HK1210777B - Quinazolinone derivatives as parp inhibitors - Google Patents

Description

Quinazolinone derivatives as PARP inhibitors

Background

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

The present invention relates to quinazolinone derivatives which inhibit the activity of Tankyrase (TANK) and poly (ADP-ribose) polymerase PARP-1. The compounds of the invention are therefore useful in the treatment of diseases such as cancer, multiple sclerosis, cardiovascular diseases, central nervous system injury and different forms of inflammation. The invention also provides processes for preparing these compounds, pharmaceutical compositions comprising these compounds and methods of treating diseases utilizing pharmaceutical compositions comprising these compounds.

The ribozyme poly (ADP-ribose) polymerase-1 (PARP-1) is a member of the PARP enzyme family. This increasing family of enzymes consists of PARPs such as PARP-1, PARP-2, PARP-3 and Vault-PARP; and TANK polymerases (TANK) such as TANK-1 and TANK-2. PARP is also known as poly (adenosine 5' -diphosphate-ribose) polymerase or PARS (poly (ADP-ribose) synthetase).

TANK-1 appears to be essential for the polymerization of mitotic spindle-associated poly (ADP-ribose). The poly (ADP-ribose) activity of TANK-1 may be critical for the accurate formation and maintenance of both polarities of the spindle. Furthermore, the PARP activity of TANK-1 has been shown to be essential for normal telomere segregation in the post-mitotic phase. Interference of tankyrase PARP activity results in mitotic abnormalities that cause transient cell cycle arrest, possibly due to spindle checkpoint activation, followed by cell death. Inhibition of tankyrase is therefore expected to have a cytotoxic effect on proliferating tumor cells (WO 2008/107478).

In clinical cancer studies, PARP inhibitors are described by M. Rouleau et al in Nature Reviews, Volume 10,293-301 (Table 2, page 298).

According to reviews by Horvath and Szabo (Drug News Perspectrum 20(3), April 2007, 171-. More recent studies have also demonstrated that PARP inhibitors inhibit angiogenesis by inhibiting growth factor expression or by inhibiting growth factor-induced cell proliferation responses. These findings may also suggest an in vivo anti-cancer mode of action of PARP inhibitors.

Studies by Tentori et al (Eur. J. Cancer, 2007, 43 (14) 2124-2133) also demonstrated that PARP inhibitors abrogate VEGF-or placental growth factor-induced migration and prevent the formation of tubule-like networks in cell-based systems and impair angiogenesis in vivo. Studies also demonstrated that growth factor-induced angiogenesis is absent in PARP-1 knockout mice. The results of the study provide evidence of targeting PARP against angiogenesis, adding new therapeutic implications for the use of PARP inhibitors in cancer therapy.

It is well known that defects in the conserved signal transduction pathway play a key role in the origin and behavior of essentially all cancers (e.a. fearon, Cancer Cell, vol. 16, Issue 5, 2009, 366-. The Wnt pathway is a target for anti-cancer therapy. A key feature of the Wnt pathway is the regulated proteolysis (degradation) of β -catenin by its complex disruption. Proteins like WTX, APC or Axin are involved in this degradation process. Proper degradation of β -catenin is important to avoid the inappropriate activation of the Wnt pathway observed in many cancers. Tankyrase inhibits Axin activity and thus inhibits degradation of β -catenin. Thus, tankyrase inhibitors increase the degradation of β -catenin. One article in journal Nature not only provides an important new view for proteins that regulate Wnt signaling, but also supports a pathway that antagonizes β -catenin levels and localization via small molecules (Huang et al, 2009; Nature, Vol 461, 614-. The compound XAV939 inhibits the growth of DLD-1-cancer cells. They found that XAV9393 blocked Wnt-stimulated β -catenin aggregation by increasing the levels of AXIN1 and AXIN2 proteins. Subsequent work by the authors established that XAV939 modulates AXIN levels by inhibiting tankyrase 1 and 2 (TNKS1 and TNKS2), both of which are members of the poly (ADP-ribose) polymerase (PARP) protein family (s.j. Hsiao et al, Biochimie 90, 2008, 83-92).

It has been found that the compounds according to the invention and their salts have very valuable pharmacological properties while being very tolerable.

The invention relates inter alia to compounds of formula I which inhibit tankyrase 1 and 2, compositions comprising these compounds and methods of their use for the treatment of TANK-induced diseases and conditions (compaint).

The compounds of formula I are additionally useful for isolating and studying TANK activity or expression. In addition, they are particularly suitable for use in diagnostic methods for diseases associated with dysregulated or disturbed TANK activity.

The host or patient may belong to any mammalian species, for example a primate species, particularly humans; rodents, including mice, rats, and hamsters; a rabbit; horses, cattle, dogs, cats, etc. The animal model has the significance of experimental research and provides a model for treating human diseases.

The sensitivity of a particular cell to treatment with a compound according to the invention can be determined by in vitro assays. Typically, a culture of cells is mixed with a compound according to the invention at various concentrations for a period of time sufficient to allow the active agent (e.g., anti-IgM) to induce a cellular response (e.g., expression of surface markers), typically about 1 hour to 1 week. In vitro tests can be performed using cultured cells from blood or from biopsy samples. The amount of surface marker expressed was assessed by flow cytometry using specific antibodies that recognize the marker.

The dosage will vary depending on the particular compound used, the particular disease, the patient's condition, and the like. The therapeutic dose is typically sufficient to significantly reduce the unwanted cell population in the target tissue while maintaining the viability of the patient. The treatment is generally continued until a significant reduction occurs, for example, a reduction in cell load of at least about 50%, and may be continued until substantially no more unwanted cells are detected in the body.

Prior Art

E. Wahlberg et al, Nature Biotechnology (2012), 30(3), 283:

quinazolinones are described below as tankyrase inhibitors

IC₅₀(TNKS1) = 590 nM, IC₅₀(TNKS2) = 600 nM; cell assay: no effect was observed at 30. mu.M.

WO 2010/106436 (Resverlogix Corp.)：

The following compounds are described as anti-inflammatory agents

(pages 108 and 111)

In EP 1020445, (aza-) isoquinolinone derivatives are described as intermediates. In WO 2010/133647 isoquinolinone derivatives are described as PARP inhibitors.

Isoquinolinone derivatives are described by:

Won-Jea Cho et al, Bioorganic and Medicinal Chemistry Letters (1998), 8, 41-46;

sung Hoon Chemon et al, Archives of pharmaceutical Research (1997), 20, 138-;

sung Hoon Chemon et al, Archives of pharmaceutical Research (2001), 24, 276-.

Brief description of the invention

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

wherein

R¹、R²Each independently of the other H, F or Cl,

R³represents H, F, Cl, CH₃Or OCH₃，

X¹、X²Each independently of the other, represents CH or N,

y represents A, Cyc or

Oxacyclopropane, oxetanyl, tetrahydrofuryl, tetrahydropyranyl, piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, thiomorpholinyl or diazepanyl which may be unsubstituted or mono-or disubstituted by = O, Hal, OH and/or A',

a' represents an unbranched or branched alkyl group having 1 to 4C atoms, wherein one CH is₂The radical may be replaced by an O atom, and/or one H atom may be replaced by OH,

a represents an unbranched or branched alkyl radical having 2 to 10C atoms in which two adjacent carbon atoms may form a double bond and/or one or two non-adjacent CH-and/or CH₂The radicals may be replaced by N-, O-and/or S-atoms, and wherein 1 to 7H-atoms may be replaced by F, Cl and/or OH,

cyc represents cycloalkyl having 3 to 7C atoms which is unsubstituted or mono-substituted by OH, Hal or A',

hal represents F, Cl, Br or I,

provided that R is¹、R²、R³Is not H, but is not H,

and with the proviso that Y is not 4-isopropyl-1-piperazinyl.

The invention also relates to optically active forms (stereoisomers), enantiomers, racemates, diastereomers and hydrates and solvates of these compounds.

The present invention relates to compounds of formula I and tautomers thereof of formula Ia

。

Furthermore, the present invention relates to pharmaceutically acceptable derivatives of the compounds of formula I.

The term solvate of a compound is used to refer to the adduction of inert solvent molecules to a compound, which is formed due to their mutual attraction. Solvates are for example mono-or dihydrate or alkoxides.

It will be appreciated that the invention also relates to solvates of the salts.

The term pharmaceutically acceptable derivatives is used to refer to, for example, salts of the compounds according to the invention as well as so-called prodrug compounds.

As used herein and unless otherwise indicated, the term "prodrug" refers to derivatives of a compound of formula I that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide an active compound, particularly a compound of formula I. Examples of prodrugs include, but are not limited to, derivatives and metabolites of compounds of formula I that include biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogs. In certain embodiments, the prodrug of the compound having a carboxyl functional group is a lower alkyl ester of a carboxylic acid. The carboxylic acid ester is suitably formed by esterifying any carboxylic acid moieties present on the molecule. Prodrugs are typically prepared using well known methods, such as those described in Burger's Medicinal Chemistry and Drug Discovery, 6 th edition (ed. Donald J. Abraham, 2001, Wiley) and the Design and use of Prodrugs (Design and Application of Prodrugs) (H.Bundgaard, 1985, Harwood Academic Publishers Gmh).

The expression "effective amount" means the amount of a drug or pharmaceutically active ingredient that elicits the biological or medical response in a tissue, system, animal or human that is being sought or desired, for example, by a researcher or physician.

In addition, the expression "therapeutically effective amount" denotes an amount which has the following consequences compared to a corresponding subject not receiving this amount:

the treatment ameliorates, cures, prevents, or eliminates the disease, syndrome, condition, symptom, disorder, or side effect or also reduces the progression of the disease, symptom, or disorder.

The expression "therapeutically effective amount" also encompasses an amount effective to increase normal physiological function.

The invention also relates to the use of mixtures of said compounds of formula I, for example mixtures of two diastereomers, for example in a ratio of 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:100 or 1: 1000.

These are particularly preferably mixtures of stereoisomeric compounds.

"tautomer" refers to isomeric forms of a compound that are in equilibrium with each other. The concentration of the isomeric form will depend on the environment in which the compound is present and may vary depending on, for example, whether the compound is a solid or in an organic or aqueous solution.

The invention relates to compounds of formula (I) and salts thereof, and to a process for the preparation of compounds of formula (I) and pharmaceutically acceptable salts, solvates, tautomers and stereoisomers thereof, characterized in that

a) Reacting a compound of formula II

Wherein R is¹、R²And R³Has the meaning indicated in claim 1, and,

with the following reaction

i) A compound of formula III

Wherein X¹、X²And Y has the meaning indicated in claim 1,

or

ii) Compounds of formula IV

Wherein X¹、X²And Y has the meaning indicated in claim 1,

or

b) The group Y is converted into another group Y by

i) The alcohol is converted into an ether group and,

ii) converting the ester to an alcohol group,

iii) converting the nitro group into an amino group,

iv) conversion of amino groups to alkylated amino groups

And/or

Converting the base or acid of formula I into one of its salts.

In the above and below, the radical R¹、R²、R³、X¹、X²And Y has the meaning indicated for formula I, unless explicitly stated otherwise.

A represents an alkyl group, which is unbranched (linear) or branched and has 2,3, 4,5, 6,7, 8, 9 or 10C atoms. A preferably represents ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore pentyl, 1-, 2-or 3-methylbutyl, 1-, 1, 2-or 2, 2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3-or 4-methylpentyl, 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, 2-or 1,2, 2-trimethylpropyl, preferably trifluoromethyl.

A very particularly preferably represents alkyl having 2,3, 4,5 or 6C atoms, preferably ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl, pentafluoroethyl or 1,1, 1-trifluoroethyl.

Further, A preferably represents CH₂OCH₃、CH₂CH₂OH or CH₂CH₂OCH₃。

Cyc represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, preferably unsubstituted or mono-substituted by OH, Hal or A'.

A' represents an alkyl group which is unbranched (linear) or branched and has 1,2,3 or 4C atoms, one of which is CH₂The radical may be replaced by an O atom and/or one H atom may be replaced by OH,

X¹preferably represents CH.

Y preferably represents 1-hydroxy-1-methyl-ethyl, (2-methoxy-ethoxy) -1-methyl-ethyl, (2-hydroxy-ethoxy) -1-methyl-ethyl, tert-butyl, 4-methyl-piperazinyl, 1-ethyl, 1-hydroxy-propyl, 2-methyltetrahydrofuran-2-yl, 1-hydroxy-cyclopentyl, 3-hydroxy-oxetan-3-yl, (2-aminoethoxy) -1-methyl-ethyl, piperazin-1-yl, 4-methyl-piperazin-1-yl, piperidin-4-yl, 1-methyl-piperidin-4-yl, 1- (2-hydroxy-ethoxy) -1-methyl-ethyl, 1-dioxo-1 l 6-thiomorpholin-4-yl, 4-hydroxymethyl-piperidin-1-yl or 4-methyl- [1,4] diazepan-1-yl.

Y particularly preferably represents 1-hydroxy-1-methyl-ethyl or tert-butyl.

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

Throughout the present invention, all groups appearing more than once may be the same or different, i.e. independent of each other.

The compounds of formula I may have one or more chiral centers and may therefore exist in various stereoisomeric forms. The formula I encompasses all of these forms.

The invention therefore relates in particular to compounds of the formula I in which at least one of the radicals has one of the preferred meanings indicated above. Some preferred groups of the compounds can be represented by the following sub-formulae Ia to Id, which correspond to formula I, and wherein the groups not specified in more detail have the meaning indicated for formula I, but wherein

In Ia, X¹Represents CH;

in Ib Y represents 1-hydroxy-1-methyl-ethyl, (2-methoxy-ethoxy) -1-methyl-ethyl, (2-hydroxy-ethoxy) -1-methyl-ethyl, tert-butyl, 4-methyl-piperazinyl, 1-ethyl, 1-hydroxy-propyl, 2-methyltetrahydrofuran-2-yl, 1-hydroxy-cyclopentyl, 3-hydroxy-oxetan-3-yl, (2-aminoethoxy) -1-methyl-ethyl, piperazin-1-yl, 4-methyl-piperazin-1-yl, piperidin-4-yl, or 1-methyl-piperidin-4-yl;

in Id, R¹、R²Each independently of the other H, F or Cl,

R³represents H, F, Cl, CH₃Or OCH₃，

X¹Represents a group of a group represented by CH,

X²represents a group of a CH or an N,

y represents A, Cyc or

Oxacyclopropane, oxetanyl, tetrahydrofuryl, tetrahydropyranyl, piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, thiomorpholinyl or diazepanyl which may be unsubstituted or mono-or disubstituted by = O, Hal, OH and/or A',

a' represents an unbranched or branched alkyl radical having 1 to 4C atoms, in which one CH is present₂The radical being replaceable by an O atom and/or one H atom being replaceable by an OH group, A representing an unbranched or branched alkyl radical having 2 to 10C atoms, one or two non-adjacent CH groups-and/or CH₂The radical being replaceable by N-and/or O atoms and in which 1 to 7H atoms are replaceable by F, Cl and/or OH,

cyc represents cycloalkyl having 3 to 7C atoms which is unsubstituted or mono-substituted by OH, Hal or A',

hal represents F, Cl, Br or I,

provided that R is¹、R²、R³Is not H, but is not H,

and with the proviso that Y is not 4-isopropyl-1-piperazinyl,

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

The compounds of the formula I and the starting materials for their preparation are additionally prepared by processes known per se, as described in the literature (for example in the authoritative literature, such as Houben-Weyl, Methoden der organischen Chemistry [ Methods of Organic Chemistry ], Georg-Thieme-Verlag, Stuttgart), in particular under reaction conditions known and suitable for the reaction in question. Variants known per se, which are not mentioned here in more detail, can also be used here.

The starting compounds of the formulae II, III and IV are generally known. However, if they are new, they can be prepared by methods known per se.

The compounds of formula I can preferably be obtained by reacting a compound of formula II with a compound of formula III or with a compound of formula IV in the presence of an oxidizing agent, for example sodium bisulfite.

Depending on the conditions used, the reaction time is between a few minutes and 14 days, and the reaction temperature is between about-10 ℃ and 160 ℃, normally between 30 ℃ and 160 ℃, in particular between about 100 ℃ and about 160 ℃. The reaction is carried out in an inert solvent.

Examples of suitable inert solvents are hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichloroethylene, 1, 2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers such as diethyl ether, diisopropyl ether, Tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether, ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; amides such as acetamide, Dimethylacetamide (DMA), N-methylpyrrolidone (NMP) or Dimethylformamide (DMF); nitriles such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids, such as formic acid or acetic acid; nitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate; or mixtures of said solvents.

Particularly preferred is DMF, NMP or DMA.

The compounds of the formula I can additionally be obtained by converting a group Y into another group Y

i) The alcohol is converted into an ether group and,

ii) converting the ester group into an alcohol group,

iii) converting the nitro group into an amino group,

iv) converting the amino group to an alkylated amino group.

Step i):

the conversion of the alcohol to an ether group is carried out under standard conditions.

Step ii):

the conversion of the ester group into an alcohol group is preferably carried out under standard conditions in the presence of cerium (III) chloride with THF containing alkyl magnesium chloride or with THF containing lithium aluminum hydride.

Steps iii) and iv):

conversion of the nitro group to an amino group or conversion of an amino group to an alkylated amino group is carried out under standard conditions.

The esters may be saponified, for example, using acetic acid or using water, water/THF or water/dioxane containing NaOH or KOH at temperatures of 0-100 ℃.

Pharmaceutically salts and other forms

The compounds according to the invention can be used in their final non-salt form. In another aspect, the invention also encompasses the use of these compounds in the form of their pharmaceutically acceptable salts, which can be obtained from a variety of organic and inorganic acids and bases by methods known in the art. The pharmaceutically acceptable salt forms of the compounds of formula I are prepared in large part by conventional methods. If the compound of formula I contains a carboxyl group, one of its suitable salts may be formed by reacting the compound with a suitable base to give the corresponding base addition salt. The base is, for example, an alkali metal hydroxide including potassium hydroxide, sodium hydroxide and lithium hydroxide; alkaline earth metal hydroxides such as barium hydroxide and calcium hydroxide; alkali metal alkoxides such as potassium ethoxide and sodium propoxide; and various organic bases such as piperidine, diethanolamine and N-methylglutamine. Also included are aluminum salts of the compounds of formula I. In the case of certain compounds of formula I, acid addition salts may be formed by treating such compounds with the following pharmaceutically acceptable organic and inorganic acids: for example hydrogen halides, such as hydrogen chloride, hydrogen bromide or hydrogen iodide; other inorganic acids and their corresponding salts, such as sulfates, nitrates or phosphates, etc.; and alkyl and monoaryl sulfonates such as ethane sulfonate, toluene sulfonate and benzene sulfonate; and other organic acids and their corresponding salts, such as acetate, trifluoroacetate, tartrate, maleate, succinate, citrate, benzoate, salicylate, ascorbate, and the like. Thus, pharmaceutically acceptable acid addition salts of said compounds of formula I include the following: acetate, adipate, arginate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate, chloride, chlorobenzoate, citrate, cyclopentanepropionate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, fumarate, formate, galactarate (derived from mucic acid), galacturonate, glucoheptonate, gluconate, glutamate, glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isethionate, isobutyrate, lactate, Lactobionate, malate, maleate, malonate, mandelate, metaphosphate, methanesulfonate, methylbenzoate, monohydrogenphosphate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, palmitate (palmoate), pectate, persulfate, phenylacetate, 3-phenylpropionate, phosphate, phosphonate, phthalate, but this does not represent a limitation.

In addition, basic salts of the compounds according to the invention include aluminum, ammonium, calcium, copper, iron (III), iron (II), lithium, magnesium, manganese (III), manganese (II), potassium, sodium and zinc salts, but this is not intended to represent a limitation. Among the above salts, ammonium, sodium and potassium alkali metals, and calcium and magnesium alkaline earth metals are preferred. Salts of the compounds of formula I derived from pharmaceutically acceptable organic non-toxic bases include the following salts: primary, secondary and tertiary amines; substituted amines, also including naturally occurring substituted amines; a cyclic amine; and basic ion exchange resins such as arginine, betaine, caffeine, chloroprocaine, choline, N-dibenzylethylenediamine (benzathine), dicyclohexylamine, diethanolamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lidocaine (lidocaine), lysine, meglumine, N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethanolamine, triethylamine, trimethylamine, tripropylamine, and tris (hydroxymethyl) methylamine (tromethamine), although this is not intended to represent a limitation.

Compounds of the invention containing basic nitrogen-containing groups can be used, for exampleQuaternization of the following reagents: (C)₁-C₄) Alkyl halides such as methyl, ethyl, isopropyl and tert-butyl chloride, bromide and iodide; sulfuric acid di (C)₁-C₄) Alkyl esters such as dimethyl sulfate, diethyl sulfate and diamyl sulfate; (C)₁₀-C₁₈) Alkyl halides such as decyl, dodecyl, lauryl, myristyl and octadecyl chlorides, bromides and iodides; and aryl (C)₁-C₄) Alkyl halides, such as benzyl chloride and phenethyl bromide. Both water-soluble and oil-soluble compounds according to the invention can be prepared using the salts.

Preferred such pharmaceutical salts include, but are not intended to be limiting, acetate, trifluoroacetate, benzenesulfonate, citrate, fumarate, gluconate, hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate, mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodium phosphate, stearate, sulfate, sulfosalicylate, tartrate, thiomalate, tosylate and tromethamine.

Particularly preferred are the hydrochloride, dihydrochloride, hydrobromide, maleate, methanesulfonate, phosphate, sulfate and succinate salts.

The acid addition salts of the basic compounds of formula I are prepared by contacting the free base form with a sufficient amount of the desired acid to cause the salt to form in conventional form. The free base may be regenerated by contacting the salt form with a base and isolating the free base in a conventional manner. The free base form differs from its corresponding salt form in some respect with respect to certain physical properties such as solubility in polar solvents; however, for the purposes of the present invention, the salts are otherwise identical to their corresponding free base forms.

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

The base addition salts of acidic compounds according to the invention are prepared by contacting the free acid form with a sufficient amount of the desired base to cause the salt to form in a conventional manner. The free acid may be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner. The free acid form differs from its corresponding salt form in some respect with respect to certain physical properties such as solubility in polar solvents; however, for the purposes of the present invention, the salts are otherwise identical to their corresponding free acid forms.

If the compounds according to the invention contain more than one group capable of forming a pharmaceutically acceptable salt of this type, the invention also covers multiple salts. Typical multiple salt forms include, for example, bitartrate, diacetate, hydrogen fumarate, dimeglumine, hydrogen phosphate, disodium and trihydrochloride, but this is not intended to represent a limitation.

With regard to the above, it can be seen that the expression "pharmaceutically acceptable salt" in this respect is used to refer to an active ingredient which comprises a compound of formula I in the form of one of its salts, which salt form confers improved pharmacokinetic properties on the active ingredient, in particular if compared to the free form of the active ingredient or any other salt form of the active ingredient used previously. The pharmaceutically acceptable salt forms of the active ingredients may also provide the active ingredient for the first time with desirable pharmacokinetic properties not previously present and may even have a favorable effect on the pharmacodynamics of the active ingredient with respect to its therapeutic efficacy in vivo.

Isotope of carbon monoxide

It is further contemplated that the compounds of formula I include isotopically labeled forms thereof. Except that one or more atoms of the compound have been replaced by one or more atoms having an atomic mass or mass number different from the atomic mass or mass number of the atom or atoms usually naturally occurringApart from the fact that the isotopically labelled form of the compound of formula I is identical to the compound. Examples of isotopes which are readily available and which can be incorporated into the compounds of formula I by well-known methods include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example each²H、³H、¹³C、¹⁴C、¹⁵N、¹⁸O、¹⁷O、³¹P、³²P、³⁵S、¹⁸F and³⁶and (4) Cl. Compounds of formula I, prodrugs thereof, or pharmaceutically acceptable salts of any of them, containing one or more of the above isotopes and/or other isotopes of other atoms are intended to be part of this invention. Isotopically-labelled compounds of formula I can be used in a number of advantageous ways. For example, having incorporated therein, for example, radioactive isotopes such as³H or¹⁴The isotopically labeled compounds of formula I of C are suitable for use in drug and/or substrate tissue distribution assays. These radioactive isotopes, i.e. tritium (A)³H) And carbon-14 (¹⁴C) It is particularly preferable because of its simple preparation and excellent detectability. By reaction of heavier isotopes such as deuterium (²H) The incorporation of compounds of formula I has therapeutic advantages due to the higher metabolic stability of the isotopically labeled compounds. Higher metabolic stability translates directly into increased in vivo half-life or decreased dosage, which in most cases will represent a preferred embodiment of the invention. Isotopically labeled compounds of formula I can generally be prepared by carrying out the procedures disclosed in the synthetic schemes and associated descriptions, examples, and preparations herein to replace a non-isotopically labeled reactant with a readily available isotopically labeled reactant.

Deuterium (D) for the purpose of manipulating the oxidative metabolism of compounds by the first-order kinetic isotope effect²H) May also be incorporated into the compounds of formula I. The first order kinetic isotope effect is a rate change in chemical reactions caused by the exchange of isotope nuclei, which in turn is caused by a change in ground state energy necessary for covalent bond formation after the isotope exchange. Exchange of heavier isotopes generally causes a reduction in the ground state energy of the chemical bonds and hence a reduction in the rate of rate-limiting bond cleavage. If the bond breaks along the multi-productThe product distribution ratio will change significantly if it occurs in or near the saddle point region of the coordinates of the reaction. For purposes of explanation: if deuterium is bonded to a carbon atom in a position which is not exchangeable, k_M/k_DA rate difference of = 2-7 is typical. If this difference is successfully applied to a compound of formula I that is sensitive to oxidation, the profile of the compound in vivo can be dramatically altered and result in improved pharmacokinetic properties.

In discovering and developing therapeutic agents, one skilled in the art attempts to optimize pharmacokinetic parameters while maintaining desirable in vitro properties. It is reasonable to assume that many compounds with poor pharmacokinetic profiles are sensitive to oxidative metabolism. The currently available in vitro liver microsomal assays provide valuable information on this type of oxidative metabolic processes, which in turn allows rational design of deuterated compounds of formula I with improved stability via resistance to said oxidative metabolism. A significant improvement in the pharmacokinetic profile of the compound of formula I is thus obtained and may be based on the in vivo half-life (t/2), concentration at maximum therapeutic effect (C)_max) Increase in area under the dose response curve (AUC) and F; and quantitatively expressed in terms of clearance, dosage and reduction in material costs.

The following is intended to illustrate the above: compounds of formula I having multiple potential sites of oxidative metabolic attack, such as benzylic hydrogen atoms and hydrogen atoms bonded to nitrogen atoms, are prepared as a series of analogs in which the hydrogen atoms of various combinations are replaced by deuterium atoms such that some, most, and all of these hydrogen atoms are replaced by deuterium atoms. The half-life measurement enables a favorable and accurate measurement of the degree of improvement in resistance to oxidative metabolism. In this way, it was determined that the half-life of the parent compound could be extended up to 100% due to this type of deuterium-hydrogen exchange.

Deuterium-hydrogen exchange in the compounds of formula I can also be used to achieve an advantageous modification of the metabolite profile of the starting compounds to reduce or eliminate unwanted toxic metabolites. For example, if toxic metabolites are produced via the cleavage of oxidized carbon-hydrogen (C-H) bonds, it is reasonable to assume that deuterated analogs will greatly reduce or eliminate the production of unnecessary metabolites, even if the particular oxidation is not a rate limiting step. Further information on the state of the art for deuterium-hydrogen exchange can be found, for example, in: hanzlik et al, J.org. chem. 55, 3992-; reider et al, J. org. chem. 52, 3326-3334, 1987; foster, adv. Drug res. 14, 1-40, 1985; gillette et al, Biochemistry 33(10) 2927-; and Jarman et al, Carcinogenesis 16(4), 683-.

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

Pharmaceutical formulations may be administered in dosage unit form containing a predetermined amount of active ingredient per dosage unit. Such units may comprise, for example, from 0.5mg to 1g, preferably from 1mg to 700mg, particularly preferably from 5mg to 100mg, of a compound according to the invention, depending on the condition to be treated, the method of administration and the age, weight and condition of the patient, or pharmaceutical preparations may be administered in dosage unit form comprising a predetermined amount of active ingredient per dosage unit. Preferred dosage unit formulations are those containing a daily dose or a portion dose, as indicated above, or a fraction thereof, of the active ingredient. In addition, pharmaceutical formulations of this type may be prepared using methods generally known in the pharmaceutical art.

The pharmaceutical formulation may be adapted for administration via any desired suitable method, for example, oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) methods. The formulations may be prepared using all methods known in the pharmaceutical art, for example by combining the active ingredient with excipients or auxiliaries.

Pharmaceutical formulations adapted for oral administration may be administered as discrete units, such as capsules or tablets; powder or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or foam foods; or an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.

Thus, for example, in the case of oral administration in the form of tablets or capsules, the active ingredient component may be combined with an oral, non-toxic and pharmaceutically acceptable inert excipient such as ethanol, glycerol, water and the like. Powders are prepared by comminuting the compound to a suitable small size and mixing it with a pharmaceutical excipient, such as an edible carbohydrate, for example starch or mannitol, which is comminuted in a similar manner. Flavoring, preservative, dispersing and coloring agents may also be present.

Capsules are produced by preparing a powder mixture as described above and filling shaped gelatin shells with it. Glidants and lubricants, for example highly disperse silicic acid, talc, magnesium stearate, calcium stearate or polyethylene glycol in solid form, can be added to the powder mixture before the filling operation. Disintegrating or solubilizing agents such as agar-agar, calcium carbonate or sodium carbonate may also be added to improve the availability of the drug after taking the capsule.

In addition, if desired or necessary, suitable binders, lubricants and disintegrants and also dyes can likewise be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, sweeteners made from corn, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. The disintegrating agent includes, without being limited thereto, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like. The tablets are formulated by, for example, preparing a powder mixture, granulating or press-drying the mixture, adding a lubricant and a disintegrant, and pressing the entire mixture to give tablets. The powder mixture is prepared by mixing the compound, comminuted in a suitable manner, with a diluent or matrix as described above and optionally a binder such as carboxymethylcellulose, alginate, gelatin or polyvinylpyrrolidone; dissolution retardants such as paraffin; absorption accelerators such as quaternary salts; and/or absorbents such as bentonite, kaolin or dicalcium phosphate. The powder mixture may be granulated by wetting it with a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials and pressing it through a screen. As an alternative to granulation, the powder mixture may be passed through a pelletiser to give a non-uniformly shaped mass which is broken up to form granules. The granules may be lubricated by the addition of stearic acid, stearate, talc or mineral oil to avoid sticking to the tablet mould. The lubricated mixture is then compressed to give tablets. The compounds according to the invention can also be combined with free-flowing inert excipients and subsequently compressed directly to give tablets without a granulation or press-drying step. There may be a transparent or opaque protective layer consisting of a shellac blocking layer, a layer of sugar or polymer material and a glossy layer of paraffin. Dyes may be added to these coatings to enable differentiation between different dosage units.

Oral liquids such as solutions, syrups and elixirs may be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound. Syrups can be prepared by dissolving the mixture in an aqueous solution with a suitable flavoring agent, while elixirs are prepared using a non-toxic alcoholic vehicle. Suspensions may be formulated by dispersing the compound in a non-toxic vehicle. Solubilizers and emulsifiers, such as ethoxylated isostearyl alcohol and polyoxyethylene sorbitol ether; a preservative; flavoring additives, such as peppermint oil; or natural sweeteners or saccharin; or other artificial sweeteners, and the like.

Dosage unit formulations for oral administration may be encapsulated in microcapsules, if desired. The formulations may also be prepared in a delayed or retarded release manner, for example by coating or embedding the particulate material in a polymer, wax or the like.

The compounds of formula I and pharmaceutically salts, tautomers and stereoisomers thereof can also be administered in the form of liposome delivery systems such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, octadecylamine or phosphatidylcholine.

The compounds of formula I and salts, tautomers and stereoisomers thereof can also be delivered using monoclonal antibodies as separate carriers to which the compound molecules are coupled. The compounds may also be coupled to soluble polymers as targeted drug carriers. The polymer may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidophenol, polyhydroxyethylaspartamylphenol, or polyethylene oxide polylysine (substituted with palmitoyl). The compounds may additionally be coupled to a class of biodegradable polymers suitable for achieving controlled release of drugs, such as polylactic acid, poly-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydroxypyrans, polycyanoacrylates and crosslinked or amphiphilic block copolymers of hydrogels.

Pharmaceutical formulations suitable for transdermal administration may be administered as a separate ointment for prolonged intimate contact with the epidermis of the recipient. Thus, for example, the active ingredient may be delivered from the paste by iontophoresis, as described in general terms in pharmaceutical research, 3(6), 318 (1986).

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

For the treatment of the eye or other external tissues such as mouth and skin, the formulation is preferably applied as a topical ointment or cream. In the case of formulations which produce ointments, the active ingredient may be employed with either a paraffinic or a water-miscible cream base. Alternatively, the active ingredients may be formulated together with an oil-in-water cream base or a water-in-oil base to produce a cream.

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

Pharmaceutical formulations suitable for topical administration in the mouth include lozenges, pastilles and mouthwashes.

Pharmaceutical preparations suitable for rectal administration may be administered in the form of suppositories or enemas.

Pharmaceutical preparations suitable for nasal administration in which the carrier material is a solid include coarse powders having a particle size, for example, in the range of 20-500 microns, which are administered by inhalation of the olfactory formulation, i.e., by rapid inhalation through the nasal passage from a powder-containing container held close to the nose. Suitable formulations for administration as nasal sprays or nasal drops with liquid as carrier material include solutions of the active ingredient in water or oil.

Pharmaceutical formulations adapted for administration by inhalation include fine particle dusts or mists, which may be generated by means of various types of pressurised dispensers, nebulisers or insufflators, with aerosols.

Pharmaceutical formulations adapted for vaginal administration may be administered as pessaries, tampons, creams, gels, pastes, foams or spray formulations.

Pharmaceutical formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions containing antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the recipient to be treated; and aqueous and non-aqueous sterile suspensions which may contain a suspending medium and a thickening agent. The formulations may be administered in single-or multi-dose containers, such as sealed ampoules and vials, and stored in a freeze-dried (lyophilized) condition, so that only a sterile carrier liquid, for example water for injection purposes, needs to be added immediately prior to use. Injections and suspensions prepared according to this formulation can be prepared from sterile powders, granules and tablets.

It goes without saying that, with regard to the particular formulation type, the formulation may contain, in addition to the ingredients specifically mentioned above, other agents commonly used in the art; thus, for example, formulations suitable for oral administration may contain flavoring agents.

The therapeutically effective amount of a compound of formula I will depend on a number of factors including, for example, the age and weight of the animal, the precise condition to be treated and its severity, the nature of the formulation and the method of administration, and will ultimately be determined by the treating physician or veterinarian. However, an effective amount of a compound according to the invention is generally in the range of 0.1-100mg/kg body weight of the recipient (mammal) per day and particularly typically in the range of 1-10mg/kg body weight per day. Thus, the actual amount per day for an adult mammal having a body weight of 70kg is typically 70-700mg, wherein the amount may be administered in a single daily dose or typically in a series of multiple doses per day (e.g. 2,3, 4,5 or 6), such that the total daily dose is the same. An effective amount of a salt or solvate or physiologically functional derivative thereof may be determined as a fraction of the effective amount of the compound of the invention itself. Similar dosages may be considered suitable for the treatment of the other conditions mentioned above.

This type of combination therapy can be achieved by means of simultaneous, sequential or separate dispensing of the individual components of the treatment. This type of combination product employs the compounds according to the invention.

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

The invention also relates to a set (kit) consisting of the following individual packages:

(a) an effective amount of a compound of formula I and/or pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios,

and

(b) an effective amount of other pharmaceutically active ingredients.

The kit comprises suitable containers, such as boxes (boxes), individual bottles, bags or ampoules. The kit may for example comprise separate ampoules, each containing an effective amount of a compound of formula I and/or pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios,

and an effective amount of other pharmaceutically active ingredients in dissolved or lyophilized form.

As used herein, "treating" or "treatment" refers to alleviating, in whole or in part, symptoms associated with a disease or disorder, or slowing or halting further progression or worsening of those symptoms, or preventing a disease or disorder in a subject at risk of developing the disease or disorder.

The term "effective amount" with respect to a compound of formula (I) may refer to an amount that is capable of completely or partially alleviating the symptoms associated with a disease or disorder, or slowing or halting further progression or worsening of those symptoms, or preventing a disease or disorder in a subject having or at risk of developing a disease disclosed herein, such as an inflammatory condition, an immune condition, a cancer, or a metabolic condition.

In one embodiment, an effective amount of a compound of formula (I) is an amount that inhibits tankyrase in a cell, e.g., in vitro or in vivo. In some embodiments, the effective amount of the compound of formula (I) inhibits tankyrase in a cell by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 99% compared to the activity of tankyrase in an untreated cell. An effective amount of a compound of formula (I), for example in a pharmaceutical composition, may be at a level to produce the desired effect; for example, for both oral and parenteral administration, from about 0.005mg/kg to about 10mg/kg of subject body weight in a unit dose.

Use of

The compounds of the invention are suitable as pharmaceutically active ingredients for mammals, in particular humans, for the treatment of cancer, multiple sclerosis, cardiovascular diseases, central nervous system injury and different forms of inflammation.

The invention includes the use of a compound of formula I and/or pharmaceutically acceptable salts, tautomers and stereoisomers thereof in the manufacture of a medicament for the treatment or prevention of cancer, multiple sclerosis, cardiovascular disease, central nervous system injury, and different forms of inflammation.

Examples of inflammatory diseases include rheumatoid arthritis, psoriasis, contact dermatitis, delayed type hypersensitivity reactions, and the like.

Also included is the use of a compound of formula I and/or pharmaceutically acceptable salts, tautomers and stereoisomers thereof, wherein for this method a therapeutically effective amount of a compound of the invention is administered to a diseased mammal in need of such treatment, in the manufacture of a medicament for the treatment or prevention of a tankyrase-induced disease or a tankyrase-induced condition in a mammal. The amount of treatment will vary depending on the particular disease and can be determined by one skilled in the art without undue effort.

The expression "tankyrase-induced disease or condition" refers to a pathological condition which is dependent on the activity of one or more tankyrase enzymes. Diseases associated with tankyrase activity include cancer, multiple sclerosis, cardiovascular disease, central nervous system injury and different forms of inflammation.

The invention relates in particular to compounds of formula I and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios, for use in the treatment of diseases in which inhibition, modulation and/or modulation inhibition of tankyrase plays a role.

The invention relates in particular to compounds of formula I and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios, for use in inhibiting tankyrase.

The invention relates in particular to compounds of formula I and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios, for use in the treatment of cancer, multiple sclerosis, cardiovascular diseases, central nervous system injury and different forms of inflammation.

The present invention relates to a method for the treatment or prevention of cancer, multiple sclerosis, cardiovascular diseases, central nervous system injury and different forms of inflammation, comprising administering to a subject in need thereof an effective amount of a compound of formula I or a pharmaceutically acceptable salt, tautomer, stereoisomer or solvate thereof.

Representative cancers for which compounds of formula I may be useful in the treatment or prevention include, but are not limited to, cancers of the head, neck, eye, mouth, pharynx, esophagus, bronchus, larynx, pharynx, chest, bone, lung, colon, rectum, stomach, prostate, bladder, uterus, cervix, breast, ovary, testis or other reproductive organs, skin, thyroid, blood, lymph nodes, kidney, liver, pancreas, brain, central nervous system, solid tumors, and hematologic tumors (blood-borne tumors).

Representative cardiovascular diseases for which compounds of formula I may be useful include, but are not limited to, restenosis, atherosclerosis, and its consequences such as stroke, myocardial infarction, ischemic injury to the heart, lung, intestine, kidney, liver, pancreas, spleen, or brain.

The present invention relates to methods of treating proliferative, autoimmune, anti-inflammatory, or infectious disease conditions comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I.

Preferably the invention relates to a method wherein said disease is cancer.

Particularly preferred the invention relates to a method wherein the disease is cancer, wherein the administration is simultaneous, sequential or alternating with the administration of the at least one further active agent.

The disclosed compounds of formula I may be administered in combination with other known therapeutic agents, including anticancer agents. As used herein, the term "anti-cancer agent" relates to any agent administered to a cancer patient for the purpose of treating cancer.

The anti-cancer treatment as defined herein may be administered as the sole therapy or may include conventional surgery or radiotherapy or chemotherapy in addition to the compounds of the invention. The chemotherapy may include one or more of the following classes of anti-neoplastic agents:

(i) antiproliferative/antineoplastic/DNA-damaging agents and combinations thereof, such as those used in medical oncology, for example alkylating agents (e.g., cisplatin, carboplatin, cyclophosphamide, mechlorethamine, melphalan, chlorambucil, busulfan, and nitrosoureas); antimetabolites (e.g., antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, letrozole, methotrexate, cytarabine, hydroxyurea, and gemcitabine); antitumor antibiotics (e.g., anthracyclines such as doxorubicin, bleomycin, doxorubicin, daunorubicin, epirubicin, idarubicin, mitomycin-C, actinomycin D, and plicamycin); antimitotic agents (e.g., vinca alkaloids such as vincristine, vinblastine, vindesine, and vinorelbine, and taxanes such as paclitaxel and taxotere); topoisomerase inhibitors (e.g., epipodophyllotoxins such as etoposide and teniposide, amsacrine, topotecan, irinotecan, and camptothecin) and cellular differentiation agents (e.g., all-trans-retinoic acid, 13-cis-retinoic acid, and fenretinide);

(ii) cytostatic agents, such as antiestrogens (e.g., tamoxifen, toremifene, raloxifene, droloxifene, and etoxifene), estrogen receptor downregulators (e.g., fulvestrant), antiandrogens (e.g., bicalutamide, flutamide, nilutamide, and cyproterone acetate), LHRH antagonists or LHRH agonists (e.g., goserelin, leuprolide, and buserelin), progestins (e.g., megestrol acetate), aromatase inhibitors (e.g., anastrozole, letrozole, vorozole, and exemestane), and inhibitors of 5 α -reductase, such as finasteride;

(iii) agents that inhibit cancer cell invasion (e.g., metalloproteinase inhibitors such as marimastat and urokinase plasminogen activator receptor function inhibitors);

(iv) inhibitors of growth factor function, e.g., including growth factor antibodies, growth factor receptor antibodies (e.g., anti-erbb 2 antibody trastuzumab [ Herceptin ]^TM]And the anti-erbb 1 antibody cetuximab [ C225]) Farnesyl transferase inhibitors, tyrosine kinase inhibitors and serine/threonine kinase inhibitors, e.g. inhibitors of the epithelial growth factor family(e.g., EGFR family tyrosine kinase inhibitors such as N- (3-chloro-4-fluorophenyl) -7-methoxy-6- (3-morpholinopropoxy) quinazolin-4-amine (gefitinib, AZD1839), N- (3-ethynylphenyl) -6, 7-bis (2-methoxyethoxy) quinazolin-4-amine (erlotinib, OSI-774), and 6-acrylamido-N- (3-chloro-4-fluorophenyl) -7- (3-morpholinopropoxy) quinazolin-4-amine (CI 1033)), for example, inhibitors of the platelet derived growth factor family and for example, inhibitors of the hepatocyte growth factor family;

(v) anti-angiogenic agents, such as those that inhibit the action of vascular endothelial growth factor (e.g., the anti-vascular endothelial growth factor antibody bevacizumab [ Avastin ]^TM]Compounds such as those disclosed in published International patent applications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354 and compounds that act by other mechanisms (e.g., linoamine, integrin α v β 3 function inhibitors and angiostatin);

(vi) vascular damaging agents, such as combretastatin a4 and the compounds disclosed in international patent applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;

(vii) antisense therapies, e.g., against the above-listed targets, e.g., ISIS 2503, anti-Ras antisense drugs (anti-Ras antisense);

(viii) gene therapy methods, including, for example, methods of replacing an aberrant gene, such as aberrant p53 or aberrant BRCA1 or BRCA 2; GDEPT (gene-directed enzyme prodrug therapy) methods, such as those with cytosine deamidase, thymidine kinase, or bacterial nitroreductase enzymes, and methods of increasing the tolerance of a patient to chemotherapy or radiation therapy, such as multi-drug resistance gene therapy; and

(ix) immunotherapy, including for example ex vivo and in vivo methods of increasing the immunogenicity of patient tumor cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte macrophage colony stimulating factor; a method of reducing T cell anergy; methods using transfected immune cells such as cytokine-transfected dendritic cells; a method using a cytokine-transfected tumor cell line, and a method using an anti-idiotype antibody.

Preferably the agents of table 1 below (but not exclusively) are combined with compounds of formula I.

The following abbreviations refer to the following definitions, respectively:

aq (aqueous), h (hr), g (g), L (L), mg (mg), MHz (megahertz), min. (min), mM (mM), mmol (mmol), mM (mmol equivalent), m.p. (melting point), eq (equivalent), mL (mL), L (microliter), ACN (acetonitrile), AcOH (acetic acid), CDCl (acetonitrile), hi (r), hi (₃(deuterated chloroform), CD₃OD (deuterated methanol), CH₃CN (acetonitrile), c-hex (cyclohexane), DCC (dicyclohexylcarbodiimide), DCM (dichloromethane), DIC (diisopropylcarbodiimide), DIEA (diisopropylethylamine), DMF (dimethylformamide), DMSO (dimethyl sulfoxide), DMSO-d₆(deuterated dimethyl sulfoxide), EDC (1- (3-dimethyl-amino-propyl) -3-ethylcarbodiimide), ESI (electrospray ionization), EtOAc (ethyl acetate), Et₂O (diethyl ether), EtOH (ethanol), HATU (dimethylamino- ([1,2, 3))]Triazolo [4,5-b]Pyridin-3-yloxy) -methylene]Dimethyl-ammonium hexafluorophosphate), HPLC (high Performance liquid chromatography), i-PrOH (2-propanol), K₂CO₃(Potassium carbonate), LC (liquid chromatography), MeOH (methanol), MgSO₄Magnesium sulfate, MS (Mass Spectrometry), MTBE (methyl Tert-butyl Ether), NaHCO₃(sodium bicarbonate), NaBH₄(sodium borohydride), NMM (N-methylmorpholine), NMR (nuclear magnetic resonance), PyBOP (benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate), RT (room temperature), RT (retention time), SPE (solid phase extraction), TBTU (2- (1-H-benzotriazol-1-yl) -1,1,3, 3-tetramethyluronium tetrafluoroborate), TEA (triethylamine), TFA (trifluoroacetic acid), THF (tetrahydrofuran), TLC (thin layer chromatography), UV (ultraviolet).

Description of in vitro assays

Abbreviations:

GST = glutathione-S-transferase

FRET = fluorescence resonance energy transfer

HTRF = (homogeneous phase time resolved fluorescence)

HEPES = 4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid buffer

DTT = dithiothreitol

BSA = bovine serum albumin

CHAPS = detergent;

CHAPS = 3- [ (3-cholamido (cholamido) propyl) dimethylammonio (ammonio) ] -1-propanesulfonate.

streptavidin-XLent is a high grade streptavidin-XL 665 conjugate for which coupling conditions have been optimized to produce conjugates with enhanced performance for some assays, particularly assays requiring high sensitivity.

Biochemical activity testing of tankyrase 1 and 2: automated poly ADP nuclear glycation (autopropsy) assay

The autopolyadp ribosylation assay was performed in two steps: enzymatic reactions (where GST-labeled tankyrase-1, resp tankyrase-2 transfer biotinylated ADP-ribose to itself from biotinylated NAD as a common substrate) and detection reactions (where time resolved FRET between cryptate-labeled anti-GST bound to GST tags of the enzyme and Xlent @ labeled-streptavidin bound to biotin-poly ADP riboylated residues) were analyzed. Autopolyadp ribosylation activity can be detected directly via an increase in HTRF signal.

The automated poly ADP ribosylation assay was performed as a 384-well HTRF (Cisbio, Codolet, France) assay format in Grarner low (Greiner low volume) nb 384-well microtiter plates and used for high throughput screening. 250 nM GST-labeled Takara polymerase-1 (1023 + 1327 aa), approximately 250 nM GST-labeled Takara polymerase-2 (873 + 1166 aa) and 5 μ M bio-NAD (Biolog, Life science Inst., Bremen, Germany), respectively, were incubated in a total volume of 5 μ l (50 mEPMHES, 4 mM magnesium chloride, 0.05% Prorhenike F-68, 1.4 mM DTT, 0.5% DMSO, pH 7.7) at 30 ℃ for 90 min in the absence or presence of test compounds (10-fold dilution). The reaction was stopped by adding 1 μ l of 50mM EDTA solution. 2 μ l of detection solution (1.6 μ M SA-Xlent ® (Cisbio, Codolet, France), 7.4 nM anti-GST-K (Eu-labeled anti-GST, Cisbio, Codolet, France) in 50mM HEPES, 800 mM KF, 0.1% BSA, 20mM EDTA, 0.1% CHAPS, pH 7.0) was added. After 1 hour incubation at room temperature, HTRF was measured with an Envision multimode reader (Perkin Elmer LAS Germany GmbH) at excitation wavelength 340 nm (laser mode) and emission wavelengths 615 nm and 665 nm. The ratio of the emitted signals is determined. The full value used is the inhibitor-free reaction. The pharmacological zero value used was XAV-939 (Tocris) in a final concentration of 5 μ M. The inhibition values (IC50) were determined using the program Symyx Assay Explorer @orCondosseo @fromGeneData.

Determination of the cytostatic Effect of tankyrase

Since tankyrase has been described as modulating the cellular level of Axin2 (Huang et al, 2009; Nature), an increase in Axin2 levels was used as a readout to determine the cytostatic effect of tankyrase in a Luminex-based assay.

Cells of colon cancer cell line DLD1 were plated at 1.5x10 per well⁴Individual cells were seeded in 96-well plates. The following day, cells were treated with serially diluted test compounds in triplicate at 0.3% final DMSO concentration in 7 steps. After 24 hours, cells were lysed in lysis buffer (20mM Tris/HCl pH 8.0, 150mM NaCl, 1% NP40, 10% glycerol) and the lysate was cleared by centrifugation through 96-well filter plates (0.65 μm). By binding to monoclonal anti-Axin 2 antibody (R) bound to fluorescent carboxyl beads (carboxybeads)&D Systems # MAB6078) were incubated together to isolate Axin2 protein from the cell lysate. Bound Axin2 was then specifically detected with polyclonal anti-Axin 2 antibody (Cell Signaling #2151) and a suitable PE-fluorescent secondary antibody. In Luminex, according to the manufacturer's instructions²⁰⁰The amount of Axin2 protein isolated was determined on the machine (Luminex Corporation) by counting 100 events per well. Inhibition of tankyrase by test compounds resulted in higher levels of Axin2, which was directly correlated with an increase in detectable fluorescence. As a control, cells were treated with solvent only (neutral control) and with the tankyrase reference inhibitor IWR-2 (3E-06M), which served as a control for the maximal increase in Axin 2. For analysis, the data obtained were targeted to untreated solvent control standardsStandardized and fitted using Assay Explorer software (Accelrys) to determine EC₅₀The value is obtained.

Description of the PARP1 assay

Biochemical activity assay of PARP-1: automated poly ADP ribosylation assay

The autopolyadp ribosylation assay was performed in two steps: enzymatic reactions (where His-tagged Parp-1 transfers biotinylated ADP-ribose/ADP-ribose to itself from biotinylated NAD/NAD as a co-substrate) and detection reactions (where time resolved FRET between cryptate-tagged anti-His antibodies bound to the enzyme's His tag and Xlent @ tagged-streptavidin bound to biotin-poly ADP riboylated residues) were analyzed. Autopolyadp ribosylation activity can be detected directly via an increase in HTRF signal.

The autopolyADP ribosylation assay was performed as a 384-well HTRF (Cisbio, Codolet, France) assay format in Graham's low nb 384-well microtiter plates. A mixture of 35 nM His-tagged Parp-1 (human, recombinant, Enzo Life Sciences GmbH, Lnurrach, Germany) and 125 nM bio-NAD (Biolog, Life science Inst., Bremen, Germany) as co-substrate and 800 nM NAD in the absence or presence of test compounds (10-fold dilution concentration) was incubated in a total volume of 6 μ L (100 mM Tris/HCl, 4 mM magnesium chloride, 0.01% IGEPAL CA630, 1mM DTT, 0.5% DMSO, pH 8, 13 ng/. mu.l activated DNA (BPS Bioscience, San Diego, US)) at 23 ℃ for 150 min. The reaction was terminated by adding 4 μ l of stop/detection solution (70 nM SA-Xlent ® (Cisbio, Codolet, France), 2.5 nM anti-His-K ® (Eu-labeled anti-His, Cisbio, Codolet, France) in 50mM HEPES, 400 mM KF, 0.1% BSA, 20mM EDTA, pH 7.0). After 1 hour incubation at room temperature, HTRF was measured with an Envision multimode reader (Perkin Elmer LAS Germany GmbH) at an excitation wavelength of 340 nm (laser mode) and emission wavelengths of 615 nm and 665 nm. The ratio of the emitted signals is determined. The full value used is the inhibitor-free reaction. The pharmacological zero value used was Olaparib (LClabs, Woburn, US) in a final concentration of 1 μ M. The inhibition values (IC50) were determined using the program Symyx Assay Explorer @orCondosseo @fromGeneData.

Description of TNKS1 and TNKS2 ELISA assays

Biochemical activity test of TNKS1 and 2: activity ELISA (automatic poly ADP ribolysis assay)

To analyze the autopolyadp-ribosylation activity of TNKS1 and 2, an activity ELISA was performed: in the first step, GST-tagged TNKS was captured on glutathione-coated plates. The activity assay was then performed with biotinylated NAD in the absence/presence of the compound. During the enzymatic reaction GST-tagged TNKS transferred biotinylated ADP-ribose to itself from biotinylated NAD as co-substrate. For detection, streptavidin-HRP conjugate bound to biotinylated TNKS was added, and thus captured to the plate. The amount of biotinylated resp autopolyadp ribosylated TNKS was detected with a luminescent substrate of HRP. The level of the luminescence signal is directly related to the amount of autopolyadp ribosylated TNKS and thus also to TNKS activity.

Activity ELISA was performed on 384-well Glutathione-coated microtiter plates (Express capture Glutathione coated plates, Biocat, Heidelberg, Germany.) plates were pre-equilibrated with PBS plates, plates were then blocked with 50 μ l of 20 ng/well GST-labeled Tnks-1 (1023-plus 1327 aa, prepared in-house), GST-labeled Tnks-2 (873-plus 1166 aa, prepared in-house), respectively, in assay buffer (50 mM HEPES, 4 mM magnesium chloride, 0.05% Pluronic F-68, 2 mM DTT, pH 7.7) overnight at 4 ℃. plates were washed 3 times with PBS-Tween-20. the plates were blocked with 50 μ l of blocking buffer (PBS, 0.05% Tween-20, 0.5% BSA) for 20 minutes at room temperature after which the plates were washed with PBS-Tween-20 (10 times) enzymatic assay compounds (10-fold) Released concentration) was performed in 50 μ l of reaction solution (50 mM HEPES, 4 mM magnesium chloride, 0.05% pluronic F-68, 1.4 mM DTT, 0.5% DMSO, pH 7.7) with 10 μ M bio-NAD (Biolog, Life science Inst., Bremen, Germany) as co-substrate at 30 ℃ for 1 hour. The reaction was stopped by washing 3 times with PBS-Tween-20. For detection, 50 μ l of 20ng/μ l streptavidin in PBS/0.05% Tween-20/0.01% BSA, HRP conjugate (MoBiTec, G tincture, Germany) were added and the plates were incubated for 30 minutes at room temperature. After 3 washes with PBS-Tween-20, 50. mu.l SuperSignal ELISA Femto maximum sensitivity (Maximumsensirity) substrate solution (ThermoFisher scientific (Pierce), Bonn, Germany) was added. After incubation for 1min at room temperature, the luminescence signal was measured at 700 nm using an Envision multimode reader (Perkin Elmer LAS Germany GmbH). The full value used is the inhibitor-free reaction. The pharmacological zero value used was XAV-939 (Tocris) in a final concentration of 5 μ M. The inhibition values (IC50) were determined using the program Symyx Assay Explorer @orCondosseo @fromGeneData.

In this context, all temperatures are expressed in degrees Celsius. In the following examples, "conventional post-processing (work-up)" means: if desired with addition of water, if desired with adjustment of the pH to a value between 2 and 10, depending on the composition of the end product, the mixture is extracted with ethyl acetate or dichloromethane, the phases are separated, the organic phase is dried over sodium sulfate and evaporated, and the residue is purified by chromatography on silica gel and/or crystallization. Rf value on silica gel; eluent: ethyl acetate/methanol 9: 1.

HPLC/MS Condition A

Column: chromolith Performance ROD RP-18e, 100 x 3mm²

Gradient: a: B = 99:1-0:100 within 1.8 min

Flow rate: 2.0 ml/min

Eluent A: water + 0.05% formic acid

Eluent B: acetonitrile + 0.04% formic acid

Wavelength: 220 nm

Mass spectrum: positive ion mode

HPLC/MS Condition B

Column: chromolith Performance ROD RP-18e, 100 x 3mm²

Gradient: a: B = 99:1 to 0:100 within 3.5 min

Flow rate: 2.0 ml/min

Eluent A is water and 0.05 percent formic acid

Eluent B is acetonitrile + 0.04% formic acid

Wavelength: 220 nm

Mass spectrum: positive ion mode

HPLC/MS Condition C

Column: chromolith Performance ROD RP-18e, 50X 4.6 mm²

Gradient: a: B = 96:4 to 0:100 within 2.8 min

Flow rate: 2.40 ml/min

Eluent A: water + 0.05% formic acid

Eluent B: acetonitrile + 0.04% formic acid

Wavelength: 220 nm

Mass spectrum: positive ion mode

¹H NMR was recorded on a Bruker DPX-300, DRX-400 or AVII-400 spectrometer using the residual signal of the deuterated solvent as an internal standard. Chemical shifts () are reported in ppm relative to residual solvent signal (for in DMSO-d)₆In (1)¹HNMR， = 2.49 ppm)。¹H NMR data are reported below: chemical shifts (multiplicities, coupling constants, and number of hydrogen atoms). The multiplicities are abbreviated as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad).

Microwave Chemistry was carried out on a single mode microwave reactor, EmrysTMOptimier from Personal Chemistry.

Example 1

Synthesis of 6-fluoro-2- [4- (1-hydroxy-1-methyl-ethyl) -phenyl ] -3H-quinazolin-4-one ("A1

A suspension of 2-amino-5-fluorobenzamide (1.00 g,6.49 mmol), methyl 4-formylbenzoate (1.06 g,6.49 mmol) and sodium bisulfite (1.26 g, 6.62 mmol) in N, N-dimethylacetamide (13 ml) was heated to 150 ℃ and stirred at this temperature for 3 hours. The reaction mixture was brought to room temperature and poured into ice water. The resulting precipitate was collected by filtration, washed with water and dried under vacuum to give 4- (6-fluoro-4-oxo-3, 4-dihydro-quinazolin-2-yl) -benzoic acid methyl ester as a yellow solid; HPLC/MS 2.08 min (C), [ M + H ] 299.

To a suspension of methyl 4- (6-fluoro-4-oxo-3, 4-dihydro-quinazolin-2-yl) -benzoate (1.53 g, 5.13mmol) in THF (20 ml) was added cerium (III) chloride (1.33 g,5.38 mmol). The mixture was stirred at room temperature for 4 hours. Methyl magnesium chloride (20% solution in THF, 7.54 ml, 20.5 mmol) was then added and the reaction mixture was stirred at room temperature for an additional 1 hour. The reaction mixture was diluted with THF and carefully added saturated sodium chloride solution. The mixture was stirred well and filtered with suction. The organic phase of the filtrate was separated, dried over sodium sulfate and evaporated. Chromatography of the residue on a silica gel column with methanol/dichloromethane as eluent to give 6-fluoro-2- [4- (1-hydroxy-1-methyl-ethyl) -phenyl ] -3H-quinazolin-4-one as a white crystalline solid; HPLC/MS 2.22 min (B), [ M + H ] 299.

¹H NMR (400 MHz, DMSO-d₆) [ppm]12.57 (s, 1H), 8.12 (m, 2H), 7.81(m, 2H), 7.71 (td,J=8.7, 3.0, 1H), 7.63 (m, 2H), 5.14 (s, 1H), 1.47 (s, 6H)。

The following compounds were prepared analogously:

2- [4- (1-hydroxy-1-methyl-ethyl) -phenyl ] -8-methoxy-3H-quinazolin-4-one ("A2")

HPLC/MS 1.61 min (C), [M+H]311;¹H NMR (400 MHz, DMSO-d₆) [ppm]12.47 (s, 1H), 8.13 (m, 2H), 7.72 (dd,J=7.8, 1.5, 1H), 7.64 (m, 2H), 7.45(t,J=7.9, 1H), 7.39 (dd,J=8.1, 1.4, 1H), 5.16 (s, 1H), 3.96 (s, 3H), 1.48(s, 6H);

8-fluoro-2- [4- (1-hydroxy-1-methyl-ethyl) -phenyl ] -3H-quinazolin-4-one ("A3")

HPLC/MS 2.11 min (B), [M+H]299;¹H NMR (400 MHz, DMSO-d₆)[ppm]12.45 (s, 1H), 8.12 (m, 2H), 7.79 (td,J=8.2, 5.7, 1H), 7.63 (m, 2H), 7.54(d,J=8.0, 1H), 7.23 (ddd,J=11.0, 8.2, 0.9, 1H), 5.15 (s, 1H), 1.47 (s, 6H);

5-fluoro-2- [4- (1-hydroxy-1-methyl-ethyl) -phenyl ] -3H-quinazolin-4-one ("A4")

HPLC/MS 1.81 min (C), [M+H]299;¹H NMR (400 MHz, DMSO-d₆) [ppm]12.63 (s, 1H), 8.14 (m, 2H), 7.96 (d,J=8.0, 1H), 7.70 (ddd,J=10.7, 8.0,1.3, 1H), 7.64 (m, 2H), 7.49 (td,J=8.0, 4.8, 1H), 5.17 (s, 1H), 1.47 (s,6H);

6-chloro-2- [4- (1-hydroxy-1-methyl-ethyl) -phenyl ] -3H-quinazolin-4-one ("A5")

HPLC/MS 2.44 min (B), [M+H]315;¹H NMR (400 MHz, DMSO-d₆) [ppm]12.64 (s, 1H), 8.12 (d,J=8.6, 2H), 8.09 (d,J=2.4, 1H), 7.85 (dd,J=8.7,2.5, 1H), 7.76 (d,J=8.7, 1H), 7.63 (d,J=8.6, 2H), 5.19 (s, 1H), 1.47 (s,6H);

8-chloro-2- [4- (1-hydroxy-1-methyl-ethyl) -phenyl ] -3H-quinazolin-4-one ("A6")

¹H NMR (400 MHz, DMSO-d₆) [ppm]12.70 (s, 1H), 8.18 (d,J=8.6, 2H),8.11 (dd,J=7.9, 1.4, 1H), 7.98 (dd,J=7.8, 1.4, 1H), 7.65 (d,J=8.6, 2H),7.47 (t,J=7.8, 1H), 5.17 (s, 1H), 1.47 (s, 6H);

HPLC/MS 2.50 min (B), [M+H]315;

6-fluoro-2- [5- (1-hydroxy-1-methyl-ethyl) -2-pyridyl ] -3H-quinazolin-4-one ("A13")

HPLC/MS 2.30 min (B), [M+H]300;

¹H NMR (400 MHz, DMSO-d₆) [ppm]11.96 (s, 1H), 8.86 (d,J=1.6, 1H),8.38 (d,J=8.3, 1H), 8.12 (dd,J=8.3, 2.2, 1H), 7.87 (m, 2H), 7.76 (td,J=8.7, 3.1, 1H), 5.42 (s, 1H), 1.52 (s, 6H);

2- [4- (1-ethyl-1-hydroxy-propyl) phenyl ] -6-fluoro-3H-quinazolin-4-one ("A14")

HPLC/MS 2.62 min (B), [M+H]327;¹H NMR (400 MHz, DMSO-d₆) [ppm]12.57 (s, 1H), 8.17 – 8.08 (m, 2H), 7.81 (m, 2H), 7.71 (td,J= 8.7, 3.0 Hz,1H), 7.57 – 7.49 (m, 2H), 4.67 (s, 1H), 1.77 (m, 4H), 0.66 (t,J= 7.3 Hz,6H)。

Example 2

Synthesis of 6-fluoro-2- {4- [1- (2-hydroxy-ethoxy) -1-methyl-ethyl ] -phenyl } -3H-quinazolin-4-one ("A7")

To a suspension of 6-fluoro-2- [4- (1-hydroxy-1-methyl-ethyl) -phenyl ] -3H-quinazolin-4-one (149 mg, 0.50mmol) in ethane-1, 2-diol (2 ml) was added toluene-4-sulfonic acid monohydrate (114 mg, 0.60 mmol). The reaction mixture was stirred at ambient temperature for 3 hours. The suspension was then heated to 80 ℃ and the resulting clear solution was stirred at this temperature for 5 hours. The reaction mixture was cooled to room temperature, and water was added. The resulting precipitate was filtered off and washed with water. Chromatography of the residue on a silica gel column using cyclohexane/ethyl acetate as eluent gave 6-fluoro-2- {4- [1- (2-hydroxy-ethoxy) -1-methyl-ethyl ] -phenyl } -3H-quinazolin-4-one as white crystals; HPLC/MS 2.28 min (B), [ M + H ]343;

¹H NMR (400 MHz, DMSO-d₆) [ppm]12.60 (s, 1H), 8.15 (d,J=8.6, 2H),7.82 (m, 2H), 7.72 (td,J=8.7, 3.0, 1H), 7.61 (d,J=8.6, 2H), 4.58 (t,J=5.7,1H), 3.50 (q,J=5.6, 2H), 3.19 (t,J=5.6, 2H), 1.51 (s, 6H)。

the following compounds were prepared analogously:

6-fluoro-2- {4- [1- (2-methoxy-ethoxy) -1-methyl-ethyl ] -phenyl } -3H-quinazolin-4-one ("A8")

HPLC/MS 2.61 min (B), [M+H]357;¹H NMR (400 MHz, DMSO-d₆) [ppm]12.60 (s, 1H), 8.15 (m, 2H), 7.82 (m, 2H), 7.72 (td,J=8.7, 3.0, 1H), 7.59(m, 2H), 3.45 (dd,J=5.7, 4.2, 2H), 3.29 (dd,J=5.7, 4.2, 2H), 3.26 (s, 3H),1.51 (s, 6H);

6-fluoro-2- {4- [1- (2-hydroxy-ethoxy) -1-methyl-ethyl ] -phenyl } -8-methyl-3H-quinazolin-4-one ("A21")

HPLC/MS 1.90 min (A), [M+H]327;¹H NMR (400 MHz, DMSO-d₆) [ppm]12.60 (s, 1H), 8.21 (d,J= 8.5 Hz, 1H), 7.73 – 7.44 (m, 4H), 4.56 (t,J=5.7 Hz, 1H), 3.52 (q,J= 5.6 Hz, 2H), 3.21 (t,J= 5.6 Hz, 2H), 2.65 (s,3H), 1.52 (s, 6H)。

Example 3

Synthesis of 2- (4-tert-butyl-phenyl) -6-fluoro-3H-quinazolin-4-one ("A9

A suspension of 2-amino-5-fluorobenzamide (154 mg, 1.0mmol), 4-tert-butylbenzaldehyde (162 mg, 1.0mmol) and sodium bisulfite (194 mg, 1.02 mmol) in N, N-dimethylacetamide (2 ml) was heated to 150 ℃ and stirred at this temperature for 3 hours. The reaction mixture was brought to room temperature and poured into ice water. The resulting precipitate was collected by filtration, washed with water and dried under vacuum to give 2- (4-tert-butyl-phenyl) -6-fluoro-3H-quinazolin-4-one as a light grey solid;

HPLC/MS 3.10 min (B), [M+H]297;

¹H NMR (400 MHz, DMSO-d₆) [ppm]12.59 (s, 1H), 8.12 (m, 2H), 7.81(ddd,J=8.9, 6.4, 4.0, 2H), 7.72 (td,J=8.7, 3.0, 1H), 7.57 (m, 2H), 1.33 (s,9H)。

the following compounds were prepared analogously:

6-fluoro-2- [4- (4-methyl-piperazin-1-yl) -phenyl ] -3H-quinazolin-4-one ("A10")

HPLC/MS 1.67 min (B), [M+H]339;¹H NMR (400 MHz, DMSO-d₆) [ppm]12.36 (s, 1H), 8.10 (d,J=9.1, 2H), 7.76 (m, 2H), 7.67 (td,J=8.7, 3.0, 1H),7.04 (d,J=9.1, 2H), 3.32 (m, 4H), 2.47 (m, 4H), 2.25 (s, 3H);

6-fluoro-2- (4-isopropyl-phenyl) -3H-quinazolin-4-one ("A22")

HPLC/MS 2.99 min (B), [M+H]283;¹H NMR (400 MHz, DMSO-d₆) [ppm]12.57 (s, 1H), 8.43 – 7.95 (m, 2H), 7.87 – 7.78 (m, 2H), 7.73 (td,J= 8.7,3.0 Hz, 1H), 7.43 (d,J= 8.1 Hz, 2H), 3.00 (hept,J= 6.8 Hz, 1H), 1.26 (d,J= 6.9 Hz, 6H)。

Example 4

Synthesis of 6-fluoro-2- [4- (2-methyltetrahydrofuran-2-yl) phenyl ] -3H-quinazolin-4-one ("A15

The second step is carried out as M.McConville et al, org.Biomol. chem., 2010, 8, 5614-.

Example 5

Synthesis of 6-fluoro-2- [4- (1-hydroxycyclopentyl) phenyl ] -3H-quinazolin-4-one ("A16

A solution of 2- (4-bromophenyl) - [1,3] dioxolane (1.15 g, 5.00 mmol) in THF (5.0 ml) was added dropwise at 55 ℃ to magnesium turnings (146 mg, 6.0 mmol) and iodine crystals in THF (5 ml). The mixture was stirred at 55 ℃ for 1 h. A solution of cyclopentanone (465 μ l, 5.25 mmol) in THF (5 ml) was then added dropwise and the mixture was stirred at 55 ℃ for another hour. The reaction mixture was diluted with THF, acidified with 1N HCl (4 ml) and washed three times with brine. The organic phase is dried over sodium sulfate, filtered and evaporated to dryness. Chromatography of the residue on a silica gel column with cyclohexane/ethyl acetate as eluent gave 1- (4- [1,3] dioxolan-2-yl-phenyl) -cyclopentanol as a yellow oil; HPLC/MS 1.71 min (A), [ M + H ] 235.

A suspension of 2-amino-5-fluorobenzamide (135 mg, 0.88 mmol), 1- (4- [1,3] dioxolan-2-yl-phenyl) -cyclopentanol (206 mg, 0.88 mmol) and sodium bisulfite (170 mg, 0.89 mmol) in N, N-dimethylacetamide (2 ml) was heated to 150 ℃ and stirred at this temperature for 3 hours. The reaction mixture was brought to room temperature and poured into ice water. The resulting precipitate was collected by filtration and washed with water. Subjecting to silica gel column chromatography with methanol/dichloromethane as eluent to give 6-fluoro-2- [4- (1-hydroxy-cyclopentyl) -phenyl ] -3H-quinazolin-4-one as a white solid; HPLC/MS 1.80 min (A), [ M + H ]325;

¹H NMR (400 MHz, DMSO-d₆) [ppm]12.59 (s, 1H), 8.13 (d,J=8.5, 2H),7.81 (m, 2H), 7.71 (td,J=8.7, 3.0, 1H), 7.69 (m, 2H), 4.93 (s, 1H), 1.89 (s,6H), 1.78 (m, 2H)。

the following compounds were prepared analogously:

6-fluoro-2- [4- (3-hydroxyoxetan-3-yl) phenyl ] -3H-quinazolin-4-one ("A17")

。

Example 6

Synthesis of 2- [4- [1- (2-aminoethoxy) -1-methyl-ethyl ] phenyl ] -6-fluoro-3H-quinazolin-4-one ("A18

。

Example 7

Synthesis of 6-fluoro-2- [4- (4-piperidinyl) phenyl ] -3H-quinazolin-4-one ("A19") and 6-fluoro-2- [4- (1-methyl-4-piperidinyl) phenyl ] -3H-quinazolin-4-one ("A20")

。

Example 8

Synthesis of 6, 8-difluoro-2- [4- (1-hydroxy-1-methyl-ethyl) phenyl ] -3H-quinazolin-4-one ("A11

A solution of 2-amino-3, 5-difluoro-benzamide (86.2 mg, 0.50mmol), methyl 4-formylbenzoate (82.1 mg, 0.50mmol) and sodium bisulfite (97 mg, 0.51 mmol) in N-methyl-pyrrolidone (1 ml) was heated to 150 ℃ and stirred at that temperature for 16 h. The reaction mixture was brought to room temperature and poured into ice water. The resulting precipitate was collected by filtration, washed with water and dried under vacuum to give 4- (6, 8-difluoro-4-oxo-3, 4-dihydro-quinazolin-2-yl) -benzoic acid methyl ester as a brown solid; HPLC/MS 1.88 min (A), [ M + H ] 316.

To a suspension of 4- (6, 8-difluoro-4-oxo-3, 4-dihydro-quinazolin-2-yl) -benzoic acid methyl ester (152 mg, 0.48mmol) in THF (20 ml) was added cerium (III) chloride (130 mg, 0.53 mmol). The mixture was stirred at room temperature for 1 hour. Methyl magnesium chloride (20% solution in THF, 671 μ l, 2.01 mmol) was then added and the reaction mixture was stirred at room temperature for 20 minutes. The reaction mixture was diluted with THF and carefully added saturated sodium chloride solution. The mixture was stirred well and filtered with suction. The organic phase of the filtrate was separated, dried over sodium sulfate and evaporated. Subjecting the residue to silica gel column chromatography with methanol/dichloromethane as eluent to give 6, 8-difluoro-2- [4- (1-hydroxy-1-methyl-ethyl) -phenyl ] -3H-quinazolin-4-one as a white powder; HPLC/MS 2.37 min (B), [ M + H ]317;

¹H NMR (400 MHz, DMSO-d₆) [ppm]12.76 (s, 1H), 8.12 (d,J=8.5, 2H),7.83 (ddd,J=10.4, 9.1, 2.9, 1H), 7.69 (m, 1H), 7.64 (d,J=8.5, 2H), 5.17 (s,1H), 1.47 (s, 6H)。

the following compounds were prepared analogously:

5, 6-difluoro-2- [4- (1-hydroxy-1-methyl-ethyl) phenyl ] -3H-quinazolin-4-one ("A12")

HPLC/MS 2.28 min (B), [M+H]317;¹H NMR (400 MHz, DMSO-d₆) [ppm]12.58 (s, 1H), 8.38 – 8.02 (m, 2H), 8.02 – 7.76 (m, 1H), 7.73 – 7.37 (m, 3H),5.16 (s, 1H), 1.46 (s, 6H);

5-chloro-2- [4- (1-hydroxy-1-methyl-ethyl) -phenyl ] -3H-quinazolin-4-one ("A23")

HPLC/MS 2.33 min (B), [M+H]315;¹H NMR (500 MHz, DMSO-d₆) [ppm]12.45 (s, 1H), 8.32 – 7.98 (m, 2H), 7.73 (t,J= 7.9 Hz, 1H), 7.66 (dd,J=8.2, 1.2 Hz, 1H), 7.65 – 7.61 (m, 2H), 7.49 (dd,J= 7.7, 1.3 Hz, 1H), 5.15(s, 1H), 1.47 (s, 6H);

2- [4- (1-hydroxy-1-methyl-ethyl) -phenyl ] -8-methyl-3H-quinazolin-4-one ("A24")

HPLC/MS 2.52 min (B), [M+H]295;¹H NMR (500 MHz, DMSO-d₆) [ppm]12.45 (s, 1H), 8.22 – 8.08 (m, 2H), 8.09 – 7.90 (m, 1H), 7.75 – 7.66 (m, 1H),7.63 (d,J= 8.5 Hz, 2H), 7.39 (t,J= 7.6 Hz, 1H), 5.14 (s, 1H), 2.62 (s,3H), 1.47 (s, 6H);

6-fluoro-2- [4- (1-hydroxy-1-methyl-ethyl) -phenyl ] -8-methyl-3H-quinazolin-4-one ("A25")

HPLC/MS 1.89 min (A), [M+H]313;¹H NMR (400 MHz, DMSO-d₆) [ppm]12.58 (s, 1H), 8.38 – 8.01 (m, 2H), 7.75 – 7.42 (m, 4H), 5.15 (s, 1H), 2.64(d,J= 0.7 Hz, 3H), 1.47 (s, 6H);

5,6, 8-trifluoro-2- [4- (1-hydroxy-1-methyl-ethyl) -phenyl ] -3H-quinazolin-4-one ("A26")

HPLC/MS 2.39 min (B), [M+H]335;¹H NMR (400 MHz, DMSO-d₆) [ppm]12.73 (s, 1H), 8.32 – 7.97 (m, 3H), 7.80 – 7.55 (m, 2H), 5.16 (s, 1H), 1.47(s, 6H);

5, 8-difluoro-2- [4- (1-hydroxy-1-methyl-ethyl) -phenyl ] -3H-quinazolin-4-one ("A27")

HPLC/MS 1.68 min (A), [M+H]317;¹H NMR (400 MHz, DMSO-d₆) [ppm]12.64 (s, 1H), 8.50 – 7.96 (m, 2H), 7.70 (ddd,J= 10.0, 9.0, 4.3 Hz, 1H),7.67 – 7.62 (m, 2H), 7.24 (ddd,J= 10.4, 9.0, 3.7 Hz, 1H), 5.16 (s, 1H),1.47 (s, 6H)。

Example 9

Synthesis of 6-fluoro-8-methyl-2- [4- (4-methyl-piperazin-1-yl) -phenyl ] -3H-quinazolin-4-one ("A28

To a solution of 2-amino-5-fluoro-3-methyl-benzoic acid (4.80 g, 28.4 mmol) in THF (60 ml) was added N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (10.9 g, 56.8 mmol), 1-hydroxybenzotriazole hydrate (4.34 g, 28.4 mmol) and a 5M aqueous ammonia solution in dioxane (283 ml, 142 mmol). The resulting slurry was stirred for 3 hours. The reaction mixture was filtered through Celite and washed with THF. The filtrate was evaporated and partitioned between water and ethyl acetate. The organic phase was dried over sodium sulfate and evaporated. The residue was crystallized from 2-propanol to give 2-amino-5-fluoro-3-methyl-benzamide as beige crystals, HPLC/MS 1.68 min (B), [ M + H ] 169.

A solution of 2-amino-5-fluoro-3-methyl-benzamide (84.1 mg, 0.50mmol), 4- (4-methyl-piperazin-1-yl) -benzaldehyde (123 mg, 0.60mmol) and sodium bisulfite (97 mg, 0.51 mmol) in N-methyl-pyrrolidone (1 ml) was heated to 150 ℃ and stirred at that temperature for 16 h. The reaction mixture was brought to room temperature and poured into ice water. The resulting precipitate was collected by filtration, washed with water and dried. Subjecting the residue to silica gel column chromatography with methanol/dichloromethane as eluent to obtain 6-fluoro-8-methyl-2- [4- (4-methyl-piperazin-1-yl) -phenyl]-3H-quinazolin-4-one as a brown powder; HPLC/MS 1.47 min (A), [ M + H]353;¹H NMR (400 MHz, DMSO-d₆) [ppm]12.34 (s, 1H), 8.69 – 7.90 (m, 2H), 7.86 – 7.26 (m, 2H), 7.28 – 6.73 (m, 2H),3.33 – 3.27 (m, 4H), 2.61 (s, 3H), 2.45 (t,J= 5.1 Hz, 4H), 2.23 (s, 3H)。

The following compounds were prepared analogously:

6-fluoro-2- [4- (4-hydroxy-piperidin-1-yl) -phenyl ] -8-methyl-3H-quinazolin-4-one ("A29")

HPLC/MS 2.54 min (B), [M+H]354;¹H NMR (400 MHz, DMSO-d₆) [ppm]12.33 (s, 1H), 8.23 – 8.03 (m, 2H), 7.72 – 7.42 (m, 2H), 7.16 – 6.91 (m, 2H),4.69 (d,J= 4.2 Hz, 1H), 3.74 (m, 3H), 3.05 (ddd,J= 13.0, 9.8, 3.1 Hz,2H), 2.62 (s, 3H), 1.89 – 1.74 (m, 2H), 1.54 – 1.35 (m, 2H);

2- [4- (1, 1-dioxo-1 l 6-thiomorpholin-4-yl) -phenyl ] -6-fluoro-8-methyl-3H-quinazolin-4-one ("A30")

HPLC/MS 1.88 min (A), [M+H]388;¹H NMR (400 MHz, DMSO-d₆) [ppm]12.41 (s, 1H), 8.46 – 8.01 (m, 2H), 7.82 – 7.47 (m, 2H), 7.30 – 6.90 (m, 2H),3.95 (m, 4H), 3.15 (m, 4H), 2.63 (s, 3H);

6-fluoro-2- [4- (4-hydroxymethyl-piperidin-1-yl) -phenyl ] -8-methyl-3H-quinazolin-4-one ("A31")

HPLC/MS 2.57 min (B), [M+H]368;¹H NMR (400 MHz, DMSO-d₆) [ppm]12.30 (s, 1H), 8.36 – 7.93 (m, 2H), 7.73 – 7.39 (m, 2H), 7.22 – 6.76 (m, 2H),4.45 (t,J= 5.3 Hz, 1H), 3.93 (dt,J= 12.7, 3.4 Hz, 2H), 3.34 – 3.25 (m,2H), 2.81 (td,J= 12.6, 2.7 Hz, 2H), 2.61 (s, 3H), 1.75 (dd,J= 13.4, 3.5Hz, 2H), 1.61 (dtd,J= 13.1, 6.6, 2.6 Hz, 1H), 1.31 – 1.11 (m, 2H);

6-fluoro-8-methyl-2- [4- (4-methyl- [1,4] diazepan-1-yl) -phenyl ] -3H-quinazolin-4-one ("A32")

HPLC/MS 2.00 min (B), [M+H]367;¹H NMR (400 MHz, DMSO-d₆, TFA-d₁) [ppm]8.19 (d,J= 8.8 Hz, 2H), 7.65 (dd,J= 8.6, 3.1 Hz, 1H), 7.57 – 7.53(m, 1H), 7.04 – 6.79 (m, 2H), 3.98 (m, 1H), 3.88 – 3.69 (m, 1H), 3.69 – 3.54(m, 2H), 3.55 – 3.44 (m, 2H), 3.35 – 3.17 (m, 2H), 2.90 (s, 3H), 2.65 (s,3H), 2.23 (m, 2H)。

Example 10

Synthesis of 6-fluoro-8-methyl-2- (4-piperidin-4-yl-phenyl) -3H-quinazolin-4-one hydrochloride ("A33

To a solution of tert-butyl 4- (4-carboxy-phenyl) -piperidine-1-carboxylate (828 mg, 2.71 mmol) in DMF (5 ml) were added methyl iodide (577 mg, 4.07 μ l) and potassium carbonate (375 mg, 2.71 mmol), and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was evaporated and the residue was treated with dichloromethane. The solid was filtered off and the filtrate was evaporated to dryness to give 4- (4-methoxycarbonyl-phenyl) -piperidine-1-carboxylic acid tert-butyl ester as a yellow solid; HPLC/MS 2.21min (A), [ M-tBu ] 264.

To a solution of tert-butyl 4- (4-methoxycarbonyl-phenyl) -piperidine-1-carboxylate (776 mg, 2.43 mmol) in dichloromethane (10 ml) was added diethylsilane (470 μ l, 3.64 mmol) and chlorobis (cyclooctene) iridium (I) dimer (22 mg, 0.025 mmol), and the mixture was irradiated in a microwave reactor at 50 ℃ for 1.5 hours. The reaction mixture was stirred vigorously with 2N hydrochloric acid (0.6ml) for 30 minutes. The organic layer was separated, dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel using cyclohexane/ethyl acetate as the eluent to give 4- (4-formyl-phenyl) -piperidine-1-carboxylic acid tert-butyl ester as a yellow resin; HPLC/MS 2.10 min (A), [ M-tBu ] 234.

A solution of 2-amino-5-fluoro-3-methyl-benzamide (84.1 mg, 0.50mmol), 4- (4-formyl-phenyl) -piperidine-1-carboxylic acid tert-butyl ester (145 mg, 0.50mmol) and sodium bisulfite (97 mg, 0.51 mmol) in N-methyl-pyrrolidone (1 ml) was heated to 160 ℃ and stirred at that temperature for 2 hours. The reaction mixture was brought to room temperature and poured into ice water. The resulting precipitate was collected by filtration and washed with water. The solid was triturated with methanol and filtered again with suction. The residue was slurried in 4N HCl in dioxane (1 ml) and methanol (0.25 ml) was added. The mixture was stirred at room temperature for 16 hours. Subjecting the reaction mixture toPreparative HPLC was chromatographed to give 6-fluoro-8-methyl-2- (4-piperidin-4-yl-phenyl) -3H-quinazolin-4-one hydrochloride as a pale beige powder; HPLC/MS 1.53 min (A), [ M + H]338;¹H NMR(400 MHz, DMSO-d₆, TFA-d₁) [ppm]8.34 – 8.20 (m, 2H), 7.70 (dd,J= 8.5, 3.1Hz, 1H), 7.52 (ddd,J= 9.3, 3.1, 1.0 Hz, 1H), 7.49 – 7.36 (m, 2H), 3.47 (dt,J= 12.7, 2.5 Hz, 2H), 3.09 (td,J= 12.8, 3.5 Hz, 2H), 3.00 (tt,J= 11.8,3.9 Hz, 1H), 2.68 (s, 3H), 2.11 – 1.85 (m, 4H)。

The following compounds were prepared analogously:

6, 8-difluoro-2- (4-piperidin-4-yl-phenyl) -3H-quinazolin-4-one hydrochloride ("A34")

HPLC/MS 1.44 min (A), [M+H]342;¹H NMR (400 MHz, DMSO-d₆, TFA-d₁) [ppm]8.35 – 8.17 (m, 2H), 7.72 (ddd,J= 8.3, 2.9, 1.4 Hz, 1H), 7.61 (ddd,J= 10.2, 8.9, 2.9 Hz, 1H), 7.52 – 7.31 (m, 2H), 3.61 – 3.38 (m, 2H), 3.08 (td,J= 12.8, 3.2 Hz, 2H), 3.00 (tt,J= 11.8, 3.9 Hz, 1H), 2.14 – 2.01 (m, 2H),2.01 – 1.86 (m, 2H)。

Example 11

Synthesis of 6, 8-difluoro-2- [4- (1-methyl-piperidin-4-yl) -phenyl ] -3H-quinazolin-4-one trifluoroacetate ("A35")

To a solution of 6, 8-difluoro-2- (4-piperidin-4-yl-phenyl) -3H-quinazolin-4-one hydrochloride (238 mg, 0.63mmol) in formic acid (2.0 ml) was added formaldehyde (37% aqueous solution, 160 μ l, 1.27 mmol).The mixture was heated to 80 ℃ and stirred at this temperature for 18 hours. The reaction mixture was evaporated and the residue was treated with 2N NaOH. The solid was filtered off and purified by preparative HPLC to give 6, 8-difluoro-2- [4- (1-methyl-piperidin-4-yl) -phenyl]-3H-quinazolin-4-one trifluoroacetate as white powder, HPLC/MS 1.43 min (A), [ M + H-]356.¹H NMR (500 MHz,DMSO-d₆) [ppm]12.80 (s, 1H), 9.58 (s, 1H), 8.23 – 8.14 (m, 2H), 7.85 (ddd,J= 10.3, 9.0, 2.9 Hz, 1H), 7.71 (ddd,J= 8.3, 2.9, 1.2 Hz, 1H), 7.46 (d,J= 8.0 Hz, 2H), 3.60 – 3.46 (m, 2H), 3.10 (t,J= 12.6 Hz, 2H), 2.92 (td,J=10.3, 8.5, 5.9 Hz, 1H), 2.12 – 2.02 (m, 2H), 2.00 – 1.80 (m, 2H)。

Preparation of 6-fluoro-8-methyl-2- [4- (1-methyl-piperidin-4-yl) -phenyl ] -3H-quinazolin-4-one ("a36") in analogy; a white powder; HPLC/MS 1.54 min (A), [ M + H ] 352.

Pharmacological data

Table 2: inhibition of tankyrase by some representative compounds of formula I

IC₅₀:<0.3μM = A 0.3 – 3μM = B 3-50μM = C

The compounds shown in Table 2 are particularly preferred compounds of the present invention.

Table 3: inhibition of tankyrase by some representative compounds of formula I

IC₅₀:<0.3μM = A 0.3 – 3μM = B 3-50μM = C

The compounds shown in Table 3 are particularly preferred compounds of the present invention.

The following examples relate to medicaments:

example A injection vial

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

Example B suppository

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

Example C: solutions of

Comprises 1g of active ingredient of formula I, 9.38 g of NaH₂PO₄∙2 H₂O、28.48 g Na₂HPO₄∙12 H₂O and 0.1 g benzalkonium chloride in 940 ml double distilled water. The pH was adjusted to 6.8 and the solution was made up to 1l and sterilised by irradiation. This solution can be used in the form of eye drops.

Example D: ointment formulation

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

Example E: tablet formulation

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

Example F: sugar-coated pill

Tablets were compressed analogously to example E and subsequently coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and dye.

Example G capsules

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

Example H: ampoule (CN)

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

Claims (6)

1. A compound selected from the group consisting of,

numbering Name (R) "A1" 6-fluoro-2- [4- (1-hydroxy-1-methyl-ethyl) -phenyl]-3H-quinazolin-4-one "A2" 2- [4- (1-hydroxy-1-methyl-ethyl) -phenyl]-8-methoxy-3H-quinazolin-4-one "A3" 8-fluoro-2- [4- (1-hydroxy-1-methyl-ethyl) -phenyl]-3H-quinazolin-4-one "A4" 5-fluoro-2- [4- (1-hydroxy-1-methyl-ethyl) -phenyl]-3H-quinazolin-4-one "A5" 6-chloro-2- [4- (1-hydroxy-1-methyl-ethyl) -phenyl]-3H-quinazolin-4-one "A6" 8-chloro-2- [4- (1-hydroxy-1-methyl-ethyl) -phenyl]-3H-quinazolin-4-one "A7" 6-fluoro-2- {4- [1- (2-hydroxy-ethoxy) -1-methyl-ethyl]-phenyl } -3H-quinazolin-4-one "A11" 6, 8-difluoro-2- [4- (1-hydroxy-1-methyl-ethyl) phenyl]-3H-quinazolin-4-one "A12" 5, 6-difluoro-2- [4- (1-hydroxy-1-methyl-ethyl) phenyl]-3H-quinazolin-4-one "A13" 6-fluoro-2- [5- (1-hydroxy-1-methyl-ethyl) -2-pyridinyl]-3H-quinazolin-4-one "A14" 2- [4- (1-ethyl-1-hydroxy-propyl) phenyl]-6-fluoro-3H-quinazolin-4-one "A16" 6-fluoro-2- [4- (1-hydroxycyclopentyl) phenyl]-3H-quinazolin-4-one "A17" 6-fluoro-2- [4- (3-hydroxyoxetan-3-yl) phenyl]-3H-quinazolin-4-one "A18" 2- [4- [1- (2-Aminoethoxy) -1-methyl-ethyl]Phenyl radical]-6-fluoro-3H-quinazolin-4-one "A19" 6-fluoro-2- [4- (4-piperidinyl) phenyl]-3H-quinazolin-4-one "A21" 6-fluoro-2- {4- [1- (2-hydroxy-ethoxy) -1-methyl-ethyl]-phenyl } -8-methyl-3H-quinazolin-4-one "A23" 5-chloro-2- [4- (1-hydroxy-1-methyl-ethyl) -phenyl]-3H-quinazolin-4-one "A24" 2- [4- (1-hydroxy-1-methyl-ethyl) -phenyl]-8-methyl-3H-quinazolin-4-one "A25" 6-fluoro-2- [4- (1-hydroxy-1-methyl-ethyl) -phenyl]-8-methyl-3H-quinazolin-4-one "A26" 5,6, 8-trifluoro-2- [4- (1-hydroxy-1-methyl-ethyl) -phenyl]-3H-quinazolin-4-one "A27" 5, 8-difluoro-2- [4- (1-hydroxy-1-methyl-ethyl) -phenyl]-3H-quinazolin-4-one "A29" 6-fluoro-2- [4- (4-hydroxy-piperidin-1-yl) -phenyl]-8-methyl-3H-quinazolin-4-one "A31" 6-fluoro-2- [4- (4-hydroxymethyl-piperidin-1-yl) -phenyl]-8-methyl-3H-quinazolin-4-one "A33" 6-fluoro-8-methyl-2- (4-piperidin-4-yl-phenyl) -3H-quinazolin-4-one "A34" 6, 8-difluoro-2- (4-piperidin-4-yl-phenyl) -3H-quinazolin-4-one hydrochloride

And pharmaceutically acceptable salts thereof, including mixtures thereof in all ratios.

2. A medicament comprising at least one compound of claim 1 and/or a pharmaceutically acceptable salt thereof, including mixtures thereof in all ratios, and optionally a pharmaceutically acceptable carrier, excipient or vehicle.

3. A compound of claim 1 and pharmaceutically acceptable salts thereof, including mixtures thereof in all ratios, for use in the treatment and/or prevention of cancer, multiple sclerosis, cardiovascular diseases, central nervous system injury and different forms of inflammation.

4. A compound according to claim 1 for use in the treatment and/or prevention of a disease selected from: head, neck, eye, mouth, throat, esophagus, bronchus, larynx, pharynx, chest, bone, lung, colon, rectum, stomach, prostate, bladder, uterus, cervix, breast, ovary, testis or other reproductive organs, skin, thyroid, blood, lymph node, kidney, liver, pancreas, brain, central nervous system, solid tumors, and hematological tumors.

5. A medicament comprising at least one compound according to claim 1 and/or a pharmaceutically acceptable salt thereof, including mixtures thereof in all ratios, and at least one further pharmaceutically active ingredient.

6. A kit consisting of the following separate packages:

(a) an effective amount of a compound of claim 1 and/or a pharmaceutically acceptable salt thereof, including mixtures thereof in all ratios,

and

(b) an effective amount of other pharmaceutically active ingredients.