WO2004030672A1 - Utilisation de 4 amino-quinazolines comme agents anticancereux - Google Patents

Utilisation de 4 amino-quinazolines comme agents anticancereux Download PDF

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Publication number
WO2004030672A1
WO2004030672A1 PCT/EP2003/009392 EP0309392W WO2004030672A1 WO 2004030672 A1 WO2004030672 A1 WO 2004030672A1 EP 0309392 W EP0309392 W EP 0309392W WO 2004030672 A1 WO2004030672 A1 WO 2004030672A1
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Prior art keywords
phenyl
methyl
quinazolin
chloro
het
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PCT/EP2003/009392
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English (en)
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Gerhard Barnickel
Hans-Michael Eggenweiler
Volker Eiermann
Rolf Gericke
Wilfried Rautenberg
Christian Sirrenberg
Burkhard Scharm
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Merck Patent Gmbh
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Priority to AU2003255482A priority Critical patent/AU2003255482A1/en
Publication of WO2004030672A1 publication Critical patent/WO2004030672A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine

Definitions

  • the present invention provides compositions and methods for modulating the activity of PKB.
  • 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.
  • 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.
  • 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.
  • 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 PKB ⁇ revealed homology within the kinase domains to the PKA (-68%) and PKC isozymes (-73%) (Jones et al., Proc.
  • PKB ⁇ 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.
  • 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)P 3 level in the cell by dephosphorylation of Ptdlns(3, 4, 5)P 3 .
  • Ptdlns(3, 4, 5)P 3 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.
  • 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.
  • 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.
  • interfering compounds Stephens et al., Biochemical J., 2000, 351 , 95- 105 were used for signal modulation.
  • Non-radioactive ELISA based assay methods use specific phospho- antibodies (AB).
  • AB phospho- antibodies
  • 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).
  • R 2 and R 3 are independently of each other H, A, cycloalkyl, -Het 3 , -(CH 2 ) 0 -OR 5 , -(CH 2 ) o -OR 6 , -(CH 2 ) 0 -Het, -(CH 2 ) 0 -NR 5 -Het, -(CHA) p -(CH 2 ) 0 -N(R 5 ) 2 , -(CH 2 )p-(CHA) p -(CH 2 ) m -Ar, -(CH 2 ) 0 -Z-(CH 2 ) q -N(R 5 ) 2 ,
  • R 2 and R 3 together are not H, or NR 2 R 3 together form a saturated monocyclic heterocyclic radical having
  • R 4 is Ar or Het 1
  • R 5 is H or A
  • R 6 is benzo[1 ,3]dioxol-5-yl
  • R 7 is H, A, cycloalkyl or -(CH 2 ) q -OR 5
  • Q is O or S
  • Y is a direct bond, (CH 2 ) n or -NR 5 -(CH 2 ) m -,
  • Z is phenylene, cyclohexylene, -NR 5 -, O, -CH(OH)-, -CA 2 - 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-(CH 2 ) p -Ph, CF 3 , OCF 3 , Hal, CN, CHO, COA, COOR 5 ,
  • Het 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 ,. 5 the heterocyclic radical can be mono- or disubstituted by A,
  • Het 2 is a unsaturated mono- or bicyclic heterocyclic radical having
  • 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, CF 3 , OCF 3 , N(R 5 ) 2 , 5 -(CH 2 ) p -(CHA)p-N(R 5 )-(CH 2 ) q -COR 5 , CHO, COA or COOR 5 ,
  • Het 3 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 3 , OCF 3 , N(R 5 ) 2 , n SO 2 A or COOR 5 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 , 2, 3, 4, 5 or 6,
  • 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.
  • 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.
  • 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.
  • R and R 1 have a meaning indicated in Claim 1 , is reacted with a compound of the formula III
  • R 4 has a meaning indicated in Claim 1 and Y is a direct bond or (CH 2 ) n , and X is CI, Br, OH or a reactive esterified OH group followed by converting the cyano group to an amide group by conventional means to give a compound of formula IV
  • R and R 1 have a meaning indicated in Claim 1 , is reacted with a compound of formula VII
  • 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.
  • 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.
  • 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.
  • 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
  • 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, 0-(CH 2 ) p -Ph, CF 3 , OCF 3 , Hal, CN, CHO, COA, COOR 5 , -(CH 2 )p-N(R 7 ) 2 , NR 5 -COA, N0 2 , S0 N(R 5 ) 2 , mor, S0 2 -mor, 5-methyl-3-oxo-2,4-dihydropyrazol-2-yl, naphthyl or Het 2 .
  • 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- or4-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- or4-methoxyphenyl, 2-, 3- or 4-ethoxyphenyl, 2-, 3- or 4-pentoxyphenyl, 2-, 3- or 4-phenoxyphenyl, 2-, 3- or 4-phenylmethoxyphenyl, 2-, 3- or
  • Ar is also preferentially unsubstituted naphthyl or biphenyl - as indicated - or alternatively mono-, di- or trisubstituted
  • biphenyl specifically preferentially biphenyl-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, n 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
  • Arylalkyl is preferentially benzyl.
  • 0-(CH ) 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 cyclopentylmethyl, cyclopentylethyl or cyclohexylmethyl; cyclopentyl, cyclohexylmethyl or cyclohexyl are particularly preferred.
  • Hal is preferably F, CI, Br or I.
  • Het 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, CF 3 , OCF 3 , N(R 5 ) 2> carbonyl oxygen, COOR 5 , Het 2 , benzyl or phenyl which is unsubstituted or mono-, di- or trisubstituted by A, OH, OA, CF 3 , OCF 3 , Hal, CN, COOR 5 , N(R 5 ) , N0 2 , S0 2 N(R 5 ) 2 .
  • Het 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-l-, -4- or -5-yl, 1 ,2,4-triazol-1-, -4- or -5-yl, 1- or 5-tetrazolyl, 1 ,2,3-oxadiazol-4- or -5-yl, 1 ,2,4-oxadiazol-3- or
  • 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-yl, 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
  • Het 1 is thiophen-2-yl which is substituted by Ar or Het 2 , in which Ar and Het 2 have one of the above or below mentioned meanings.
  • Het 2 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, CF 3 , OCF 3 , N(R 5 ) 2 , -(CH 2 )p-(CHA)p-N(R 5 )-(CH 2 ) q -COR 5 . CHO, COA or COOR 5 .
  • Het 2 is particularly preferred for Het 2 .
  • Het 3 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 3 , OCF 3 , N(R 5 ) 2 , S0 2 A or COOR 5 provided that the heterocyclic radical is not bondend via an N atom.
  • (CH 2 ) 0 -NR 5 -Het is preferentially (5-nitro-pyridin-2-yl)-amino-ethyl.
  • (CH 2 ) 0 -OR 5 is preferentially (CH 2 ) 2 -OCH 3 , (CH 2 ) 3 -OCH 3 or (CH 2 ) 3 -0(iPr).
  • (CH 2 ) o -OR° is preferentially
  • R is preferentially H or OA.
  • H, A, OA or CI is particularly preferred for R 1 .
  • R 1 is the 6- or 7-position of the quinazoline ring system.
  • R 2 and R 3 are independently of each other H, A, cycloalkyl, -Het 3 , -(CH 2 ) 0 - OR 5 , -(CH 2 )o-OR 6 , -(CH 2 ) 0 -Het, -(CH 2 ) 0 -NR 5 -Het, -(CHA) p -(CH 2 )o-N(R 5 ) 2 .
  • R 2 and R 3 together are not H, where A, Ar, cycloalkyl, Het or Het 3 have a preferred meaning indicated beforehand and R 5 , R 6 , Q, Z, m, o, p and q have a preferred meaning indicated in the following.
  • R 2 is preferentially H or A.
  • R 3 is preferentially A, cycloalkyl, -Het 3 , -(CH 2 ) 0 -OR 5 , -(CH 2 ) 0 -OR 6 , -(CH 2 ) 0 - Het, -(CH 2 ) 0 -NR 5 -Het, -(CHA) P -(CH 2 ) 0 -N(R 5 ) 2 , -(CH 2 )p-(CHA) p -(CH 2 ) m -Ar, -(CH 2 )o-Z-(CH 2 ) q -N(R 5 ) 2 -
  • NR 2 R 3 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.
  • NR 2 R 3 are particularly preferred for NR 2 R 3 .
  • R 4 is Ar or Het 1 , where Ar or Het 1 have a preferred meaning indicated beforehand.
  • R 5 is H or A, where A has a preferred meaning indicated beforehand.
  • R 6 is benzo[1 ,3]dioxol-5-yl.
  • R 7 is H, A, cycloalkyl or (CH 2 ) q -OR 5 , where A, cycloalkyl and R 5 have a preferred meaning indicated beforehand and q is preferrably 2 or 3.
  • Q is O or S, preferentially O.
  • Y is a direct bond, (CH 2 ) n or -NR 5 -(CH2)m-, where R 5 has a preferred meaning indicated beforehand and n and m have a preferred meaning indicated in the following.
  • Y is preferentially a direct bond or (CH2) n , very particularly preferably a direct bond.
  • Z is phenylene, cyclohexylene, -NR 5 -, O, -CH(OH)-, -CA 2 - or
  • Phenylene and/or cyclohexylene are particularly bonded in 1 ,4- or 1 ,3-position.
  • n is 1 , 2, 3, 4, 5 or 6, preferentially 4.
  • m is 0, 1 , 2, 3, 4, 5 or 6, preferentially 0, 1 , 2 or 3.
  • 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.
  • R 1 is H, A, OA or Hal
  • R is H or OA
  • R 1 is H, A, OA or Hal
  • Y is (CH 2 ) n ;
  • R 1 is H, A, OA or Hal
  • R 4 is Ar
  • Ar is unsubstituted phenyl
  • Y is (CH 2 ) n ;
  • Id R is H or OA
  • R 1 is H, A, OA or Hal
  • Y is a direct bond
  • R 1 is H, A, OA or Hal and Y is -N(R 5 )-(CH 2 ) m -;
  • R 1 is H, A, OA or Hal
  • R 4 is Ar and Y is a direct bond
  • R is H or OA
  • R 1 is H, A, OA or Hal
  • R 4 Ar
  • Ar is phenyl or biphenyl, which is unsubstituted or substituted by Hal, Het 2 , OA or -(CH 2 ) P -N(R 7 ) 2 , R 7 is H, A, cycloalkyl, (CH 2 ) 3 -OR 5 or (CH 2 ) 2 -OR 5 and
  • Y is a direct bond
  • R 1 is Hal
  • R 2 is H
  • R 3 is -(CH 2 ) 0 -Het, -(CHA) p -(CH 2 )o-N(R 5 ) 2 or
  • R 4 is Ar
  • Ar is unsubstituted phenyl and Y is a direct bond
  • R 1 is Hal
  • R 2 is H
  • R 3 is -(CH 2 ) 0 -Het, -(CHA) p -(CH 2 )o-N(R 5 ) 2 , -(CH 2 ) 0 -NR 5 -Het,
  • R 4 is Ar
  • Ar is biphenyl-4-yl
  • Y is a direct bond
  • R 1 is Hal
  • R 2 is H or A
  • R 3 is A, cycloalkyl, -Het 3 , -(CH 2 ) 0 -OR 5 , -(CH 2 ) 0 -OR 6 , -(CH 2 ) 0 -Het, -(CH 2 ) 0 -NR 5 -Het, -(CHA) p -(CH 2 )o-N(R 5 )2, -(CH 2 ) P -(CHA) P -
  • (CH 2 )m-Ar, -(CH2)o-Z-(CH 2 ) q -N(R 5 )2, or NR 2 R 3 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,
  • R 4 is Ar
  • Ar is phenyl which is substituted by Br and
  • Y is a direct bond
  • R 3 is -(CH 2 ) 0 -Het or -(CHA)p-(CH 2 ) 0 -N(R 5 ) 2 ,
  • R 4 is Ar, Ar is phenyl or biphenyl, which is unsubstituted or substituted by
  • R 7 is H, A, cycloalkyl, (CH 2 ) 3 -OR 5 or (CH 2 ) 2 -OR 5 and
  • Y is a direct bond
  • R 1 is Hal
  • R 2 is H
  • R 3 is -(CH 2 ) 0 -Het or -(CHA) p -(CH 2 )o-N(R 5 ) 2 ,
  • R 4 is Het 1 , Het 1 is thiophen-2-yl, which is substituted by Ar or Het 2 ,
  • R 7 is H, A, cycloalkyl, (CH 2 ) 3 -OR 5 or (CH 2 ) 2 -OR 5 and
  • Y is a direct bond; in In R is H, R 1 is Hal, R 2 is H, R 3 is -(CH 2 ) 0 -Het or -(CHA) P -(CH 2 ) 0 -N(R 5 ) 2 ,
  • R 4 is Het 1 ,
  • Het 1 is 5-(4-fluoro-phenyl)-thiophen-2-yl, 5-(2-methoxy-phenyl)- thiophen-2-yl, 5-(2-cyano-phenyl)-thiophen-2-yl, 5-(2,5- dimethoxy-phenyl)-thiophen-2-yl, 2-[2,2']bithiophenyl-5-yl, 5- (1 H-indol-5-yl)-thiophen-2-yl, 5-pyridine-4-yl-thiophen-2-yl, 5- quinolin-8-yl-thiophen-2-yl or 5-benzo[b]thiophen-2-yl- thiophen-2-yl
  • R 7 is H, A, cycloalkyl, (CH 2 ) 3 -OR 5 or (CH 2 ) 2 -OR 5 and Y is a direct bond.
  • the starting substances 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.
  • 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.
  • acyl group is to be interpreted in the widest sense in connection with the present process.
  • 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.
  • 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
  • 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 0,0- or 0,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.
  • 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-, benzyliden
  • the groups BOC and O-tert-butyl can preferably be removed, for example, using TFA in dichloromethane or using approximately 3 to 5N HCl 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.
  • 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 MJ. 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.
  • 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.
  • the quinazolines of formula I in which Y is a direct bond or (CH ) 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 5 )-(CH 2 ) 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.
  • the 2,4-dichloro-quinazolines of formula II in which R and R 1 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.
  • aldehydes of formula III 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.
  • amines of formula VII or X in which R 2 , R 3 , NR 2 R 3 , R 5 , R 4 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.
  • Pd(ll)CI 2 dppf, PdOAc 2 + 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 R 1 into other radicals R and R 1 , for e.g. to convert a halogen substituted quinazolines to a quinazoline substituted by substituted or unsubstituted phenyl.
  • an appropriate compound of the formula I in which R 4 is quinazoline chloride, quinazoline bromide or quinazoline iodide can be reacted with allyltributyltin in a Stille type coupling reaction.
  • reaction time is between a few minutes and a number of days.
  • an inert solvent or solvent mixture e.g. DMF or 1 ,4-dioxane at temperatures between 0° and 150°, preferably between 60° and 120°.
  • the reaction time is between a few minutes and a number of days.
  • phosphines as coordination ligands, e.g. Pd(P(Ph) 3 ) 2 , Pd(ll)CI 2 dppf,
  • 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.
  • 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.
  • compounds of the formula I with bases can be converted into the corresponding metal salts, in particular alkali metal or alkaline earth metal salts, or into the corresponding ammonium salts.
  • compositions 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 ICso-value, in the range of 100 ⁇ mol or below, preferably 10 ⁇ mol or below, more preferably in the range of 3 -/mol or below, even more preferably in the range of 1 ⁇ mol or below and most preferably in the nanomolar range.
  • kinase-inhibitors as defined above/below, that show an activity, determined as IC 50 -value, to one or more PKB-kinases, preferably including PKB ⁇ and/or PKB ⁇ and/or PKB ⁇ i and /or PKB ⁇ and /or PKB ⁇ i, in the range of 0.5 ⁇ mol or below and especially in the range of 0.1 ⁇ mol or below.
  • an IC 50 -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 ICso-values that lie between the above given upper limits and a lower limit in the region of 0.0001 ⁇ mol 0.001 ⁇ mol, 0.01 ⁇ mol or even above 0.1 ⁇ mol are sufficient to indicate the desired pharmaceutical activity.
  • 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.
  • 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.
  • 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.
  • 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 inten ening 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.
  • 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.
  • 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.
  • tissue remodeling or repair or reproductive tissue e.g., uterine, testicular and ovarian carcinomas, endometriosis, squamous and glandular epithelial carcinomas of the cervix, etc.
  • 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 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.
  • 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 (ILC) 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.
  • Non-small cell lung cancer is made up of three general subtypes of lung cancer.
  • Epidermoid carcinoma also called squamos cell carcinoma
  • 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.
  • melanoma 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.
  • hyperproliferative diseases of interest relate to epidermal hyperproliferation, tissue, remodeling and repair.
  • 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 lymphoproliferative 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).
  • SLE systemic lupus erythematosus
  • 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.
  • 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.
  • N 1 ,N 1 -diethyl-pentane-1.4-diamine to obtain N 4 -[2-(4-bromo-phenyl)-6-methyl-quinazolin-4-yl]-N 1 ,N 1 -diethyl-pentane-
  • Example 7 Analogously to example 3, 2-(4-bromo-phenyl)-4-chloro-6,7-dimethoxy- quinazoline is reacted
  • N 1 ,N 1 -dimethyl-ethane-1 ,2-diamine N'-[2-(4-bromo-phenyl)-6,7-dimethoxy-quinazolin-4-yl]-N,N-dimethyl- ethane-1 ,2-diamine; MS calc: 431 ,33; found: 432;
  • N 1 ,N 1 -diethyl-ethane-1 ,2-diamine N 1 ,N 1 -diethyl-ethane-1 ,2-diamine to obtain N'-[2-(4-bromo-phenyl)-6,7-dimethoxy-quinazolin-4-yl]-N,N-diethyl- ethane-1 ,2-diamine;
  • N 1 ,N 1 -diethyl-ethane-1 ,2-diamine N'-(2-biphenyl-4-yl-7-chloro-quinazolin-4-yl)-N,N-diethyl-ethane-1 ,2- diamine;
  • N 1 ,N 1 -diethyl-propane-1 ,3-diamine N'-(2-biphenyl-4-yl-7-chloro-quinazolin-4-yl)-N,N-diethyl-propane-1 ,3- diamine;
  • N'-[7-chloro-2-(4'-chloro-biphenyl-4-yl)-quinazolin-4-yl]-N,N- diethyl-propane-1 ,3-diamine is obtained.
  • Example 14 Analogously to example 3, 2-(4-bromo-phenyl)-4,7-dichloro-quinazoline
  • N 1 ,N -diethyl-pentane-1 ,4-diamine to obtain N ,N -diethyl-N -[2-(4-phenyl-butyl)-quinazolin-4-yl]-pentane-1 ,4- diamine;
  • N N 22 ((55--bbrroommoo--22--fflluuoorroo--bbeennzzyyll)-7-chloro-N 4 -(4-diethylamino-1-methyl- butyl )-quinazoline-2,4-diamine;
  • 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.
  • 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.
  • a solution is prepared from 1 g of an active compound of the formula I, 9.38 g of NaH P0 4 .2H 2 0, 28.48 g of Na 2 HP0 4 .12H 2 0 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.
  • 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.
  • 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 ampule contains 10 mg of active compound.

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Abstract

Cette invention a trait à l'utilisation de quinazolines correspondant à la formule (I) ainsi qu'à leurs sels ou solvates utilisés comme inhibiteurs de la protéine kinase B. Dans cette formule, R, R1, R2, R3, R4 et Y sont tels qu'indiqué dans les revendications 1 à 7.
PCT/EP2003/009392 2002-10-02 2003-08-25 Utilisation de 4 amino-quinazolines comme agents anticancereux WO2004030672A1 (fr)

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