ph is phenyl, n is 1 or 2, m is 0, 1 or 2, o is 1 , 2, 3 or 7, p is 0 or 1 and q is 1 , 2 or 3;

in lb-4

R and R¹ are independently of each other H, Hal, allyl, CH=CH-COOR⁵,

CH=CHCON(R⁵)₂ or 4-methylphenyl, R² and R³ are independently of each other H, cyclohexylmethyl,

-(CH₂)₀-Het¹, -(CHA)p-(CH₂)o-N(R⁵)₂, -(CH₂)p-(CHA)p-(CH₂)m-

Ar or -(CH₂)o-Z-(CH₂)_q-N(R⁵)2, provided that R² and R³ together are not H, R⁴ is Ar, R⁵ is H or A,

Y is (CH=CH)_n,

Z is phenylene, cyclohexylene, -NR⁵-, O, -CH(OH)-, -CA₂- or

A is unbranched or branched alkyl having 1 to 6 carbon atoms,

Ar is phenyl, which is mono-, di- or trisubstituted by O-(CH )_p-Ph, naphthyl or Het², or biphenyl, which is unsubstituted or mono-, di- or trisubstituted by A, OH, OA, CF₃, Hal, COA, N(R⁵)₂, NO₂, NR⁵-COA or Het², Het¹ is 4-methyl-piperazin-1-yl, imidazol-1 -yl or morpholin-4-yl,

Het² is thiophen-2-yl, pyridin-3-yl or benzo[b]thiophen-2-yl, Hal is F, CI, Br or l,

Ph is phenyl, n is 1 or 2, m is O, 1 or 2, o is 1 , 2, 3 or 7,

P is 0 or 1 and q is 1 , 2 or 3;

III. for group Ic in lc-1

R and R¹ aarree iinnddeeppeennddeerntly of each other H, A, OH, OA, Hal, N(R⁵)₂, NO₂, CN, C(O)R², CON(R⁵)₂, COOR⁵, allyl, CH=CH-COOR⁵, CH=CHCON(R⁵)₂, SO₂A or phenyl, which is unsubstituted or mono-, di- or trisubstituted by A, R² and R³ are independently of each other H, A, cycloalkyl, -Het³,

-(CH₂)o-OR⁵, -(CH₂)₀-OR⁶, -(CH₂)₀-Het¹, -(CH₂)₀-NR⁵-Het¹,

-(CHA)_p-(CH₂)o-N(R⁵)₂, -(CH₂)_p-(CHA)_p-(CH₂)_m-Ar,

-(CH₂)_o-Z-(CH₂)_q-N(R⁵)₂,

provided that R² and R³ together are not H, or NR²R³ together form a saturated monocyclic heterocyclic radical having 5 to 6 ring members, where 1 or 2 N atoms are present and the heterocyclic radical can be mono- or disubstituted by OH, Ar, OAr or arylalkyl, R⁴ is Het¹,

R⁵ is H or A,

R⁶ is benzo[1 ,3]dioxol-5-yl, Q is O or S, Y is (CH=CH)_n,

Z is phenylene, cyclohexylene, -NR -, O, -CH(OH)-, -CA₂- or

A is unbranched or branched alkyl having 1 to 6 carbon atoms,

Ar is phenyl, naphthyl or biphenyl, which is unsubstituted or mono-, di- or trisubstituted by A, OH, OA, cycloalkyloxy, O-(CH₂)_p-Ph, CF₃, OCF₃, Hal, CN, CHO, COA, COOR⁵, N(R⁵)₂, NR⁵-COA, NO₂, SO₂N(R⁵)₂, mor, SO₂-mor, 5-methyl- 3-oxo-2,4-dihydropyrazol-2-yl, naphthyl or Het²,

Het¹ is a saturated, partially or completely unsaturated mono- or bicyclic heterocyclic radical having 5 to 10 ring members, where 1 or 2 N and/or 1 or 2 S or O atoms can be present and the heterocyclic radical can be mono- or disubstituted by A, Hal, OH, OA, CF₃, OCF₃, N(R⁵)₂, carbonyl oxygen, COOR⁵, Het², benzyl or phenyl which is unsubstituted or mono-, di- or trisubstituted by A, OH, OA, CF₃, OCF₃, Hal, CN, COOR⁵, N(R⁵)₂, NO₂or SO₂N(R⁵)₂,

Het² is a unsaturated mono- or bicyclic heterocyclic radical having

5 to 10 ring members, where 1 or 2 N and/or 1 or 2 S or O atoms can be present and the heterocyclic radical can be mono- or disubstituted by A, Hal, OH, OA, CF₃, OCF₃, N(R⁵)₂ or COOR⁵,

Het³ is a partially or completely unsaturated mono- or bicyclic heterocyclic radical having 5 to 10 ring members, where 1 or 2 N atoms are present and the heterocyclic radical can be mono- or disubstituted by A, Hal, OH, OA, CF₃, OCF₃, N(R⁵)₂, SO₂A or COOR⁵ provided that the heterocyclic radical is not bondend via an N atom,

Hal is F, CI, Br or l, mor is morpholin-4-yl,

Ph is phenyl, n is 1 or 2, m is O, 1 , 2, 3, 4, 5 or 6,

0 is 1 , 2, 3, 4, 5, 6 or 7,

P is O, 1 , 2, 3 or 4 and q is 1 , 2, 3 or 4;

in lc-2

R and R¹ are independently of <

CH=CHCON(R⁵)₂ or phenyl, which is unsubstituted or mono-, di- or trisubstituted by A, R² and R³ are independently of each other H, cycloalkyl, -(CH2)₀-Het¹,

-(CHA)_p-(CH₂)o-N(R⁵)₂ or -(CH₂)o-Z-(CH₂)_q-N(R⁵)2, provided that R² and R³ together are not H,

R⁴ is Het¹,

R⁵ is H or A,

Y is (CH=CH)_n,

Z is phenylene, cyclohexylene, -NR⁵-, O, -CH(OH)-, -CA₂- or

A is unbranched or branched alkyl having 1 to 6 carbon atoms,

Het¹ is a saturated, partially or completely unsaturated mono- or bicyclic heterocyclic radical having 5 to 10 ring members, where 1 or 2 N and/or 1 or 2 S or O atoms can be present and the heterocyclic radical can be mono- or disubstituted by A, Hal, OH, OA, CF₃, OCF₃, N(R⁵)₂, carbonyl oxygen, COOR⁵, Het², benzyl or phenyl which is unsubstituted or mono-, di- or trisubstituted by A, OH, OA, CF₃, OCF₃, Hal, CN, COOR⁵,

N(R⁵)₂, NO₂ or SO₂N(R⁵)₂, Het² is a unsaturated mono- or bicyclic heterocyclic radical having

5 to 10 ring members, where 1 or 2 N and/or 1 or 2 S or O atoms can be present and the heterocyclic radical can be mono- or disubstituted by A, Hal, OH, OA, CF₃, OCF₃, N(R⁵)₂ or COOR⁵,

Hal is F, CI, Br or l, n is 1 or 2, o is 1 , 2, 3 or 7, p is 0, 1 , 2 or 3 and q is 1 , 2 or 3;

in lc-3

R and R¹ are independently of each other H or Hal,

R² and R³ are independently of each other H, cycloalkyl, -(CH₂)₀-Het¹, -(CHA)p-(CH₂)o-N(R⁵)₂ or -(CH₂)o-Z-(CH₂)_q-N(R⁵)2, provided that R² and R³ together are not H,

R⁴ is Het¹,

R⁵ is H or A,

Y is (CH=CH)_n, Z is phenylene, cyclohexylene, -NR⁵-, O, -CH(OH)-, -CA₂- or

A is unbranched or branched alkyl having 1 to 6 carbon atoms, Het¹ is thiophen-2-yl, tetrahydro-furan-2-yl, 1-methyl-octahydro- indol-3-yl, benzo[1 ,3]dioxol-5-yl, piperazin-1-yl, 4-methyl- piperazin-1-yl, piperidin-1-yl, piperidin-4-yl, 4-benzyl-piperidin- 1-yl, 2-methyl-piperidin-1-yl, 1-ethyl-pyrrolidin-2-yl, 1-methyl- pyrrolidin-2-yl, 2-oxo-pyrrolidin-1-yl, pyridin-2-yl, pyridin-4-yl, 5-nitro-pyridin-2-yl, imidazol-1 -yl, morpholin-4-yl, 5-methoxy-

1 H-indol-2-yl, 5-(3-chlorophenyl)-furan-2-yl, 5-(4- fluorophenyl)-thiophen-2-yl, 5-(2-methoxyphenyl)-thiophen-2- yl, 5-(2-cyanophenyl)-thiophen-2-yl, 5-(2,5-dimethoxyphenyl)- thiophen-2-yl, 2-[2,2']bithiophenyl-5-yl, 2-(5-pyridin-4-yl- thiophen-2-yl, 5-(1 H-indol-5-yl)-thiophen-2-yl, 5-quinolin-8-yl- thiophen-2-yl or 5-(benzo[b]thiophen-2-yl)-thiophen-2-yl, Hal is F. CI, Br or l, n is 1 or 2, o is 1 , 2, 3 or 7, p is 0, 1 , 2 or 3 and q is 1, 2 or 3;

in lc-4

R and R¹ are independently of each other H or Hal, R² and R³ are independently of each other H, cycloalkyl, -(CH₂)₀-Het¹, -(CHA)p-(CH₂)o-N(R⁵)₂ or -(CH₂)₀-Z-(CH₂)_q-N(R⁵)₂, provided that R² and R³ together are not H,

R⁴ is Het¹,

Het¹ in R⁴ is 2-[2,2']bithiophenyl-5-yl or 5-(3-chlorophenyl)-furan-2-yl, R⁵ is H or A,

Y is (CH=CH)_n, Z is phenylene, cyclohexylene, -NR⁵-, O, -CH(OH)-, -CA₂- or

A is unbranched or branched alkyl having 1 to 6 carbon atoms,

Het¹ in -(CH₂)₀-Het¹ is thiophen-2-yl, tetrahydro-furan-2-yl, 1-methyl- octahydro-indol-3-yl, benzo[1 ,3]dioxol-5-yl, piperazin-1-yl, 4- methyl-piperazin-1-yl, piperidin-1-yl, piperidin-4-yl, 4-benzyl- piperidin-1-yl, 2-methyl-piperidin-1-yl, 1-ethyl-pyrrolidin-2-yl, 1* methyl-pyrrol id in-2-yl, 2-oxo-pyrrolidin-1-yl, pyridin-2-yl, pyridin-4-yl, 5-n itro-py rid i n-2-yl , imidazol-1 -yl, morpholin-4-yl,

5-methoxy-1H-indol-2-yl, 5-(3-chlorophenyl)-furan-2-yl, 5-(4- fluorophenyl)-thiophen-2-yl, 5-(2-methoxyphenyl)-thiophen-2- yl, 5-(2-cyanophenyl)-thiophen-2-yl, 5-(2,5-dimethoxyphenyl)- thioρhen-2-yl, 2-[2,2']bithiophenyl-5-yl, 2-(5-pyridin-4-yl- thiophen-2-yl, 5-(1 H-indol-5-yl)-thiophen-2-yl, 5-quinolin-8-yl- thiophen-2-yl or 5-(benzo[b]thiophen-2-yl)-thiophen-2-yl,

Hal isF.CI, Brorl, n is 1 or 2, o is 1, 2, 3 or 7, p is 0, 1, 2 or 3 and q is 1,2 or 3;

in lc-5

R and R¹ are independently of each other H or Hal,

R² and R³ are independently of each other H, cycloalkyl, -(CH₂)₀-Het¹, -(CHA)p-(CH₂)o-N(R⁵)₂ or-(CH₂)o-Z-(CH₂)_q-N(R⁵)2, provided that R² and R³ together are not H,

R⁴ is Het¹,

Het¹ in R⁴ is 2-[2,2']bithiophenyl-5-yl,

R⁵ is H or A,

Y is (CH=CH)_n, Z is phenylene, cyclohexylene, -NR⁵-, O, -CH(OH)-, -CA₂- or

A is unbranched or branched alkyl having 1 to 6 carbon atoms,

Het¹ in -(CH₂)₀-Het¹ is piperidin-4-yl or pyridin-4-yl,

Hal isF, CI, Brorl, n is 1, o is 1,2, 3 or 7,

P isO, 1,2 or 3 and q is 1,2 or 3. The invention relates additionally to the use of substituted 4-amino- quinazolines of the formula I according to group la and their pharmaceutically tolerable salts and solvates.

The invention relates additionally to the use of substituted 4-amino- quinazolines of the formula I according to group lb and their pharmaceutically tolerable salts and solvates.

The invention relates additionally to the use of substituted 4-amino- quinazolines of the formula I according to group Ic and their pharmaceutically tolerable salts and solvates.

The invention relates further to the use of substituted 4-amino-quinazolines of the formula I according to groups la-lc and their pharmaceutically tolerable salts and solvates as a medicament.

The invention relates to the use of substituted 4-amino-quinazolines of the formula I according to groups la-lc and their pharmaceutically tolerable salts and solvates as a glycoprotein IblX antagonist.

The invention relates further to the use of special compounds of formula I selected from the group a) (7-chloro-2-styryl-quinazolin-4-yl)-(3-imidazol-1-yl-propyl)-amine, b) N'-(7-chloro-2-styryi-quinazolin*4-yl)-N,N-diethyl-ethane-1 ,2-diamine, c) N'-(7-chloro-2-styryl-quinazolin-4-yl)-N,N-diethyl-propane-1 ,3-diamine, d) (7-chloro-2-styryl-quinazolin-4-yl)-(3-morpholin-4-yl-propyl)-amine, e) 1-[3-(7-chloro-2-styryl-quinazolin-4-ylamino)-propyl]-pyrrolidin-2-one, f) [2-(4-amino-phenyl)-ethyl]-(7-chloro-2-styryl-quinazolin-4-yl)-amine, g) N⁴-{2-[2-(4-bromo-phenyl)-vinyl]-7-chloro-quinazolin-4-yl}-N¹,N¹-diethyl- pentane-1 ,4-diamine and h) N⁴-[7-chloro-2-(4-phenyl-buta-1 ,3-dienyl)-quinazolin-4-yl]-N¹ ,N¹-diethyl- pentane-1 ,4-diamine and their pharmaceutically tolerable salts and solvates.

The invention relates further to the use of substituted 4-amino-quinazolines a) to h) of the formula I and their pharmaceutically tolerable salts and solvates as a medicament for the inhibition of PKB.

DETAILED DESCRIPTION

The compounds of the formula I and also the starting substances for their preparation are otherwise prepared by methods known per se, such as are described in the literature (e.g. in the standard works such as Houben- Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart), namely under reaction conditions which are known and suitable for the reactions mentioned. In this case, use can also be made of variants which are known per se, but not mentioned here in greater detail. The starting substances, if desired, can also be formed in situ such that they are not isolated from the reaction mixture, but immediately reacted further to give the compounds of the formula I.

The compounds of the formula I can be obtained by liberating them from their functional derivatives by solvolysis, in particular hydrolysis or by hydrogenolysis.

Preferred starting substances for the solvolysis or hydrogenolysis are those which otherwise correspond to the formula I, but instead of one or more free amino and/or hydroxyl groups contain corresponding protected amino and/or hydroxyl groups, in particular those which instead of an H-N- group carry an R'-N- group, in which R' is an amino protective group and/or those which instead of the H atom of a hydroxyl group carry a hydroxyl protective group, e.g. those which correspond to the formula I, but instead of a group -COOH carry a group -COOR", in which R" is a hydroxyl protective group.

A number of - identical or different - protected amino and/or hydroxyl groups can also be present in the molecule of the starting substance. If the protective groups present are different from one another, in many cases they can be removed selectively (lit.: T.W. Greene, P.G.M. Wuts, Protective Groups in Organic Chemistry, 2nd ed., Wiley, New York 1991 or P.J. Kocienski, Protecting Groups, 1st ed., Georg Thieme Verlag, Stuttgart - New-York, 1994).

The expression "amino protective group" is generally known and relates to groups which are suitable for protecting (for blocking) an amino group against chemical reactions, but which are easily removable after the desired chemical reaction has been carried out at other positions in the molecule. Typical groups of this type are, in particular, unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups. Since the amino protective groups are removed after the desired reaction (or reaction sequence), their nature and size is otherwise not critical; however, those having 1-20, in particular 1-8, C atoms are preferred. The expression "acyl group" is to be interpreted in the widest sense in connection with the present process. It includes acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids and, in particular, alkoxycarbonyl groups, aryloxycarbonyl groups and especially aralkoxycarbonyl groups. Examples of acyl groups of this type are alkanoyl such as acetyl, propionyl, butyryl; aralkanoyl such as phenylacetyl; aroyl such as benzoyl or toluyl; aryloxyalkanoyl such as POA; alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC, 2-iodoethoxycarbonyl; aralkyloxycarbonyl such as CBZ ("carbobenzoxy"), 4-methoxybenzyloxycarbonyl (MOZ), 4-Nitro- benzyloxycarbonyl oder 9-fluorenylmethoxycarbonyl (Fmoc); 2- (phenylsulfonyl)ethoxycarbonyl; trimethylsilylethoxycarbonyl (Teoc) or arylsulfonyl such as 4-methoxy-2,3,6-trimethylphenyl-sulfonyl (Mtr). Preferred amino protective groups are BOC, furthermore CBZ, Fmoc, benzyl and acetyl; particularly preferred Fmoc.

The expression "hydroxyl protective group" is also generally known and relates to groups which are suitable for protecting a hydroxyl group against chemical reactions, but which are easily removable after the desired chemical reaction has been carried out at other positions in the molecule.

Typical groups of this type are the above mentioned unsubstituted or substituted aryl, aralkyl, aroyl or acyl groups, furthermore also alkylgroups, alkyl-, aryl- or aralkylsilylgroups or O,O- or O,S-acetals. The nature and size of the hydroxyl protective groups is not critical, since they are removed again after the desired chemical reaction or reaction sequence; groups having 1-20, in particular 1-10 C atoms, are preferred. Examples of hydroxyl protective groups are, inter alia, benzyl, 4-methoxybenzyl or 2,4- dimethoxybenzyl, aroyl groups such as benzoyl or p-nitrobenzoyl, acyl groups such as acetyl or pivaloyl, p-toluolsulfonyl, alkyl groups such as methyl or tert-butyl, but also allyl, alkylsilyl groups such as trimethylsilyl (TMS), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS) or triethylsilyl, trimethylsilylethyl, aralkylsilyl groups such as tert-butyldiphenylsilyl (TBDPS), cyclic acetals such as isopropylidene-, cyclopentylidene-, cyclohexylidene-, benzylidene-, p-methoxybenzylidene- or o,p- dimethoxybenzylideneacetal, acyclic acetales such as tetrahydropyranyl (Thp), methoxymethyl (MOM), methoxyethoxymethyl (MEM), benzyloxymethyl (BOM) or methylthiomethyl (MTM). Acetyl, benzyl, tert- butyl or TBS being particularly preferred.

The liberation of the compounds of the formula I from their functional derivatives depending on the protective group used is known in the present literature such as T.W. Greene, P.G.M. Wuts, Protective Groups in Organic Chemistry, 2nd ed., Wiley, New York 1991 , P.J. Kocienski, Protecting Groups, 1st ed., Georg Thieme Verlag, Stuttgart - New- York, 1994. In this case, use can also be made of variants which are known per se, but not mentioned here in greater detail.

The groups BOC and O-tert-butyl can preferably be removed, for example, using TFA in dichloromethane or using approximately 3 to 5N HCI in dioxane at 15-30°C, the Fmoc group using an approximately 5 to 50% solution of dimethylamine, diethylamine or piperidine in DMF at 15-30°C.

Preferred starting substances for the solvolysis or hydrogenolysis includes also those which otherwise correspond to the formula I, but are attached to a solid phase. The liberation of the compounds of the formula I from the solid phase is known in the present literature such as Novabiochem - The Combinatorial Chemistry Catalog, March 99 and cited literature.

The solid phase with a carbonate moiety as terminal functional group can preferably be removed, for example, using TFA (50%) in dichloromethane.

The quinazolines of formula I can also preferably be prepared, using either solution or solid-phase techniques.

The term solid phase indicates a resin for solid-phase chemistry, especially for combinatorial chemistry, i.e. by robot- and computer-assisted syntheses, and subjected to mass screening as indicated in US 5,463,564; M. A. Gallop et al., J. Med. Chem. 1994, 37, 1233-1251 and 1385-1401 and M.J. Sofia, Drug Discovery Today 1996, 1 , 27-34). The polymeric material of the solid phase is generally chosen from the group consisting of cross-linked polystyrene, cross-linked polyacrylamide or other resins, natural polymers or silicagels.

The group of cross-linked polystyrene, cross-linked polyacrylamide or other resins includes e.g. polyacrylamide, polymethacrylamide, polyhydroxyethylmethacrylate, polyamide, polystyrene, (meth)acrylate copolymers, for instance from (methy)acrylic acid, esters of (meth)acrylic acid and/or 2-methylene-succinic acid, but-2-enoic acid or maleic acid, polyurethanes or other copolymers.

Suitable terminal functional groups or linkers on the surface of the resin have to be chosen to attach the compounds to the resin. There exists a variety of commercially available resins, e.g. in Novabiochem - The Combinatorial Chemistry Catalog, March 99. Examples for suitable resins are carbonate resins with a modified carbonate group as terminal functional group like p-nitrophenylcarbonate resin, halogenated resins like Merrifield resin (chloromethylpolystyrene) or carboxy resins like carboxy polystyrene resin or NovaSyn^® TG Carboxy Resin. p-Nitrophenylcarbonate resin is particularly preferred. These and other types of resins well known in the art can be used in the subject invention.

The quinazolines of formula I, in which Y is a direct bond or (CH₂)_n- can preferably be prepared by combining and reacting a 2-amino-benzonitrile of formula II with an aldehyde of formula III followed by converting the cyano group to an amide group, reacting the given formula IV with a base, chlorinating the given quinazolin-4-one of formula V and reacting the given formula VI with an amine of formula VII. The conversion of the cyano group to the amide group occurs by conventional means which are known to a skilled artisan. Particularly, the conversion occurs via oxidation within the presence of a base.

The quinazolines of formula I, in which Y is -N(R )-(CH2)_m-_> can be prepared by reacting a 2,4-dichloro-quinazoline of formula VIII with an amine of formula VII and reacting the given formula IX with an amine of formula X. As a rule, the starting compounds of the formulae II, III, VII, VIII and X are known or commercially available.

The unknown compounds, however, can be prepared by methods known per se.

The 2,4-dichloro-quinazolines of formula II in which R and R have a meaning indicated in claim 1 can be prepared by reacting a substituted anthranilic acid with KOCN/acetic acid in the presence of a base and chlorinating the given 1 H-quinazoline-2,4-dione.

The aldehydes of formula III, as a rule, are also commercially available. Furthermore, syntheses for the preparation of aldehydes of formula III, such as, for example, the oxidation of an alcohol, can be used.

The amines of formula VII or X in which R², R³, NR²R³, R⁵, R⁴ and m have a meaning indicated in claim 1 , as a rule, are also commercially available and can be attached to the suitable resin or to a compound of formula VI, VIII or IX by coupling procedures well known in the art and as described in the ensuing Examples. Furthermore, syntheses for the preparation of amines of formula VII or X, such as, for example, the Gabriel synthesis, can be used.

For the preparation of compounds of the formula I in which R⁴ is unsubstituted or substituted biphenyl, heteroarylsubstituted phenyl or aryl- or heteroaryl-substituted thiophenyl, an appropriate compound of the formula I in which R⁴ is phenyl chloride, phenyl bromide, phenyl iodide, thiophenyl chloride, thiophenyl bromide or thiophenyl iodide can be reacted with the appropriate boronic acid derivatives in a Suzuki type coupling reaction. This reaction is expediently carried out under Palladium catalysis with different phosphines as coordination ligands, e.g. Pd(P(Ph)₃) ,

Pd(ll)CI₂dppf, PdOAc₂ + P(R^*)₃ (R^* = phenyl, cyclohexyl, tert-butyl) etc. in the presence of a base such as potassium carbonate, cesium carbonate, DBU, NaOH, in an inert solvent or solvent mixture, e.g. DMF or 1 ,4-dioxane at temperatures between 0° and 150°, preferably between 60° and 120°.

Depending on the conditions used, the reaction time is between a few minutes and a number of days. The boronic acid derivatives can be prepared by conventional methods or are commercially available. The reactions can be carried out in analogy to the methods indicated in Suzuki et al., J. Am. Chem. Soc. 1989, 111 , 314ff., Suzuki et al., Chem. Rev.

1995, 95, 2457ff and G.C. Fu et al. Angew. Chem 1998, 110, 3586.

The Suzuki type coupling reaction can be furthermore used to convert radicals R and R¹ into other radicals R and R¹, for e.g. to convert a halogen substituted quinazolines to a quinazoline substituted by substituted or unsubstituted phenyl.

For the preparation of compounds of the formula I in which R or R¹ is allyl, an appropriate compound of the formula I in which R⁴ is quinazoline chloride, quinazoline bromide or quinazoline iodide can be reacted with allyltributyltin in a Stille type coupling reaction. This reaction is expediently carried out under Palladium catalysis with different phosphines as coordination ligands, e.g. Pd(P(Ph)₃)₂, Pd(ll)CI₂dppf, PdOAc₂ + P(R^*)₃ (R* = phenyl, cyclohexyl, tert-butyl) etc. in an inert solvent or solvent mixture, e.g. DMF or 1 ,4-dioxane at temperatures between 0° and 150°, preferably between 60° and 120°. Depending on the conditions used, the reaction time is between a few minutes and a number of days.

For the preparation of compounds of the formula I in which R or R¹ is CH=CH-COOR⁵ or CH=CH-CON(R⁵)₂, an appropriate compound of the formula I in which R⁴ is quinazoline chloride, quinazoline bromide or quinazoline iodide can be reacted with substituted acrylate in a Heck type coupling reaction. This reaction is expediently carried out under Palladium catalysis with different phosphines as coordination ligands, e.g.

Pd(P(Ph)₃)₂, Pd(ll)CI₂dppf, PdOAc₂ + P(R^*)₃ (R^* = phenyl, cyclohexyl, tert- butyl) etc. in the presence of a base such as triethyl amine or a catalyst tetrabutylammonium iodide, in an inert solvent or solvent mixture, e.g. DMF or 1,4-dioxane at temperatures between 0° and 150°, preferably between 60° and 120°. Depending on the conditions used, the reaction time is between a few minutes and a number of days.

A base of the formula I can be converted into the associated acid addition salt using an acid, for example by reaction of equivalent amounts of the base and of the acid in an inert solvent such as ethanol and subsequent evaporation. Acids which give physiologically acceptable salts are particularly suitable for this reaction. Thus inorganic acids can be used, e.g. sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, furthermore organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, e.g. formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- or ethanesulfonic acid, p-toluenesulfonic acid, naphthalenemono- and disulfonic acids or laurylsulfuric acid. Salts with physiologically unacceptable acids, e.g. picrates, can be used for the isolation and/or purification of the compounds of the formula I.

On the other hand, compounds of the formula I with bases (e.g sodium or potassium hydroxide or carbonate) can be converted into the corresponding metal salts, in particular alkali metal or alkaline earth metal salts, or into the corresponding ammonium salts.

Pharmaceutical preparations comprising at least one compound of the formula I and/or one of its physiologically acceptable salts, are prepared, in particular, in a non-chemical way. In this case, the compounds of the formula I according to the invention can be brought into a suitable dose form together with at least one solid, liquid and/or semi-liquid excipient or auxiliary and, if appropriate, in combination with one or more other active compounds.

These preparations can be used as medicaments in human or veterinary medicine. Possible excipients are organic or inorganic substances which are suitable for enteral (e.g. oral) or parenteral administration or topical application and do not react with the novel compounds, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glyceryl triacetate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc and petroleum jelly. Tablets, pills, coated tablets, capsules, powders, granules, syrups, juices or drops are used, in particular, for oral administration, suppositories are used for rectal administration, solutions, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants, are used for parenteral administration, and ointments, creams or powders are used for topical application. The novel compounds can also be lyophilized and the lyophilizates obtained used, for example, for the production of injection preparations. The preparations indicated can be sterilized and/or can contain auxiliaries such as lubricants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts for affecting the osmotic pressure, buffer substances, colorants, flavorings and/or one or more other active compounds, e.g. one or more vitamins.

Those of skill will readily appreciate that dose levels can vary as a function of the specific compound, the severity of the symptoms and the susceptibility of the subject to side effects. Some of the specific compounds are more potent than others. Preferred dosages for a given compound are readily determinable by those of skill in the art by a variety of means. A preferred means is to measure the physiological potency of a given compound.

For use in the subject methods, the subject compounds may be formulated with other pharmaceutically active agents, particularly other anti-metastatic, antitumor or anti-angiogenic agents. Angiostatic compounds of interest include angiostatin, enclostatin, carboxy terminal peptides of collagen alpha (XV), etc. Cytotoxic and cytostatic agents of interest include adriamycin, aleran, Ara-C, BICNU, busulfan, CNNU, cisplatinum, cytoxan, daunorubicin, DTIC, 5-FU, hydrea, ifosfamicle, methotrexate, mithramycin, mitomycin, mitoxantrone, nitrogen mustard, velban, vincristine, vinblastine, VP-16, carboplatinum, fludarabine, gemcitabine, idarubicin, irinotecan, leustatin, navelbine, taxol, taxotere, topotecan, etc.

In general, compounds according to the invention are to be regarded as suitable kinase-modulators and especially suitable kinase-inhibitors according to the invention if they show an effect or an activity to one or more kinases, preferably to one or more PKB-kinases that preferably lies, determined as IC₅o-value, in the range of 100 /mol or below, preferably 10 μmol or below, more preferably in the range of 3 /mol or below, even more preferably in the range of 1 μmol or below and most preferably in the nanomolar range. Especially preferred for use according to the invention are kinase-inhibitors as defined above/below, that show an activity, determined as ICso-value, to one or more PKB-kinases, preferably including PKBα and/or PKBβ and/or PKBβi and /or PKBγ and /or PKBγ* , in the range of 0.5 μmol or below and especially in the range of 0.1 μmoi or below. In many cases an ICso-value at the lower end of the given ranges is advantageous and in some cases its highly desirable that the ICso-value is as small as possible or the he ICso-values are as small as possible, but in general IC₅₀-values that lie between the above given upper limits and a lower limit in the region of 0.0001 μmol 0.001 μmol, 0.01 μmol or even above 0.1 μmol are sufficient to indicate the desired pharmaceutical activity. However, the activities measured can vary depending on the respective testing system chosen. The dose will vary depending on the specific compound utilized, specific disorder, patient status, etc. Typically a therapeutic dose will be sufficient to substantially decrease the undesirable cell population in the targeted tissue, while maintaining patient viability. Treatment will generally be continued until there is a substantial reduction, e.g., at least about 50 %, decrease in the cell burden, and may be continued until there are essentially none of the undesirable cells detected in the body

The compounds of the invention have been shown to have antiproliferative effect in an in vivo xenograft tumor model. The subject compounds are administered to a subject having a hyperproliferative disorders, e.g., to inhibit tumor growth, to decrease inflammation associated with a lymphoproliferative disorder, to inhibit graft rejection, or neurological damage due to tissue repair, etc. The present compounds are useful for prophylactic or therapeutic purposes. As used herein, the term "treating" is used to refer to both prevention of disease, and treatment of pre-existing conditions. The prevention of proliferation is accomplished by administration of the subject compounds prior to development of overt disease, e.g., to prevent the growth of tumors, prevent metastatic growth, diminish restenosis associated with cardiovascular surgery, etc.

Alternatively the compounds are used to treat ongoing disease, by stabilizing or improving the clinical symptoms of the patient.

The host, or patient, may be from any mammalian species, e.g., primate sp., particularly human; rodents, including mice, rats and hamsters; rabbits; equines, bovines, canines, felines; etc. Animal models are of interest for experimental investigations, providing a model for treatment of human disease. The compounds also find use in the specific inhibition of signaling pathway mediated by protein kinases. Protein kinases are involved in signaling pathways for such important cellular activities as responses to extracellular signals and cell cycle checkpoints. Inhibition of specific protein kinases provided a means of intervening in these signaling pathways, for example to block the effect of an extracellular signal, to release a cell from cell cycle checkpoint, etc. Defects in the activity of protein kinases are associated with a variety of pathological or clinical conditions, where there is a defect in the signaling mediated by protein kinases. Such conditions include those associated with defects in cell cycle regulation or in response to extracellular signals, e.g., immunological disorders, autoimmune and immunodeficiency diseases; hyperproliferative disorders, which may include psoriasis, arthritis, inflammation, endometriosis, scarring, cancer, etc. The compounds of the present invention are active in inhibiting purified kinase proteins preferably PKB kinases, e.g., there is a decrease in the phosphorylation of a specific substrate in the presence of the compound.

The compounds of formula I may also be useful as reagents for the examination of PKB dependent signal transduction pathways in animal and /or cell culture models or any of the clinical disorders listed throughout this application.

There are many disorders associated with a deregulation of cellular proliferation and cell death (apoptose). The conditions of interest include, but are not limited to, the following conditions. The subject compounds are useful in the treatment of a variety of conditions where there is proliferation and/or migration of smooth muscle cells, and/or inflammatory cells into the intimal layer of a vessel, resulting in restricted blood flow through that vessel, e.g., neointimal occlusive lesions. Occlusive vascular conditions of interest include atherosclerosis, graft coronary vascular disease after transplantation, vein graft stenosis, peri-anastomatic prothetic graft stenosis, restenosis after angioplasty or stent placement, and the like.

Diseases where there is hyperproliferation and tissue remodeling or repair or reproductive tissue, e.g., uterine, testicular and ovarian carcinomas, endometriosis, squamous and glandular epithelial carcinomas of the cervix, etc. are reduced in cell number by administration of the subject compounds. The growth and proliferation of neural cells is also of interest.

Tumor cells are characterized by uncontrolled growth, invasion to surrounding tissues, and metastatic spread to distant sites. Growth and expansion requires an ability not only to proliferate, but also to down- modulate cell death (apoptosis) and activate angiogenesis to product a tumor neovasculature.

Tumors of interest for treatment include carcinomas, e.g., colon, duodenal, prostate, breast, melanoma, ductal, hepatic, pancreatic, renal, endometrial, stomach, dysplastic oral mucosa, polyposis, invasive oral cancer, non-small cell lung carcinoma, transitional and squamous cell urinary carcinoma etc.; neurological malignancies; e.g. neuroplastoma, gliomas, etc.; hematological malignancies, e.g., childhood acute leukaemia, non-Hodgkin's lymphomas, chronic lymphocytic leukaemia, malignant cutaneous T-cells, mycosis fungoides, non-MF cutaneous T-cell- lymphoma, lymphomatoid papulosis, T-cell rich cutaneous lymphoid hyperplasia, bullous pemphigoid, discoid lupus erythematosus, lichen planus, etc.; and the like.

Tumors of neural tissue are of particular interest, e.g., gliomas, neuromas, etc. Some cancers of particular interest include breast cancers, which are primarily adenocarcinoma subtypes. Ductal carcinoma in situ is the most common type of noninvasive breast cancer. In DCIS, the malignant cells have not metastasized through the walls of the ducts into the fatty tissue of the breast. Infiltration (or invasive) ductal carcinoma (IDC) has metastasized through the wall of the duct and invaded the fatty tissue of the breast. Infiltrating (or invasive) lobular carcinoma (I.LC) is similar to IDC, in that it has the potential metastasize elsewhere in the body. About 10 % to 15 % of invasive breast cancers are invasive lobular carcinomas.

Also of interest is non-small cell lung carcinoma. Non-small cell lung cancer (NSCLC) is made up of three general subtypes of lung cancer. Epidermoid carcinoma (also called squamos cell carcinoma) usually starts in one of the larger bronchial tubes and grows relatively slowly. The size of these tumors can range from very small to quite large. Adenocarcinoma starts growing near the outside surface of the lung and may vary in both size and growth rate. Some slowly growing adenocarcinomas are described as alveolar cell cancer. Large cell carcinoma starts near the surface of the lung, grows rapidly, and the growth is usually fairly large when diagnosed. Other less common forms of lung cancer are carcinoid, cylindroma, mucoepidermoid, and malignant mesothelioma.

Melanoma is a malignant tumor of melanocytes. Although most melanomas arise in the skin, they also may arise from mucosal surfaces or at other sites to which neural crest cells migrate. Melanoma occurs predominantly in adults, and more than half of the cases arise in apparently normal areas of the skin. Prognosis is affected by clinical and histological factors and by anatomic location of the lesion. Thickness and/or level of invasion of the melanoma, mitotic index, tumor infiltrating lymphocytes, and ulceration or bleeding at the primary site affect the prognosis. Clinical staging is based on whether the tumor has spread to regional lymph nodes or distant sites. For disease clinically confined to the primary site, the greater the thickness and depth of local invasion of the melanoma, the higher the chance of lymph node metastases and the worse the prognosis. Melanoma can spread by local extension (through lymphatics) and/or by hematogenous routes to distant sites. Any organ may be involved by metastases, but lungs and liver are common sites.

Other hyperprol iterative diseases of interest relate to epidermal hyperproliferation, tissue, remodeling and repair. For example, the chronic skin inflammation of psoriasis is associated with hyperplastic epidermal keratinocyctes as well as infiltrating mononuclear cells, including CD4+ memory T cells, neutrophils and macrophages.

The proliferation of immune cells is associated with a number of autoimmune and lymphoprol iterative disorders. Diseases of interest include multiple sclerosis, rheumatoid arthritis and insulin dependent diabetes mellitus. Evidence suggests that abnormalities in apoptosis play a part in the pathogenesis of systemic lupus erythematosus (SLE). Other lymphoproliferative conditions the inherited disorder of lymphocyte apoptosis, which is an autoimmune lymphoproliferative syndrome, as well as a number of leukemia's and lymphomas. Symptoms of allergies to environmental and food agents, as well as inflammatory bowel disease, may also be alleviated by the compounds of the invention.

Above and below, all temperatures are indicated in °C. In the following examples, "customary working-up" for solution reactions means: if necessary, water is added, if necessary, depending on the constitution of the final product, the mixture is adjusted to pHs between 2 and 10 and extracted with ethyl acetate or dichloromethane, the organic phase is separated off, dried over sodium sulfate and evaporated, and the residue is purified by chromatography on silica gel and/or by crystallization.

"Customary working-up" for solid-phase reactions means: the crude reaction is filtered and washed with DMF twice, then successively with methanol and methylene chloride three times, and finally once with methyl tert-butyl ether. The resin is then dried in vacuum. Mass spectrometry (MS) apparatuses Kratos OMIT and Finnigan LCQ. (M+H)⁺ values or M⁺ values are determined.

EXAMPLES

Example 1 :

(3-Aminomethyl-cyclohexylmethyl)-[2-(2-naphthalen-1-yl-vinyl)-quinazolin-4- yl]-amine

1. Anthranilic acid (0,29 mole) is added to 170 ml acetic anhydride. The solution is heated to 140° for 3 h. After cooling to room temperature (rt), the white solid is collected by filtration and washed with diethyl ether. Air drying give 2-methylbenzoxazin-4-one.

2. 2-Methyibenzoxazin-4-one (0,24 mole) and ammonium acetate (0,30 mole) is given in 50 ml of N,N-dimethylacetamide and then heated to 160° under a nitrogen blanket for 2 h. After cooling to rt, the white solid is collected by filtration and washed with diethyl ether. Air drying give 2- methyl-quinazolin-4-one.

3. 2-Methylquinazolin-4-one (50 mmol) and naphthalene-1-carbaldehyde (54 mmol) are suspended in 80 ml acetic acid. The mixture is heated to 100° for 24 h. After cooling to rt, the product crystallize out. After filtration, washing with etyl acetate and air drying, 2-(2-naphthalen-1-yl-vinyl)-3H- quinazolin-4-one is given.

4. 2-(2-Naphthalen-1-yl-vinyl)-3H-quinazolin-4-one (11 mmol), phosphorus oxychloride (20 ml) and N,N-diethylaniline (1 ,0 ml) is added to a round- bottomed flask. The mixture is heated at 110° for 12 h. After cooling to rt, the reaction is quenched with ice-water and the crude product is collected by suction filtration. The crude solid is dissolved in ethyl acetate. Customary working up afforded 4-chloro-2-(2-naphthalen-1-yl-vinyl)-3,4- dihydro-quinazoline.

5. 4-Chloro-2-(2-naphthalen-1 -yl-vinyl)-3,4-dihydro-quinazoline (0,08 mmol), C-(3-aminomethyl-cyclohexyl)-methylamine (0,24 mmol) and 2 ml ethyl alcohol are placed in an 8 ml glass vial sealed with a teflon-lined scew cap. The mixture is heated at 80° for 3 hrs. After cooling to rt, the ethyl alcohol is removed. Ethyl acetate (3ml) and water (3ml) are added to the vial. After agitation, the water was removed. The procedure is repeated with water and aq. NaCI (sat.). Purification with silica gel afforded (3- aminomethyl-cyclohexylmethyl)-[2-(2-naphthalen-1-yl-vinyl)-quinazolin-4-yl]- amine;

MS calc: 422.6 ; found: 423.5.

Example 2:

Analogously to example 1 , 2-methylquinazolin-4-one is reacted with 4-pentyloxy-benzaldehyde, chlorinated and reacted with C-(3- aminomethyl-cyclohexyl)-methylamine to obtain (3-aminomethyl-cyclohexylmethyl)-{2-[2-(4-pentyloxy-phenyl)-vinyl]- quinazolin-4-yl}-amine;

MS calc: 458.6 ; found: 459.5;

with 3-phenyl-propenal, chlorinated and reacted with C-(3-aminomethyl- cyclohexyl)-methylamine to obtain

(3-aminomethyl-cyclohexylmethyl)-[2-(4-phenyl-buta-1 ,3-dienyl)- quinazolin-4-yl]-amine; MS calc: 398.6 ; found: 399.4;

with 3-fluoro-benzaldehyde, chlorinated and reacted with C-(3- aminomethyl-cyclohexyl)-methylamine to obtain (3-aminomethyl-cyclohexylmethyl)-{2-[2-(3-fluoro-phenyl)-vinyl]- quinazolin-4-yl}-amine; MS calc: 390.5 ; found: 391.4;

with 2-fluoro-benzaldehyde, chlorinated and reacted with C-(3- aminomethyl-cyclohexyl)-methylamine to obtain

(3-aminomethyl-cyclohexylmethyl)-{2-[2-(2-fIuoro-phenyl)-vinyl]- quinazolin-4-yl}-amine; MS calc: 390.5 ; found: 391.3;

with 4-chloro-benzaldehyde, chlorinated and reacted with C-(3- aminomethyl-cyclohexyl)-methylamine to obtain

(3-aminomethyl-cyclohexylmethyl)-{2-[2-(4-chloro-phenyl)-vinyl]- quinazolin-4-yl}-amine; MS calc: 407.0 ; found: 410.3;

with 3-chloro-benzaldehyde, chlorinated and reacted with C-(3- aminomethyl-cyclohexyl)-methylamine to obtain

(3-aminomethyl-cyclohexylmethyl)-{2-[2-(3-chloro-phenyl)-vinyl]- quinazolin-4-yl}-amine; MS calc: 407.0 ; found: 407.3; with 4-amino-benzaldehyde, chlorinated and reacted with C-(3- aminomethyl-cyclohexyl)-methylamine to obtain

(3-aminomethyl-cyclohexylmethyl)-{2-[2-(4-amino-phenyl)-vinyl]- quinazolin-4-yl}-amine; MS calc: 387.5 ; found: 388.4;

with 4-methoxy-benzaldehyde, chlorinated and reacted with C-(3- aminomethyl-cyclohexyl)-methylamine to obtain

(3-aminomethyl-cyclohexylmethyl)-{2-[2-(4-methoxy-phenyl)-vinyl]- quinazolin-4-yl}-amine;

MS calc: 402.5 ; found: 403.3;

with 3-methoxy-benzaldehyde, chlorinated and reacted with C-(3- aminomethyl-cyclohexyl)-methylamine to obtain (3-aminomethyl-cyclohexylmethyl)-{2-[2-(3-methoxy-phenyl)-vinyl]- quinazolin-4-yl}-amine; MS calc: 402.5 ; found: 403.3;

with 4-methyl-benzaldehyde, chlorinated and reacted with C-(3- aminomethyl-cyclohexyl)-methylamine to obtain

(3-aminomethyl-cyclohexylmethyl)-{2-[2-(4-methyl-phenyl)-vinyl]- quinazolin-4-yl}-amine; MS calc: 386.5 ; found: 387.3;

with 3-methyl-benzaldehyde, chlorinated and reacted with C-(3- aminomethyl-cyclohexyl)-methylamine to obtain

(3-aminomethyl-cyclohexylmethyl)-{2-[2-(3-methyl-phenyl)-vinyl]- quinazolin-4-yl}-amine; MS calc: 386.5 ; found: 387.3;

with 2-methyl-benzaldehyde, chlorinated and reacted with C-(3- aminomethyl-cyclohexyl)-methylamine to obtain (3-aminomethyl-cyclohexylmethyl)-{2-[2-(2-methyl-phenyl)-vinyl]- quinazolin-4-yl}-amine; MS calc: 386.5 ; found: 387.3;

with 2-nitro-benzaldehyde, chlorinated and reacted with C-(3-aminomethyl- cyclohexyl)-methylamine to obtain

(3-aminomethyl-cyclohexylmethyl)-{2-[2-(2-nitro-phenyl)-vinyl]-quinazolin-

4-yl}-amine;

MS calc: 417.5 ; found: 418.3;

with 3-nitro-benzaldehyde, chlorinated and reacted with C-(3-aminomethyl- cyciohexyl)-methylamine to obtain

(3-aminomethyl-cyclohexylmethyl)-{2-[2-(3-nitro-phenyl)-vinyl]-quinazolin-

4-yl}-amine; MS calc: 417.5 ; found: 418.3;

with 4-nitro-benzaldehyde, chlorinated and reacted with C-(3-aminomethyl- cyclohexyl)-methylamine to obtain

(3-aminomethyl-cyclohexylmethyl)-{2-[2-(4-nitro-phenyl)-vinyl]-quinazolin- 4-yl}-amine;

MS calc: 417.5 ; found: 418.3;

with 3,4,5-trimethoxy-benzaldehyde, chlorinated and reacted with C-(3- aminomethyl-cyclohexyl)-methylamine to obtain (3-aminomethyl-cyclohexylmethyl)-{2-[2-(3,4,5-trimethoxy-phenyl)-vinyl]- quinazolin-4-yl}-amine;

with 4-carboxy-benzaldehyde, chlorinated and reacted with C-(3- aminomethyl-cyclohexyl)-methylamine to obtain (3-aminomethyl-cyclohexylmethyl)-{2-[2-(4-carboxy-phenyl)-vinyl]- quinazolin-4-yl}-amine; MS calc: 416.5 ; found: 417.3 and with 3-carboxy-benzaldehyde, chlorinated and reacted with C-(3- aminomethyl-cyclohexyl)-methylamine to obtain

(3-aminomethyl-cyclohexylmethyl)-{2-[2-(3-carboxy-phenyl)-vinyl]- quinazolin-4-yl}-amine; MS calc: 416.5 ; found: 417.3.

Analogously to example 1 , 7-chloro-2-methylquinazolin-4-one is reacted with 4-bromo-benzaldehyde, chlorinated and reacted

with C-(3-aminomethyl-cyclohexyl)-methylamine to obtain

(3-aminomethyl-cyclohexylmethyl)-{2-[2-(4-bromo-phenyl)-vinyl]-7- chloro-quinazolin-4-yl}-amine; MS calc: 485.9 ; found: 487.2.

Example 3:

Analogously to example 1 , 7-chloro-2-methylquinazolin-4-one is reacted with 3-phenoxy-benzaldehyde, chlorinated and reacted

with N¹,N¹-diethyl-pentane-1 ,4-diamine to obtain

N N⁴⁴--{{77--cchhlloorroo--22--[[22--((33--pphheenncoxy-phenyl)-vinyl]-quinazolin-4-yl}- N¹,N¹- diethyl-pentane-1 ,4-diamine;

with C-(3-aminomethyl-cyclohexyl)-methylamine to obtain

(3-aminomethyl-cyclohexylmethyl)-{7-chloro-2-[2-(3-phenoxy-phenyl)- vinyl]-quinazolin-4-yl}-amine; MS calc: 499.1 ; found: 499.5;

with 3-aminomethyl-benzylamine to obtain

(3-aminomethyl-benzyl)-{7-chloro-2-[2-(3-phenoxy-phenyl)-vinyl]- quinazolin-4-yl}-amine; MS calc: 493.0 ; found: 493.4 and

with heptane-1 ,7-diamine

N¹-{7-chloro-2-[2-(3-phenoxy-phenyl)-vinyl]-quinazolin-4-yl}-heptane-1 ,7- diamine;

MS calc: 487.0 ; found: 487.5.

Example 4:

Analogously to example 1, 2-methylquinazolin-4-one is reacted with 4-benzyloxy-benzaldehyde, chlorinated and reacted

with C-(3-aminomethyl-cyclohexyl)-methylamine to obtain

(3-aminomethyl-cyclohexylmethyl)-{2-[2-(4-benzyloxy-phenyl)-vinyl]- quinazolin-4-yl}-amine; MS calc: 478.6 ; found: 479.4;

with 3-(3-amino-propoxy)-propylamine to obtain

[3-(3-amino-propoxy)-propyl]-{2-[2-(4-benzyloxy-phenyl)-vinyl]- quinazolin-4-yl}-amine; MS calc: 468.6 ; found: 469.3;

with 2,2-dimethyl-propane-1 ,3-diamine to obtain

N¹-{2-[2-(4-benzyloxy-phenyl)-vinyl]-quinazolin-4-yl}-2,2-dimethyl- propane-1 ,3-diamine; MS calc: 438.6 ; found: 439.3;

with N¹-(2-diethylamino-ethyl)-ethane-1 ,2-diamine to obtain

N-{2-[2-(4-benzyloxy-phenyl)-vinyl]-quinazolin-4-yl}-N'-(2-diethylamino- ethyl)-ethane-1 ,2-diamine; MS calc: 495.7 ; found: 496.3;

with heptane-1 ,7-diamine to obtain

N¹-{2-[2-(4-benzyloxy-phenyl)-vinyl]-quinazolin-4-yl}-heptane-1 ,7- diamine;

MS calc: 466.6 ; found: 467.3;

with 4-(2-amino-ethyl)-phenylamine to obtain

[2-(4-amino-phenyl)-ethyl]-{2-[2-(4-benzyloxy-phenyl)-vinyl]-quinazolin-4- y!}-amine;

MS calc: 472.6 ; found: 473.2;

with 3-morpholin-4-yl-propylamine to obtain

{2-[2-(4-benzyloxy-phenyl)-vinyl]-quinazolin-4-yl}-(3-morpholin-4-yl- propyl)-amine;

MS calc: 480.6 ; found: 481.3;

with N¹,N¹-diethyl-propane-1 ,3-diamine to obtain N'-{2-[2-(4-benzyloxy-phenyl)-vinyl]-quinazolin-4-yl}-N,N-diethyl-propane-

1 ,3-diamine; MS calc: 466.6 ; found: 467.3; with N¹,N¹-diethyl-ethane-1 ,2-diamine to obtain

N'-{2-[2-(4-benzyloxy-phenyl)-vinyl]-quinazolin-4-yl}-N,N-diethyl-ethane- 1 ,2-diamine; MS calc: 452.6 ; found: 453.2;

with 3-imidazol-1-yl-propylamine to obtain

{2-[2-(4-benzyloxy-phenyl)-vinyl]-quinazolin-4-yl}-(3-imidazol-1-yl-propyl)- amine; MS calc: 461.6 ; found: 462.2;

Analogously to example 1 , 7-chloro-2-methylquinazolin-4-one is reacted with 4-benzyloxy-benzaldehyde, chlorinated and reacted

with N¹,N¹-diethyl-pentane-1 ,4-diamine to obtain

N⁴-{2-[2-(4-benzyloxy-phenyl)-vinyl]-7-chloro-quinazolin-4-yl}- N¹,N¹- diethyl-pentane-1 ,4-diamine;

with C-(3-aminomethyl-cyclohexyl)-methylamine to obtain

(3-aminomethyl-cyclohexylmethyl)-{2-[2-(4-benzyloxy-phenyl)-vinyl]-7- chloro-quinazolin-4-yl}-amine; MS calc: 513.1 ; found: 513.3.

Analogously to example 1 , 6-iodo-2-methylquinazolin-4-one is reacted with 4-benzyloxy-benzaldehyde, chlorinated and reacted with N¹,N¹-diethyl-pentane-1 ,4-diamine to obtain

N⁴-{2-[2-(4-benzyloxy-phenyl)-vinyl]-6-iodo-quinazolin-4-yl}- N¹,N¹- diethyl-pentane-1 ,4-diamine; MS calc: 620.6 ; found: 621.1 ;

with C-(3-aminomethyl-cyclohexyl)-methylamine to obtain

(3-aminomethyl-cyclohexylmethyl)-{2-[2-(4-benzyloxy-phenyl)-vinyl]-6- iodo-quinazolin-4-yl}-amine; MS calc: 604.5 ; found: 605.2.

Analogously to example 1 , 6-bromo-2-methylquinazolin-4-one is reacted with 4-benzyloxy-benzaldehyde, chlorinated and reacted

with N¹,N¹-diethyl-pentane-1 ,4-diamine to obtain N⁴-{2-[2-(4-benzyloxy-phenyl)-vinyl]-6-bromo-quinazolin-4-yl}- N¹,N¹- diethyl-pentane-1 ,4-diamine; MS calc: 573.6 ; found: 575.1 ;

with C-(3-aminomethyl-cyclohexyl)-methylamine to obtain (3-aminomethyl-cyclohexylmethyl)-{2-[2-(4-benzyloxy-phenyl)-vinyl]-6- bromo-quinazolin-4-yl}-amine; MS calc: 557.5 ; found: 559.2.

Example 5: 3-{4-[(3-Aminomethyl-cyclohexylmethyl)-amino]-2-[2-(4-benzyloxy-phenyl)- vinyl]-quinazolin-6-yl}-acrylic acid ethyl ester

1. Synthesis of resin-bound (3-aminomethyl-cyclohexylmethyl)-carbamate

(V p-Nitrophenyl carbonate Wang resin (2,7 mmol, 0,54 mmol/g), 1 ,3- cyclohexane-bis(dimethylamine) (2,18 g, 15 mmol) and 75 ml DMF (dimethylformamide) are added to a sealed fritted polypropylene tube. The mixture is agitated for 72 h. After evacuation of the solvent, the resin is customary worked up for solid phase reactions.

2. Analogously to example 1 , 6-iodo-2-methylquinazolin-4-one is reacted with 4-benzyloxy-benzaldehyde and chlorinated to obtain 2-[2-(4-benzyloxy-phenyl)-vinyl]-4-chloro-6-iodo-quinazoline.

3. The resin-bound carbamate (1) (4,8 g, 0,54 mmol/g), 2-[2-(4-benzyloxy- phenyl)-vinyl]-4-chloro-6-iodo-quinazoline (6,6 mmol), triethylamine (1 ml) and 50 ml DMF are placed in a fritted polypropylene tube. The mixture is stirred at 80° for 60 hrs. After cooling to rt, the resin is customary worked up for solid phase reactions. Resin bound carbamate (2) is obtained.

4. The solid supported 6-iodoquinazoline (2) (0,054 mmol, 0,54 mmol/g), ethyl acrylate (50 mg, 0,5 mmol), Pd(PPh₃) (20 mg), Bu₄NI (tetra- butylammonium-iodie, 32 mg, 0,08 mmol) and 2 ml DMF are placed in a fritted polypropylene tube. The mixture is agitated at 80° for 24 h. After cooling to rt, the solvent is evacuated and the resin is customary worked up for solid phase reactions. The solid supported 6-ethoxyacrylquinazoline and 2 ml of a mixture of H₂O, TFA (trifluoracetic acid) and dichloromethane (1 :49:50) is placed in a fritted polypropylene tube. The contents are shaken for 2 h at rt. The suspension is filtered and the resin is washed with dichloromethane (1 ml) and methanol (1 ml) respectively. Evaporation of the combined filtrates give 3-{4-[(3-aminomethyl-cyclohexylmethyl)-amino]-2-[2-(4-benzyloxy-phenyl)- vinyl]-quinazolin-6-yl}-acrylic acid ethyl ester; MS calc: 576.7 ; found: 577.3.

Analogously to example 5.4, solid supported 6-iodoquinazoline (2) is reacted with N,N-dimethyl-acrylamide to obtain

3-{4-[(3-aminomethyl-cyclohexylmethyl)-amino]-2-[2-(4-benzyloxy-phenyl)- vinyl]-quinazolin-6-yl}-N,N-dimethyl-acrylamide;

MS calc: 575.8 ; found: 576.4.

Example 6:

Solid supported 6-iodoquinazoline (2) [synthesized according to example 5] (0,054 mmol, 0,54 mmol/g), allyltributyltin (140 mg, 0,5 mmol), Pd(PPh₃)₄ (20 mg), and 2 ml DMF are placed in a fritted polypropylene tube. The mixture is agitated at 80° got 24 h. After cooling to rt, the mixture is customary worked up for solid phase reactions. The solid supported

6-allylquinazoline and 2 ml of a mixture of H₂O, TFA and dichloromethane (1 :49:50) is placed in a fritted polypropylene tube. The contents are shaken for 2 h at rt. The suspension is filtered and the resin is washed with dichloromethane (1 ml) and methanol (1 ml) respectively. Evaporation of the combined filtrates give

{6-allyl-2-[2-(4-benzyloxy-phenyl)-vinyl]-quinazolin-4-yl}-(3-aminomethyl- cyclohexylmethyl)-amine;

MS calc: 518.7 ; found: 519.3.

Example 7:

Solid supported 6-iodoquinazoline (2) [synthesized according to example 5] (0,054 mmol, 0,54 mmol/g), 4-methylphenylboronic acid (0,5 mmol), Pd(PPh₃)₄ (20 mg), and 2 ml DMF are placed in a fritted polypropylene tube. The mixture is agitated at 80° got 24 h. After cooling to rt, the mixture is customary worked up for solid phase reactions. The. solid supported 6-(4- methylphenyl)quinazoline and 2 ml of a mixture of H2O, TFA and dichloromethane (1 :49:50) are placed in a fritted polypropylene tube. The contents are shaken for 2 h at rt. The suspension is filtered and the resin is washed with dichloromethane (1 ml) and methanol (1 ml) respectively. Evaporation of the combined filtrates give (3-aminomethyl-cyclohexylmethyl)-{2-[2-(4-benzyloxy-phenyl)-vinyl]-6-4- tolyl-quinazolin-4-yl}-amine;

MS calc: 568.8 ; found: 569.4.

Example 8:

Analogously to example 1, 7-chloro-2-methylquinazolin-4-one is reacted with 3,4-bis-benzyloxy-benzaldehyde, chlorinated and reacted

with C-(3-aminomethyl-cyclohexyl)-methylamine to obtain

(3-aminomethyl-cyclohexylmethyl)-{2-[2-(3,4-bis-benzyloxy-phenyl)- vinyl]-7-chloro-quinazolin-4-yl}-amine;

with N¹,N¹-diethyl-pentane-1 ,4-diamine to obtain

N⁴-{2-[2-(3,4-bis-benzyloxy-phenyl)-vinyl]-7-chloro-quinazolin-4-yl}-

N¹ ,N¹-diethyl-pentane-1 ,4-diamine;

with N¹ ,N¹-diethyl-propane-1 ,3-diamine to obtain

N'-{2-[2-(3,4-bis-benzyloxy-phenyl)-vinyl]-7-chloro-quinazolin-4-yl}-N,N- diethyl-propane-1 ,3-diamine; MS calc: 466.6 ; found: 467.3;

with 3-(4-methyl-piperazin-1-yl)-propylamine to obtain

{2-[2-(3,4-bis-benzyloxy-phenyl)-vinyl]-7-chloro-quinazolin-4-yl}-[3-(4- methyl-piperazin-1-yl)-propyl]-amine;

with 2,2-dimethyl-propane-1 ,3-diamine to obtain

N¹-{2-[2-(3,4-bis-benzyloxy-phenyl)-vinyl]-7-chloro-quinazolin-4-yl}-2,2- dimethyl-propane-1 ,3-diamine;

with 3-aminomethyl-benzylamine to obtain (3-aminomethyl-benzyI)-{2-[2-(3,4-bis-benzyloxy-phenyl)-vinyl]-7-chloro- quinazolin-4-yl}-amine;

with heptane-1 ,7-diamine to obtain

N¹-{2-[2-(3,4-bis-benzyloxy-phenyl)-vinyl]-7-chloro-quinazolin-4-yl}- heptane-1 ,7-diamine;

with N¹-(3-amino-propyl)-N¹-methyl-propane-1 ,3-diamine to obtain

N¹-(3-{2-[2-(3,4-bis-benzyloxy-phenyl)-vinyl]-7-chloro-quinazolin-4- ylamino}-propyl)-N¹-methyl-propane-1 ,3-diamine;

with 3-[4-(3-amino-propyl)-piperazin-1-yl]-propylamine to obtain

{3-[4-(3-amino-propyl)-piperazin-1-yl]-propyl}-{2-[2-(3,4-bis-benzyloxy- phenyl)-vinyl]-7-chloro-quinazolin-4-yl}-amine;

with C-cyclohexyl-methylamine to obtain ¹⁰ {2-[2-(3,4-bis-benzyloxy-phenyl)-vinyl]-7-chloro-quinazolin-4-yl}- cyclohexyl ethyl-amine;

with 3-(3-amino-propoxy)-propylamine to obtain

[3-(3-amino-propoxy)-propyl]-{2-[2-(3,4-bis-benzyloxy-phenyl)-vinyl]-7-

Λ chloro-quinazolin-4-yl}-amine;

with 3-morpholin-4-yl-propylamine to obtain

{2-[2-(3,4-bis-benzyloxy-phenyl)-vinyl]-7-chloro-quinazolin-4-yl}-(3- morpholin-4-yl-propyl)-amine.

20

Example 9:

Analogously to example 1 , 7-chloro-2-methylquinazolin-4-one is reacted with benzaldehyde, chlorinated and reacted

5 with 3-imidazol-1-yl-propylamine to obtain

(7-chloro-2-styryl-quinazolin-4-yl)-(3-imidazol-1-yl-propyl)-amine;

with N¹,N¹-diethyl-ethane-1 ,2-diamine to obtain

N^,-(7-chloro-2-styryl-quinazolin-4-yl)-N,N-diethyl-ethane-1 ,2-diamine;

30 with N¹,N¹-diethyl-propane-1 ,3-diamine to obtain N'-(7-chloro-2-styryl-quinazolin-4-yl)-N,N-diethyl-propane-1 ,3-diamine;

with 3-morpholin-4-yl-propylamine to obtain

(7-chloro-2-styryl-quinazolin-4-yl)-(3-morpholin-4-yl-propyl)-amine;

with 1-(3-amino-propyl)-pyrrolidin-2-one to obtain

1-[3-(7-chloro-2-styryl-quinazolin-4-ylamino)-propyl]-pyrrolidin-2-one;

with 4-(2-amino-ethyl)-phenylamine to obtain [2-(4-amino-phenyl)-ethyl]-(7-chloro-2-styryl-quinazolin-4-yl)-amine.

Analogously to example 1 , 7-chloro-2-methylquinazolin-4-one is reacted with 4-bromo-benzaldehyde, chlorinated and reacted

with N¹,N¹-diethyl-pentane-1 ,4-diamine to obtain

N⁴-{2-[2-(4-bromo-phenyl)-vinyl]-7-chloro-quinazolin-4-yl}- N¹,N¹-diethyl- pentane-1 ,4-diamine; MS calc: 501.9 ; found: 501.9.

Analogously to example 1 , 7-chloro-2-methylquinazolin-4-one is reacted with 3-phenyl-propenal, chlorinated and reacted

with N¹,N¹-diethyl-pentane-1 ,4-diamine to obtain

N⁴-[7-chloro-2-(4-phenyl-buta-1 ,3-dienyl)-quinazolin-4-yl]-N¹,N¹-diethyl- pentane-1 ,4-diamine;

MS calc: 414.6 ; found: 415.3.

Example 10:

1. Analogously to example 1 , 2-methylquinazolin-4-one is reacted with 4-bromo-benzaldehyde and chlorinated to obtain 2-[2-(4-bromo-phenyl)-vinyl]-4-chloro-quinazoline. 2. The resin-bound carbamate (1 ) (4,8 g, 0,54 mmol/g) [synthesized analogously to example 5.1], 2-[2-(4-bromo-phenyl)-vinyl]-4-chloro- quinazoline (6,6 mmol), triethylamine (1 ml) and 50 ml DMF are placed in a fritted polypropylene tube. The mixture is stirred at 80° for 60 hrs. After cooling to rt, the resin is customary worked up for solid phase reactions. Resin bound carbamate (3) is obtained.

3. The solid supported 2-bromostyrylquinazoline (3) (0,054 mmol, 0,54 mmol/g), phenylboronic acid (0,5 mmol), Pd(PPh₃)₄ (20 mg), triethylamine (20 ml) and 2 ml DMF are placed in a fritted polypropylene tube. The mixture is agitated at 80° for 24 h. After cooling to rt, the mixture is customary worked up for solid phase reactions. The solid-supported 2-(2- biphenyl-4-yl-vinyl)-quinazoline and 2 ml of a mixture of H₂O, TFA and dichloromethane (1 :49:50) is placed in a fritted polypropylene tube. The contents are shaken for 2 h at rt. The suspension is filtered and the resin is washed with dichloromethane (1 ml) and methanol (1 ml) respectively.

Evaporation of the combined filtrates give

(3-aminomethyl-cyclohexylmethyl)-[2-(2-biphenyl-4-yl-vinyl)-quinazolin-4-yl]- amine;

MS calc: 448.6 ; found: 449.4.

Analogously to example 10, 2-methylquinazolin-4-one is reacted with 4-bromo-benzaldehyde, chlorinated, reacted with resin bound carbamate (4) [synthesized analogously to example 5.1]

and phenylboronic acid to obtain N⁴-[2-(2-biphenyl-4-yl-vinyl)-7-chloro-quinazolin-4-yl]-N¹,N¹-diethyl- pentane-1 ,4-diamine; MS calc: 464.7 ; found: 465.2.

Example 11 : Analogously to example 10, 7-chloro-2-methylquinazolin-4-one is reacted with 4-bromo-benzaldehyde, chlorinated, reacted with resin bound carbamate (1 ) and phenylboronic acid to obtain (3-aminomethyl-cyclohexylmethyl)-[2-(2-biphenyl-4-yl-vinyl)-7-chloro- quinazolin-4-yl]-amine; MS calc: 483.1 ; found: 483.3.

Analogously to example 10, 7-chloro-2-methylquinazolin-4-one is reacted with 4-bromo-benzaldehyde, chlorinated, reacted

with resin bound carbamate (5) [synthesized analogously to example 5.1]

and phenylboronic acid to obtain N¹-[2-(2-biphenyl-4-yl-vinyl)-7-chloro-quinazolin-4-yl]-heptane-1 ,7- diamine; MS calc: 471.0 ; found: 471.4;

with resin bound carbamate (6) [synthesized analogously to example 5.1]

(6)

and phenylboronic acid to obtain

[3-(3-amino-propoxy)-propyl]-[2-(2-biphenyl-4-yl-vinyl)-7-chloro- quinazolin-4-yl]-amine; MS calc: 473.0 ; found: 473.3;

with resin bound carbamate (7) [synthesized analogously to example 5.1]

and phenylboronic acid to obtain

1-amino-3-[2-(2-biphenyl-4-yl-vinyl)-7-chloro-quinazolin-4-ylamino]- propan-2-ol; MS calc: 430.9 ; found: 431.2;

with resin bound carbamate (8) [synthesized analogously to example 5.1]

and phenylboronic acid to obtain

N¹-[2-(2-biphenyl-4-yl-vinyl)-7-chloro-quinazolin-4-yl]-2,2-dimethyl- propane-1 ,3-diamine;

with resin bound carbamate (9) [synthesized analogously to example 5.1]

and phenylboronic acid to obtain

{3-[4-(3-amino-propyl)-piperazin-1-yl]-propyl}-[2-(2-biphenyl-4-yl-vinyl)-7- chloro-quinazolin-4-yl]-amine; MS calc: 541.1 ; found: 541.3;

with resin bound carbamate (10) [synthesized analogously to example 5.1]

and phenylboronic acid to obtain N¹-{3-[2-(2-biphenyl-4-yl-vinyl)-7-chloro-quinazolin-4-ylamino]-propyl}-Nⁱ- methyl-propane-1 ,3-diamine; MS calc: 486.1 ; found: 486.2.

Example 12: Analogously to example 10, 6-iodo-2-methylquinazolin-4-one is reacted with 4-bromo-benzaldehyde, chlorinated, reacted with resin bound carbamate (1 ) and phenylboronic acid to obtain

(3-aminomethyl-cyclohexylmethyl)-[2-(2-biphenyl-4-yl-vinyl)-6-iodo- quinazolin-4-yl]-amine; MS calc: 574.5 ; found: 575.2.

Analogously to example 10, 6-iodo-2-methylquinazolin-4-one is reacted with 4-bromo-benzaldehyde, chlorinated, reacted

with resin bound carbamate (5) and phenylboronic acid to obtain

N¹-[2-(2-biphenyl-4-yl-vinyl)-6-iodo-quinazolin-4-yl]-heptane-1 ,7-diamine; MS calc: 562.5 ; found: 563.3;

with resin bound carbamate (6) and phenylboronic acid to obtain [3-(3-amino-propoxy)-propyl]-[2-(2-biphenyl-4-yl-vinyl)-6-iodo-quinazolin-

4-yl]-amine; MS calc: 564.5 ; found: 565.2;

with resin bound carbamate (7) and phenylboronic acid to obtain 1-amino-3-[2-(2-biphenyl-4-yl-vinyl)-6-iodo-quinazolin-4-ylamino]-propan-

2-ol; MS calc: 522.4 ; found: 523.2; with resin bound carbamate (8) and phenylboronic acid to obtain

N¹-[2-(2-biphenyl-4-yl-vinyl)-6-iodo-quinazolin-4-yl]-2,2-dimethyl- propane-1 ,3-diamine; MS calc: 534.4 ; found: 535.2;

with resin bound carbamate (9) and phenylboronic acid to obtain

{3-[4-(3-amino-propyl)-piperazin-1-yl]-propyl}-[2-(2-biphenyl-4-yl-vinyl)-6- iodo-quinazolin-4-yl]-amine; MS calc: 632.6 ; found: 633.2;

with resin bound carbamate (10) and phenylboronic acid to obtain

N¹-{3-[2-(2-biphenyl-4-yl-vinyl)-6-iodo-quinazolin-4-ylamino]-propyl}-N¹- methyl-propane-1 ,3-diamine; MS calc: 577.5 ; found: 578.1.

Example 13:

Analogously to example 10, 7-chloro-2-methylquinazolin-4-one is reacted with 4-bromo-benzaldehyde, chlorinated, reacted with resin bound carbamate (1 ) and

2-methylphenylboronic acid to obtain

(3-aminomethyl-cyclohexylmethyl)-{7-chloro-2-[2-(2'-methyl-biphenyl-4- yl)-vinyl]-quinazolin-4-yl}-amine; MS calc: 497.1 ; found: 497.4;

2,4-dichlorophenylboronic acid

(3-aminomethyl-cyclohexylmethyl)-{7-chloro-2-[2-(2',4'-dichloro-biphenyl- 4-yl)-vinyl]-quinazolin-4-yl}-amine; MS calc: 551.9 ; found: 551.3;

4-fluorophenylboronic acid (3-aminomethyl-cyclohexylmethyl)-{7-chloro-2-[2-(4'-fluoro-biphenyl-4-yl)- vinyl]-quinazolin-4-yl}-amine; MS calc: 501.1 ; found: 501.4;

naphthylboronic acid

(3-aminomethyl-cyclohexylmethyl)-{7-chloro-2-[2-(4-naphthalen-1-yl- phenyl)-vinyl]-quinazolin-4-yl}-amine; MS calc: 533.1 ; found: 533.4;

4-methoxyphenylboronic acid

(3-aminomethyl-cyclohexylmethyl)-{7-chloro-2-[2-(4'-methoxy-biphenyl-4- yl)-vinyl]-quinazolin-4-yl}-amine; MS calc: 513.1 ; found: 513.4;

3,4, 5-trimethoxyphenylboronic acid

(3-aminomethyl-cyclohexylmethyl)-{7-chloro-2-[2-(3',4^,,5^,-trimethoxy- biphenyl-4-yl)-vinyl]-quinazolin-4-yl}-amine; MS calc: 573.1 ; found: 573.4;

3-acetylaminophenylboronic acid

N-[4'-(2-{4-[(3-aminomethyl-cyclohexylmethyl)-amino]-7-chloro- quinazolin-2-yl}-vinyl)-biphenyl-3-yl]-acetamide; MS calc: 540.1 ; found: 540.4;

3-acetylphenylboronic acid 1-[4'-(2-{4-[(3-aminomethyl-cyclohexylmethyl)-amino]-7-chloro- quinazolin-2-yl}-vinyl)-biphenyl-3-yl]-ethanone; MS calc: 525.1 ; found: 525.4;

benzo[b]-thiophen-2-ylboronic acid

(3-aminomethyl-cyclohexylmethyl)-{2-[2-(4-benzo[b]thiophen-2-yl- phenyl)-vinyl]-7-chloro-quinazolin-4-yl}-amine;

3,5-bis-trifluoromethylphenylboronic acid (3-aminomethyl-cyclohexylmethyl)-{2-[2-(3\5'-bis-trifluoromethyl- biphenyl-4-yl)-vinyl]-7-chloro-quinazolin-4-yl}-amine;

3-nitrophenylboronic acid

(3-aminomethyl-cyclohexylmethyl)-{7-chloro-2-[2-(3'-nitro-biphenyl-4-yl)- vinyl]-quinazolin-4-yl}-amine;

MS calc: 528.1 ; found: 528.3;

thiophenylboronic acid

(3-aminomethyl-cyclohexylmethyl)-{7-chloro-2-[2-(4-thiophen-2-yl- phenyl)-vinyl]-quinazolin-4-yl}-amine; MS calc: 489.1 ; found: 489.4;

3-aminophenylboronic acid

(3-aminomethyl-cyclohexylmethyl)-{7-chloro-2-[2-(3'-amino-biphenyl-4- yl)-vinyl]-quinazolin-4-yl}-amine; MS calc: 498.1 ; found: 498.4;

3-isopropylphenylboronic acid

(3-aminomethyl-cyclohexylmethyl)-{7-chloro-2-[2-(3'-isopropyl-biphenyl- 4-yl)-vinyl]-quinazolin-4-yl}-amine;

MS calc: 525.1 ; found: 525.4;

pyridin-3-ylboronic acid

(3-aminomethyl-cyclohexylmethyl)-{7-chloro-2-[2-(4-pyridin-3-yl-phenyl)- vinyl]-quinazolin-4-yl}-amine;

MS calc: 484.0 ; found: 484.4.

Example 14:

Analogously to example 10, 7-chloro-2-methylquinazolin-4-one is reacted with 5-bromo-furan-2-carbaldehyde, chlorinated, reacted with resin bound carbamate (1) and

3-chlorophenylboronic acid to obtain

(3-aminomethyl-cyclohexylmethyl)-(7-chloro-2-{2-[5-(3-chloro-phenyl)- furan-2-yl]-vinyl}-quinazolin-4-yl)-amine; MS calc: 507.5 ; found: 507.8.

Example 15:

Analogously to example 10, 7-chloro-2-methylquinazolin-4-one is reacted with 5-bromo-tfιiophene-2-carbaldehyde, chlorinated, reacted with resin bound carbamate (1 ) and thiophen-2-ylboronic acid to obtain

(3-aminomethyl-cyclohexylmethyl)-[2-(2-[2,2']bithiophenyl-5-yl-vinyl)-7- chloro-quinazolin-4-yl]-amine

Analogously to example 10, 7-chloro-2-methylquinazolin-4-one is reacted with 5-bromo-thiophene-2-carbaldehyde, chlorinated, reacted

with resin bound carbamate (4) and thiophenylboronic acid to obtain

N⁴-[2-(2-[2,2^,]bithiophenyl-5-yl-vinyl)-7-chloro-quinazolin-4-yl]-N¹,N¹- diethyl-pentane-1 ,4-diamine; MS calc: 511.2 ; found: 511.1 ;

with resin bound carbamate (11 )

and thiophenylboronic acid to obtain

N'-[2-(2-[2,2']bithiophenyl-5-yl-vinyl)-7-chloro-quinazolin-4-yl]-N,N-diethyl- ethane-1,2-diamine; MS calc: 469.1 ; found: 469.1 ;

with resin bound carbamate (12)

and thiophenylboronic acid to obtain N^*-[2-(2-[2,2^,]bithiophenyl-5-yl-vinyl)-7-chloro-quinazolin-4-yl]-N,N-diethyl- propane-1 ,3-diamine; MS calc: 483.1 ; found: 483.1 ;

with resin bound carbamate (13)

and thiophenylboronic acid to obtain N¹-[2-(2-[2,2']bithiophenyl-5-yl-vinyl)-7-chloro-quinazolin-4-yl]-propane-

1 ,3-diamine; MS calc: 427.0 ; found: 427.4;

with resin bound carbamate (14)

and thiophenylboronic acid to obtain

(3-aminomethyl-benzyl)-[2-(2-[2,2']bithiophenyl-5-yl-vinyl)-7-chloro- quinazolin-4-yl]-amine;

MS calc: 489.1 ; found: 489.1 ;

with resin bound carbamate (5) and thiophenylboronic acid to obtain N¹-[2-(2-[2,2']bithiophenyl-5-yl-vinyl)-7-chloro-quinazolin-4-yl]-heptane- 1 ,7-diamine;

MS calc: 483.1 ; found: 483.2;

with resin bound carbamate (10) and thiophenylboronic acid to obtain N¹-{3-[2-(2-[2,2']bithiophenyl-5-yl-vinyl)-7-chloro-quinazolin-4-ylamino]- propyl}-N¹-methyl-propane-1 ,3-diamine; MS calc: 498.1 ; found: 498.1 ; with resin bound carbamate (9) and thiophenylboronic acid to obtain

{3-[4-(3-amino-propyl)-piperazin-1-yl]-propyl}-[2-(2-[2,2']bithiophenyl-5-yl- vinyl)-7-chloro-quinazolin-4-yl]-amine;

MS calc: 553.2 ; found: 553.2;

with resin bound carbamate (15) o rγ ^Λ°-o (I,

and thiophenylboronic acid to obtain

[2-(2-[2,2']bithiophenyl-5-yl-vinyl)-7-chloro-quinazolin-4-yl]-piperidin-4- ylmethyl-amine; MS calc: 467.1 ; found: 467.2;

with resin bound carbamate (6) and thiophenylboronic acid to obtain

[3-(3-amino-propoxy)-propyl]-[2-(2-[2,2']bithiophenyl-5-yl-vinyl)-7-chloro- quinazolin-4-yl]-amine; MS calc: 485.1 ; found: 485.2;

with resin bound carbamate (16)

and thiophenylboronic acid to obtain [2-(2-[2,2']bithiophenyl-5-yl-vinyl)-7-chloro-quinazolin-4-yl]-pyridin-4- ylmethyl-amine; MS calc: 461.0 ; found: 461.2.

Analogously to example 10, 6-iodo-2-methylquinazolin-4-one is reacted with 5-bromo-thiophene-2-carbaldehyde, chlorinated, reacted with resin bound carbamate (1) and thiophen-2-ylboronic acid to obtain

(3-aminomethyl-cyclohexylmethyl)-[2-(2-[2,2']bithiop.henyl-5-yl-vinyl)-6- iodo-quinazolin-4-yl]-amine.

with resin bound carbamate (12) and thiophen-2-ylboronic acid to obtain

N'-[2-(2-[2,2']bithiophenyl-5-yl-vinyl)-6-iodo-quinazolin-4-yl]-N,N-diethyl- propane-1 ,3-diamine; MS calc: 574.5 ; found: 575.2.

EXAMPLES RELATED TO PHARMACOLOGICAL PREPARATIONS

Example A: Injection vials

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 3 I of double-distilled water using 2N hydrochloric acid, sterile-filtered, dispensed into injection vials, lyophilized under sterile conditions and aseptically sealed. Each injection vial contains 5 mg of active compound.

Example B: 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 moulds and allowed to cool. Each suppository contains 20 mg of active compound.

Example C: Solution

A solution is prepared from 1 g of an active compound of the formula I, 9.38 g of NaH₂PO₄.2H₂O, 28.48 g of Na₂HPO₄.12H₂O and 0.1 g of benzalkonium chloride in 940 ml of double-distilled water. The mixture is adjusted to pH 6.8, made up to 1 I and sterilized by irradiation. This solution can be used in the form of eye drops.

Example D: Ointment 500 mg of an active compound of the formula I is mixed with 99.5 g of petroleum jelly under aseptic conditions.

Example E: Tablets A mixture of 1 kg of active compound of the formula I, 4 kg of lactose,

1.2 kg of potato starch, 0.2 g of talc and 0.1 kg of magnesium stearate is compressed in a customary manner to give tablets such that each tablet contains 10 mg of active compound.

Example F: Coated tablets

Analogously to Example E, tablets are pressed which are then coated with a coating of sucrose, potato starch, talc, tragacanth and colorant in a customary manner.

Example G: Capsules

2 kg of active compound of the formula I are dispensed into hard gelatin capsules in a customary manner such that each capsule contains 20 mg of the active compound.

Example H: Ampules

A solution of 1 kg of active compound of the formula I in 60 ml of double- distilled water is sterile-filtered, dispensed into ampoules, lyophilized under sterile conditions and aseptically sealed. Each ampoule contains 10 mg of active compound.

Claims

What is claimed is:

Use of compounds of the formula I

in which R and R¹ are independently of each other H, A, OH, OA, Hal, N(R )₂, NO₂, CN, C(O)R², CON(R⁵)₂, COOR⁵, allyl, CH=CH-COOR⁵, CH=CHCON(R⁵)₂, SO₂A or phenyl, which is unsubstituted or mono-, di- or trisubstituted by A,

R² and R³ aarree iinnddeeppeennddeennttllyy ooff eeaacchh ootthheerr H, A, cycloalkyl, -Het³, -(CH₂)_o-OR⁵, -(CH₂)₀-OR⁶, -(CH₂)o-Het¹, -(CH₂)₀-NR⁵-Het¹,

- ((CCHHAA))pp--((CCHH₂₂))o₀--NN((RR⁵⁵))₂₂,, --((CH₂)_p-(CHA)_p-(CH₂)m-Ar, (CH₂)o-Z-(CH₂)_q-N(R⁵)2,

provided that R² and R³ together are not H, or

NR²R³ together form a saturated monocyclic heterocyclic radical having 5 to 6 ring members, where 1 or 2 N atoms are present and the heterocyclic radical can be mono- or disubstituted by OH, Ar, OAr or arylalkyl,

R⁴ is Ar or Het¹,

R⁵ is H or A,

R⁶ is benzo[1 ,3]dioxol-5-yl, Q is O or S,

Y is (CH=CH)_n,

Z is phenylene, cyclohexylene, -NR⁵-, O, -CH(OH)-, -CA₂- or

A is unbranched or branched alkyl having 1 to 6 carbon atoms,

Ar is phenyl, naphthyl or biphenyl, which is unsubstituted or mono-, di- or trisubstituted by A, OH, OA, cycloalkyloxy, _fJ O-(CH₂)_p-Ph, CF₃, OCF₃, Hal, CN, CHO, COA, COOR⁵,

N(R⁵)₂, NR⁵-COA, NO₂, SO₂N(R⁵)₂, mor, SO₂-mor, 5-methyl- 3-oxo-2,4-dihydropyrazol-2-yl, naphthyl or Het², Het¹ is a saturated, partially or completely unsaturated mono- or bicyclic heterocyclic radical having 5 to 10 ring members, c where 1 or 2 N and/or 1 or 2 S or O atoms can be present and the heterocyclic radical can be mono- or disubstituted by A, Hal, OH, OA, CF₃, OCF₃, N(R⁵)₂, carbonyl oxygen, COOR⁵, Het², benzyl or phenyl which is unsubstituted or mono-, di- or trisubstituted by A, OH, OA, CF₃, OCF₃, Hal, CN, COOR⁵, o ^N(^R5)2. NO₂ or SO₂N(R⁵)₂,

Het² is a unsaturated mono- or bicyclic heterocyclic radical having

5 to 10 ring members, where 1 or 2 N and/or 1 or 2 S or O atoms can be present and the heterocyclic radical can be mono- or disubstituted by A, Hal, OH, OA, CF₃, OCF₃, N(R⁵)_{2 5} or COOR⁵,

Het³ is a partially or completely unsaturated mono- or bicyclic heterocyclic radical having 5 to 10 ring members, where 1 or 2 N atoms are present and the heterocyclic radical can be mono- or disubstituted by A, Hal, OH, OA, CF_3l OCF₃, N(R⁵)₂, Q SO₂A or COOR⁵ provided that the heterocyclic radical is not bondend via an N atom, Hal is F. CI, Br or l, mor is morpholin-4-yl,

Ph is phenyl, n is 1 or 2, m is 0, 1 , 2, 3, 4, 5 or 6, o is 1, 2, 3, 4, 5, 6 or 7, p is 0, 1 , 2, 3 or 4, q is 1 , 2, 3 or 4, and their pharmaceutically tolerable salts and solvates for the preparation of a medicament for the treatment of hyperproliferative disorders.

2. Use according to claim 1 wherein the disorders are selected from cancer, psoriasis, arthritis, inflammation, endometriosis, scarring or begnin prostatic hyperplasia.

3. Use according to claim 1 or 2 of compounds of the formula I

in which R and R¹ are independently of each other H, A, OH, OA, Hal, N(R⁵)₂,

NO₂, CN, C(O)R², CON(R⁵)₂, COOR⁵, allyl, CH=CH-COOR⁵,

CH=CHCON(R⁵)₂, SO₂A or phenyl, which is unsubstituted or mono-, di- or trisubstituted by A,

R is H, R³ is -(CH₂)₀-Z-(CH₂)_q-N(R⁵)₂, R⁴ is Ar, R⁵ is H or A, Y is (CH=CH)_n, z is phenylene, cyclohexylene, -NR⁵-, O, -CH(OH)-, -CA₂- or

A is unbranched or branched alkyl having 1 to 6 carbon atoms, Ar is phenyl or naphthyl, which is unsubstituted or mono-, di- or trisubstituted by A, OH, OA, CF₃, OCF₃, Hal, CN, CHO, COA,

COOR⁵, N(R⁵)₂, NO₂ or SO₂N(R⁵)₂,

Hal is F, CI, Br or l, n is 1 or 2, o is 1, 2, 3, 4, 5, 6 or 7, q is 1 , 2, 3 or 4, and their pharmaceutically tolerable salts and solvates.

Use according to claim 1 or 2 of compounds of the formula I

in which R and R¹ are independently of each other H, A, OH, OA, Hal, N(R⁵)₂,

NO₂, CN, C(O)R², CON(R⁵)₂, COOR⁵, allyl, CH=CH-COOR⁵,

CH=CHCON(R⁵)₂, SO₂A or phenyl, which is unsubstituted or mono-, di- or trisubstituted by A,

R² and R³ are independently of each other H, A, cycloalkyl, -Het³,

-(CH₂)o-OR⁵, -(CH₂)₀-OR⁶, -(CH₂)₀-Het¹, -(CH₂)₀-NR⁵-Het¹,

-(CHA)_P-(CH₂)₀-N(R⁵)₂, -(CH₂)_p-(CHA)_p-(CH₂)_m-Ar or

-(CH₂)o-Z-(CH₂)_q-N(R⁵)₂, provided that R² and R³ together are not H,

R⁴ is Ar, is H or A, R⁶ is benzo[1 ,3]dioxol-5-yl,

Y is (CH=CH)_n,

Z is phenylene, cyclohexylene, -NR⁵-, O, -CH(OH)-, -CA₂- or

A is unbranched or branched alkyl having 1 to 6 carbon atoms,

Ar is phenyl, which is mono-, di- or trisubstituted by O-(CH₂)_p-Ph, naphthyl or Het², or biphenyl, which is unsubstituted or mono-, ₁₀ di- or trisubstituted by A, OH, OA, CF₃, OCF₃, Hal, CN, CHO,

COA, COOR⁵, N(R⁵)₂, NR⁵-COA, NO₂, SO₂N(R⁵)₂, naphthyl or Het², Het¹ is a saturated, partially or completely unsaturated mono- or bicyclic heterocyclic radical having 5 to 10 ring members, Λ _c where 1 or 2 N and/or 1 or 2 S or O atoms can be present and the heterocyclic radical can be mono- or disubstituted by A, Hal, OH, OA, CF_3l OCF₃, N(R⁵)₂, carbonyl oxygen, COOR⁵, Het², benzyl or phenyl which is unsubstituted or mono-, di- or trisubstituted by A, OH, OA, CF₃, OCF₃, Hal, CN, COOR⁵, 0 N(R⁵)2, NO₂ or SO₂N(R⁵)₂,

Het² is a unsaturated mono- or bicyclic heterocyclic radical having

5 to 10 ring members, where 1 or 2 N and/or 1 or 2 S or O atoms can be present and the heterocyclic radical can be mono- or disubstituted by A, Hal, OH, OA, CF₃, OCF₃, N(R⁵)_{2 5} or COOR³

Het³ is a partially or completely unsaturated mono- or bicyclic heterocyclic radical having 5 to 10 ring members, where 1 or 2 N atoms are present and the heterocyclic radical can be mono- or disubstituted by A, Hal, OH, OA, CF₃, OCF₃, N(R⁵)₂, Q SO₂A or COOR⁵ provided that the heterocyclic radical is not bondend via an N atom,

Hal is F, CI, Br or l, Ph is phenyl, n is 1 or 2, m is O, 1 , 2, 3, 4, 5 or 6,

0 is 1 , 2, 3,

4, 5, 6 or 7,

P is O, 1 , 2, 3 or 4, q is 1 , 2, 3 or 4, and their pharmaceutically tolerable salts and solvates.

5. Use according to claim 1 or 2 of compounds of the formula

in which R and R¹ are independently of each other H, A, OH, OA, Hal, N(R⁵)₂, NO₂, CN, C(O)R², CON(R⁵)₂, COOR⁵, allyl, CH=CH-COOR⁵, CH=CHCON(R⁵)₂, SO₂A or phenyl, which is unsubstituted or mono-, di- or trisubstituted by A,

R² and R³ are independently of each other H, A, cycloalkyl, -Het³, -(CH₂)_o-OR⁵, -(CH₂)_o-OR⁶, -(CH₂)₀-Het¹, -(CH₂)₀-NR⁵-Het¹, -(CHA)_p-(CH₂)o-N(R⁵)₂, -(CH₂)p-(CHA)p-(CH₂)_m-Ar, -(CH₂)o-Z-(CH₂)_q-N(R⁵)2,

provided that R² and R³ together are not H, or NR²R³ together form a saturated monocyclic heterocyclic radical having 5 to 6 ring members, where 1 or 2 N atoms are present and the heterocyclic radical can be mono- or disubstituted by OH, Ar, OAr or arylalkyl, 5 R⁴ is Het¹,

R⁵ is H or A,

R⁶ is benzo[1 ,3]dioxol-5-yl,

Q is O or S,

Y is (CH=CH)_n,

10 Z is phenylene, cyclohexylene, -NR⁵-, O, -CH(OH)-, -CA₂- or

A is unbranched or branched alkyl having 1 to 6 carbon atoms,

,_{| c} Ar is phenyl, naphthyl or biphenyl, which is unsubstituted or mono-, di- or trisubstituted by A, OH, OA, cycloalkyloxy, 0-(CH₂)_p-Ph, CF₃, OCF₃, Hal, CN, CHO, COA, COOR⁵, N(R⁵)₂, NR⁵-COA, NO₂, SO₂N(R⁵)₂, mor, SO₂-mor, 5-methyl- 3-oxo-2,4-dihydropyrazol-2-yl, naphthyl or Het², 0 Het¹ is a saturated, partially or completely unsaturated mono- or bicyclic heterocyclic radical having 5 to 10 ring members, where 1 or 2 N and/or 1 or 2 S or O atoms can be present and the heterocyclic radical can be mono- or disubstituted by A, Hal, OH, OA, CF₃, OCF₃, N(R⁵)₂, carbonyl oxygen, COOR⁵, Het², benzyl or phenyl which is unsubstituted or mono-, di- or trisubstituted by A, OH, OA, CF₃, OCF₃, Hal, CN, COOR⁵, N(R⁵)_2> Nθ2θr SO₂N(R⁵)2, Het² is a unsaturated mono- or bicyclic heterocyclic radical having

5 to 10 ring members, where 1 or 2 N and/or 1 or 2 S or Q O atoms can be present and the heterocyclic radical can be mono- or disubstituted by A, Hal, OH, OA, CF₃, OCF₃, N(R⁵)₂ or COOR⁵, Het³ is a partially or completely unsaturated mono- or bicyclic heterocyclic radical having 5 to 10 ring members, where 1 or 2 N atoms are present and the heterocyclic radical can be mono- or disubstituted by A, Hal, OH, OA, CF₃, OCF₃, N(R⁵)₂, SO₂A or COOR⁵ provided that the heterocyclic radical is not bondend via an N atom,

Hal is F. CI, Br or l, mor is morpholin-4-yl,

Ph is phenyl, n is 1 or 2, m is 0, 1 , 2, 3, 4, 5 or 6, o is 1 , 2, , 3, 4, 5, 6 or 7, p is 0, 1 , 2, 3 or 4, q is 1 , 2, 3 or 4, and their pharmaceutically tolerable salts and solvates.

6. Use of compounds of the formula I according to claim 1 or 2 selected from the group a) (7-chloro-2-styryl-quinazolin-4-yl)-(3-imidazol-1-yl-propyl)-amine, b) N'-(7-chloro-2-styryl-quinazolin-4-yl)-N,N-diethyl-ethane-1 ,2-diamine, c) N'-(7-chloro-2-styryl-quinazolin-4-yl)-N,N-diethyl-propane-1 ,3-diamine, d) (7-chloro-2-styryl-quinazolin-4-yl)-(3-morpholin-4-yl-propyl)-amine, e) 1-[3-(7-chloro-2-styryl-quinazolin-4-ylamino)-propyl]-pyrrolidin-2-one, f) [2-(4-amino-phenyl)-ethyl]-(7-chloro-2-styryl-quinazolin-4-yl)-amine, g) N⁴-{2-[2-(4-bromo-phenyl)-vinyl]-7-chloro-quinazolin-4-yl}-N¹,N¹- diethyl-pentane-1 ,4-diamine and h) N⁴-[7-chloro-2-(4-phenyl-buta-1 ,3-dienyl)-quinazolin-4-yl]-N¹ ,N¹- diethyl-pentane-1 ,4-diamine and their pharmaceutically tolerable salts and solvates.

7. Use of compounds of the formula I according to claim 1 or 2 selected from the group a) N'-[2-(2-[2,2']bithiophenyl-5-yl-vinyl)-6-iodo-quinazolin-4-yl]-N,N- diethyl-propane-1 ,3-diamine, b) (3-aminomethyl-cyclohexylmethyl)-[2-(2-[2,2']bithiophenyl-5-yl-vinyl)-7- chloro-quinazolin-4-yl]-amine and their physiologically acceptable salts and solvates.

8. Use of compounds of the formula I according to claim 1 and their physiologically acceptable salts or solvates as PKB inhibitors.

9. Use according to claim 8 of compounds of formula I and there physiological acceptable salts or solvates for inhibiting PKBα and/or PKBβ and/or PKBβ- and /or PKBγ and /or PKBγ_t.

10. Use according to claim 8 or 9 of compounds of the formula I and their physiologically acceptable salts or solvates as PKB inhibitor for the control of hyperproliferative disorders.

11. Use according to claim 10 of compounds of the formula I for the treatment of hyperproliferative disorders, wherein the disease is cancer.

12. Use according to claim 11 of compounds of formula I, wherein the diseases are cancers of brain, lung, squamous cell, bladder, stomach, pancreas, liver, kidney, colon, breast, head, neck, oesophagus, cervix, placenta, thyroid, skin and melanoma, lymphoma, chronic leukaemia and acute leukaemia.

13. Use according to claim 10 of compounds of the formula I for the treatment of hyperproliferative disorders, wherein the diseases are psoriasis, arthritis, inflammation, endometriosis, scarring or begnin prostatic hyperplasia.

14. Use according to claim 9 or 10 of compounds of the formula I for the examination of PKB dependent signal transduction in animal and/or cell culture models.