HK1092463B - Substituted dihydrochinazolines having antiviral properties - Google Patents

Description

Substituted dihydroquinazolines having antiviral properties

The invention relates to substituted dihydroquinazolines, to methods for the production thereof, and to the use thereof for producing medicaments for the treatment and/or prophylaxis of diseases, in particular as antiviral agents, in particular against cytomegaloviruses.

The synthesis of dihydroquinazolines is described in Saito T. et al, Tetrahedron Lett., 1996, 37, 209-865 and in Wang F. et al, Tetrahedron Lett., 1997, 38, 8651-8654.

Although agents with antiviral activity and different structures are available on the market, development has always been made for drug resistance. There is therefore a need for new agents for effective treatment.

It is therefore an object of the present invention to provide novel compounds having the same or improved antiviral action for the treatment of viral infectious diseases in humans and animals.

It has surprisingly been found that the substituted dihydroquinazolines described in the present invention have an antiviral effect.

The present invention provides compounds of the formula:

wherein:

ar represents an aryl group which may be substituted by 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of alkyl, alkoxy, formyl, carboxy, alkylcarbonyl, alkoxycarbonyl, trifluoromethyl, halogen, cyano, hydroxy, amino, alkylamino, aminocarbonyl and nitro,

wherein the alkyl group may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, amino, alkylamino, hydroxy and aryl,

or two substituents on the aryl group together with the carbon atom to which they are attached form a 1, 3-dioxolane, cyclopentane or cyclohexane ring, and any third substituent which may be present is independently selected from the mentioned groups,

R¹represents hydrogen, amino, alkyl, alkoxy, alkylamino, alkylthio, cyano, halogen, nitro or trifluoromethyl,

R²represents hydrogen, alkyl, alkoxy, alkylthio, cyano, halogen, nitro or trifluoromethyl,

R³represents amino, alkyl, alkoxy, alkylamino, alkylthio, cyano, halogen, nitro, trifluoromethyl, alkylsulfonyl or alkylaminosulfonyl,

or

Radical R¹、R²And R³One of which represents hydrogen, alkyl, alkoxy, cyano, halogen, nitro or trifluoromethyl and the other two, together with the carbon atom to which they are attached, form a 1, 3-dioxolane, cyclopentane ring or cyclohexane ring,

R⁴represents hydrogen or an alkyl group, or a salt thereof,

R⁵represents hydrogen or alkyl

Or

Group R in the piperazine ring⁴And R⁵Are linked to directly opposite carbon atoms and form a methylene bridge optionally substituted by 1 or 2 methyl groups,

R⁶represents alkyl, alkoxy, alkylthio, or methylAcyl, carboxyl, aminocarbonyl, alkylcarbonyl, alkoxycarbonyl, trifluoromethyl, halogen, cyano, hydroxyl or nitro,

R⁷represents hydrogen, alkyl, alkoxy, alkylthio, formyl, carboxyl, alkylcarbonyl, alkoxycarbonyl, trifluoromethyl, halogen, cyano, hydroxyl or nitro,

and

R⁸represents hydrogen, alkyl, alkoxy, alkylthio, formyl, carboxy, alkylcarbonyl, alkoxycarbonyl, trifluoromethyl, halogen, cyano, hydroxy or nitro.

The compounds according to the invention are compounds of formula (I) and salts, solvates and solvates of said salts, the compounds mentioned below as embodiments and the salts, solvates and solvates of said salts, as long as the compounds comprised by structural formula (I) are not already salts, solvates and solvates of said salts.

The compounds according to the invention may, depending on their structure, exist in stereoisomeric forms (enantiomers, diastereomers). The present invention thus relates to enantiomers or diastereomers and corresponding mixtures thereof. The stereomerically pure components can be separated from these mixtures of enantiomers and/or diastereomers in a known manner.

If the compounds according to the invention can exist in tautomeric forms, the invention encompasses all such tautomeric forms.

Preferred salts for the purposes of the present invention are physiologically acceptable salts of the compounds of the invention. The invention also includes salts which are not suitable per se for pharmaceutical applications but which can be used, for example, for the isolation or purification of the compounds according to the invention.

Physiologically acceptable salts of the compounds according to the invention include acid addition salts of inorganic acids, carboxylic and sulfonic acids, for example salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.

Physiologically acceptable salts of the compounds according to the invention also include salts of customary bases, such as, for example and with preference, alkali metal salts (for example sodium and potassium salts), alkaline earth metal salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having from 1 to 16 carbon atoms, such as, for example and with preference, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.

Solvates refer, for the purposes of the present invention, to those forms of the compounds according to the invention which form complexes by coordination with solvent molecules in the solid or liquid state. Hydrates are a special form of solvates, where the complexation is performed using water.

For the purposes of the present invention, unless otherwise indicated, the substituents have the following meanings:

alkyl itself and alkoxy, alkylamino, alkylcarbonyl, alkylsulfonyl, alkylamino "alkyl" and "alkyl" of alkylsulfonyl and alkoxycarbonyl groupsAre straight-chain or branched alkyl radicals having generally from 1 to 6, preferably from 1 to 4, particularly preferably from 1 to 3, carbon atoms, such as, for example and preferably, methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl.

Alkoxy radicalAre for example and preferably methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.

Alkylamino radicalIs an alkylamino radical having one or two alkyl substituents, selected independently of one another, such as, and preferably, methylamino, ethylamino, N-propylamino, isopropylamino, tert-butylamino, N-pentylamino, N-hexylamino, N, N-dimethylamino, N, N-di-alkylaminoEthylamino, N-ethyl-N-methylamino, N-methyl-N-propylamino, N-isopropyl-N-propylamino, N-tert-butyl-N-methylamino, N-ethyl-N-pentylamino and N-hexyl-N-methylamino. C₁-C₃Alkylamino is, for example, a monoalkylamino group having from 1 to 3 carbon atoms or a dialkylamino group having from 1 to 3 carbon atoms per alkyl substituent in each case.

Alkyl sulfonyl radicalAre for example and preferably methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, tert-butylsulfonyl, n-pentylsulfonyl and n-hexylsulfonyl.

Alkylamino sulfonyl radicalIs an alkylaminosulfonyl group having one or two alkyl substituents, selected independently of each other, such as, and preferably, methylaminosulfonyl, ethylaminosulfonyl, N-propylaminosulfonyl, isopropylaminosulfonyl, tert-butylaminosulfonyl, N-pentylaminosulfonyl, N-hexylaminosulfonyl, N-dimethylaminosulfonyl, N-diethylaminosulfonyl, N-ethyl-N-methylaminosulfonyl, N-methyl-N-propylaminosulfonyl, N-isopropyl-N-propylaminosulfonyl, N-tert-butyl-N-methylaminosulfonyl, N-ethyl-N-pentylaminosulfonyl and N-hexyl-N-methylaminosulfonyl. C₁-C₃Alkylaminosulfonyl is, for example, a monoalkylaminosulfonyl radical having from 1 to 3 carbon atoms or a dialkylaminosulfonyl radical having from 1 to 3 carbon atoms per alkyl substituent in each case.

Alkyl carbonylAre for example and preferably acetyl and propionyl.

Alkoxycarbonyl radicalAre for example and preferably methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl and n-hexoxycarbonyl.

Aryl radicalsIs a mono-to tricyclic aromatic carbocyclic group having typically 6 to 14 carbon atoms; example (b)Such as and preferably phenyl, naphthyl and phenanthryl.

Halogen elementAre fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.

The symbol on a carbon atom means that the compound exists in enantiomerically pure form with respect to the configuration on that carbon atom, which is understood in the present invention to mean an enantiomeric excess of more than 90% (> 90% ee).

Preferred compounds of formula (I):

ar represents phenyl which may be substituted by 1 to 3 substituents, wherein the substituents are independently from each other selected from C₁-C₆-alkyl radical, C₁-C₆Alkoxy, carboxyl, C₁-C₆-alkylcarbonyl group, C₁-C₆Alkoxycarbonyl, trifluoromethyl, fluoro, chloro, bromo, cyano, hydroxy, amino, C₁-C₆-an alkylamino group and a nitro group,

or two substituents on the phenyl group together with the carbon atom to which they are attached form a 1, 3-dioxolane ring, and the possible third substituents are independently selected from said groups,

R¹represents hydrogen, C₁-C₃-alkyl radical, C₁-C₃-alkoxy radical, C₁-C₃Alkylthio, fluorine or chlorine,

R²represents hydrogen, C₁-C₃-alkyl radical, C₁-C₃-alkoxy radical, C₁-C₃Alkylthio, fluorine or chlorine,

R³is represented by C₁-C₄Alkyl, cyano, fluoro, chloro, nitro, trifluoromethyl or C₁-C₃-an alkylsulfonyl group,

or

Radical R¹、R²And R³One represents hydrogen, C₁-C₃-alkyl radical, C₁-C₃Alkoxy radical, cyanoHalogen, nitro or trifluoromethyl, and the other two together with the carbon atom to which they are attached form a cyclopentane or cyclohexane ring,

R⁴represents hydrogen or a methyl group,

R⁵represents hydrogen, and is represented by the formula,

R⁶is represented by C₁-C₃-alkyl radical, C₁-C₃Alkoxy, carboxyl, aminocarbonyl, trifluoromethyl, fluorine, chlorine, cyano, hydroxyl or nitro,

R⁷represents hydrogen, C₁-C₃-alkyl radical, C₁-C₃Alkoxy, fluoro, chloro, cyano or hydroxy,

and

R⁸represents hydrogen, C₁-C₃-alkyl radical, C₁-C₃Alkoxy, fluoro, chloro, cyano or hydroxy.

Among the particularly preferred compounds of formula (I):

ar represents phenyl which may be substituted by 1 or 2 substituents, wherein the substituents are independently from each other selected from methyl, methoxy, fluoro and chloro,

R¹represents hydrogen, methyl, methoxy, methylthio, fluoro or chloro,

R²represents hydrogen, and is represented by the formula,

R³represents methyl, isopropyl, tert-butyl, cyano, fluoro, chloro, nitro or trifluoromethyl,

R⁴represents hydrogen, and is represented by the formula,

R⁵represents hydrogen, and is represented by the formula,

R⁶represents aminocarbonyl, fluorine, chlorine, cyano or hydroxy,

R⁷represents hydrogen, and is represented by the formula,

and

R⁸represents hydrogen, fluorine or chlorine.

Among the compounds of the formula (I) which are likewise particularly preferred:

ar represents phenyl which may be substituted by 1 or 2 substituents, wherein the substituents are independently from each other selected from methyl, methoxy, fluoro and chloro,

R¹represents hydrogen, methyl, methoxy, methylthio, fluoro or chloro,

R²represents hydrogen, and is represented by the formula,

R³represents methyl, tert-butyl, cyano, fluorine, chlorine, nitro or trifluoromethyl,

R⁴represents hydrogen, and is represented by the formula,

R⁵represents hydrogen, and is represented by the formula,

R⁶represents aminocarbonyl, fluorine, chlorine, cyano or hydroxy,

R⁷represents hydrogen, and is represented by the formula,

and

R⁸represents hydrogen, fluorine or chlorine.

Among the particularly preferred compounds of formula (I):

ar represents phenyl which may be substituted by 1 or 2 substituents, wherein the substituents are independently from each other selected from methyl, methoxy, fluoro and chloro,

R¹represents hydrogen or a methoxy group, and a salt thereof,

R²represents hydrogen, and is represented by the formula,

R³represents methyl, tert-butyl, chlorine or trifluoromethyl,

R⁴represents hydrogen, and is represented by the formula,

R⁵represents hydrogen, and is represented by the formula,

R⁶represents aminocarbonylA group or a fluorine group,

R⁷represents hydrogen, and is represented by the formula,

and

R⁸represents hydrogen or fluorine.

Also preferred is where R¹A compound of formula (I) representing hydrogen, methyl, methoxy or fluoro.

Of these, particularly preferred is the compound wherein R¹A compound of formula (I) representing a methoxy group.

Preference is also given to compounds of the formula (I) in which R is¹Attached to the phenyl ring at a position adjacent to the point of attachment of the phenyl ring. For the purposes of the present invention, a radical R¹、R²And R³The point of attachment of the substituted phenyl ring is understood to mean the carbon atom of the phenyl ring which is attached to one of the two nitrogen atoms of the dihydroquinazoline according to formula (I).

Particularly preferred compounds of the formula (I) are those in which R¹Represents methoxy and R¹Attached to the phenyl ring at a position adjacent to the point of attachment of the phenyl ring.

Also preferred are compounds of formula (I) wherein R²Represents hydrogen.

Wherein R is preferably wherein³Those compounds of formula (I) which represent trifluoromethyl, chloro, methyl, isopropyl or tert-butyl.

Wherein R is particularly preferably wherein³Those compounds of formula (I) which represent trifluoromethyl, chlorine or methyl.

Wherein R is particularly preferably wherein³Those compounds of formula (I) which represent trifluoromethyl.

Also preferred are those wherein R¹Attached to the phenyl ring via a position adjacent to the point of attachment of the phenyl ring and R³Through reaction with R¹A compound of formula (I) attached to the phenyl ring meta to the point of attachment of the opposite phenyl ring.

Particularly preferred are thoseWherein R is¹Attached to the phenyl ring via a position adjacent to the point of attachment of the phenyl ring, R³Represents trifluoromethyl, chlorine or methyl and R³Through reaction with R¹A compound of formula (I) attached to the phenyl ring meta to the point of attachment of the opposite phenyl ring.

Of these, particularly preferred is the compound wherein R¹Attached to the phenyl ring via a position adjacent to the point of attachment of the phenyl ring, R³Represents trifluoromethyl and R³Through reaction with R¹A compound of formula (I) attached to the phenyl ring meta to the point of attachment of the opposite phenyl ring.

Also preferred are those wherein R⁴And R⁵A compound of formula (I) representing hydrogen.

Also preferred are those wherein R⁶A compound of formula (I) representing fluorine.

Particularly preferred are those in which R⁶Represents fluorine and R⁶A compound of formula (I) attached to an aromatic group of a dihydroquinazoline as described by the following structural formula:

also preferred are those wherein R⁷A compound of formula (I) representing hydrogen.

Of these, those in which R is particularly preferred⁸A compound of formula (I) representing hydrogen, methyl or fluorine.

Of these, those in which R is particularly preferred⁸A compound of formula (I) representing hydrogen.

Also preferred are those compounds of formula (I) wherein Ar represents phenyl which may be substituted by 1 or 2 substituents independently selected from methyl, methoxy, fluoro and chloro.

The radical definitions given individually in the respective combinations or preferred combinations of radicals are also optionally replaced by radical definitions of other combinations, independently of the radical combination given in each case.

Combinations of two or more of the preferred ranges mentioned above are particularly preferred.

The present invention further provides a process for the preparation of a compound of formula (I) comprising reacting a compound of the formula:

wherein

Ar，R¹，R²，R³，R⁴，R⁵，R⁶，R⁷And R⁸The definition is as above-mentioned,

and

R⁹represents an alkyl group, preferably a methyl or ethyl or tert-butyl group.

In the case of methyl and ethyl, the reaction is generally carried out using a base in an inert solvent, preferably at a temperature ranging from room temperature to the reflux temperature of the solvent at atmospheric pressure.

The base is, for example, an alkali metal hydroxide, such as sodium hydroxide, lithium hydroxide or potassium hydroxide, or an alkali metal carbonate, such as cesium carbonate, sodium carbonate or potassium carbonate, if appropriate in aqueous solution; sodium hydroxide in water is preferred.

Inert solvents are, for example, ethers such as 1, 2-dimethoxyethane, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, or mixtures of solvents; preferred is dioxane or tetrahydrofuran.

In the case of t-butyl, the reaction is generally carried out using an acid in an inert solvent, preferably at a temperature in the range of 0 to 40 degrees celsius, at atmospheric pressure.

Suitable acids here are hydrogen chloride in dioxane, hydrogen bromide in acetic acid or trifluoroacetic acid in dichloromethane.

Compounds of formula (II) are known or may be prepared by reacting a compound of the formula:

wherein

R⁶，R⁷，R⁸And R⁹The definition is as above-mentioned,

first with a compound of the formula:

wherein

R¹，R²And R³The definition is as above-mentioned,

and subsequently reacting with a compound of the formula:

wherein

Ar，R⁴And R⁵As defined above.

The reaction is generally carried out in two steps in an inert solvent, preferably at a temperature in the range of room temperature to 100 degrees celsius, at atmospheric pressure. In a second step, silica gel is added, if appropriate, to the reaction mixture. The reaction is preferably worked up between the first and second steps.

Inert solvents are, for example, halogenated hydrocarbons, such as dichloromethane, trichloromethane, carbon tetrachloride, trichloroethane, tetrachloroethane, 1, 2-dichloroethane or trichloroethylene, ethers, such as diethyl ether, methyl tert-butyl ether, 1, 2-dimethoxyethane, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane or mineral oil fractions, or other solvents, such as dimethylformamide, dimethylacetamide, acetonitrile or ethyl acetate, or mixtures of solvents; preferred is dichloromethane.

The compounds of the formula (IV) are known or can be synthesized by known methods from the corresponding starting materials.

The compounds of the formula (V) are known or can be synthesized by known methods from the corresponding starting materials, for example by the Buchwald-Hartwig reaction according to the following synthesis scheme (reviewed in: C.G.Frost, P.Mendonca, J.chem.Soc., Perkin Trans I, 1998, 2615-2623):

buchwald-hartwig reaction:

the starting materials required for this are known or can be synthesized by known methods from the corresponding starting materials.

Compounds of formula (M) are known or may be prepared by reacting a compound of formula:

wherein

R⁶，R⁷，R⁸And R⁹The definition is as above-mentioned,

with triphenylphosphine and carbon tetrachloride.

The reaction is generally carried out in an inert solvent in the presence of a base, preferably at a temperature in the range of room temperature to 50 degrees celsius, at atmospheric pressure.

Suitable inert solvents are, for example, ethers, such as diethyl ether, methyl tert-butyl ether, 1, 2-dimethoxyethane, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane or mineral oil fractions, or other solvents, such as dimethylformamide, dimethylacetamide, acetonitrile or pyridine; acetonitrile is preferred.

Suitable bases are, for example, alkali metal and alkaline earth metal carbonates, such as cesium carbonate, sodium carbonate or potassium carbonate, or amines, such as triethylamine, diisopropylethylamine, N-methylmorpholine or pyridine; triethylamine is preferred.

The compounds of the formula (VI) are known or can be synthesized by known methods from the corresponding starting materials, for example by the Heck reaction or the Wittig-Homer reaction, according to the following synthesis scheme:

heck reaction:

Wittig-Horner reaction:

the starting materials required for this are known or can be synthesized by known methods from the corresponding starting materials.

The preparation of the compounds according to the invention can be illustrated by the following synthetic schemes.

The synthesis scheme is as follows:

the compounds of the general formula (I) according to the invention have a range of surprising effects which cannot be predicted. They have an antiviral action on the representative herpes viruses (herpesviruses), in particular on Cytomegalovirus (CMV), in particular on Human Cytomegalovirus (HCMV).

Areas of indications that may be mentioned are, for example:

1) treating and preventing HCMV infection (retinitis, pneumonia, gastrointestinal infection) in AIDS patients.

2) Treatment and prevention of cytomegalovirus infections in bone marrow and organ transplant patients with commonly life-threatening HCMV pneumonia or encephalitis, as well as gastrointestinal and systemic HCMV infections.

3) Treatment and prevention of HCMV infection in newborns and infants.

4) Treating acute HCMV infection in pregnant women.

5) Treatment of HCMV infection in immunosuppressed patients associated with cancer and cancer therapy.

6) HCMV positive cancer patients whose purpose is to reduce HCMV-mediated tumor development (see j. cinatl et al, FEMS Microbiology Reviews, 2004, 28, 59-77).

The invention further provides the use of the compounds according to the invention for the treatment and/or prophylaxis of diseases, in particular of viruses, in particular of infections caused by the abovementioned viruses, and of infectious diseases caused by these infections. Hereinafter, viral infections are understood to include viral infections and diseases caused by viral infections.

The invention also provides the use of a compound according to the invention for the treatment and/or prophylaxis of disorders, in particular of the disorders mentioned above.

The invention also provides the use of a compound according to the invention for the preparation of a medicament for the treatment and/or prophylaxis of disorders, in particular of the disorders mentioned above.

The compounds according to the invention are preferably used for the production of medicaments suitable for the prophylaxis and/or treatment of infections with the representative herpes viruses, in particular cytomegaloviruses, in particular human cytomegaloviruses.

The invention also provides a method for the treatment and/or prophylaxis of disorders, in particular of the disorders mentioned above, using an antiviral effective amount of a compound according to the invention.

The invention also provides a medicament comprising at least one compound according to the invention and at least one or more further active compounds, in particular for the treatment and/or prophylaxis of the abovementioned conditions. Suitable combined active compounds are, for example and preferably, antiviral active compounds such as ganciclovir or acyclovir.

The compounds according to the invention may act systemically and/or locally. For this purpose, they can be administered in a suitable manner, e.g., by oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival or otic route, or as an implant or stent.

For these routes of administration, the compounds according to the invention can be administered in a suitable administration form.

Suitable for oral administration are administration forms which act according to the prior art, rapidly and/or with modified delivery of the compounds according to the invention, comprising the compounds according to the invention in crystalline and/or amorphous and/or dissolved form, such as tablets (uncoated or coated tablets, for example tablets with coatings which control the release of the compounds according to the invention, are resistant to gastric juice or dissolve slowly or are insoluble), tablets which disintegrate rapidly in the oral cavity and/or films/wafers, films/lyophilisates, capsules (for example hard or soft gelatin capsules), sugar-coated tablets, pills, granules, powders, emulsions, suspensions, aerosols or solutions.

Parenteral administration may be carried out avoiding adsorption steps (e.g. intravenous, intraarterial, cardiac, intraspinal or intralumbar) or in situations involving adsorption (e.g. intramuscular, subcutaneous, intradermal, transdermal or intraperitoneal). Administration forms suitable for parenteral administration are, in particular, injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilizates or sterile powders.

Examples of other administration routes suitable for use are e.g. pharmaceutical forms for inhalation (especially powder inhalers, nebulizers), nasal drops/solutions/sprays; tablets for lingual, sublingual or buccal administration, films/wafers or capsules, suppositories, preparations for the eye or ear, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems, milks, pastes, foams, dusting powders, implants or stents.

The compounds according to the invention can be converted into the administration forms described. This can be done in a known manner by mixing inert, non-toxic, pharmaceutically acceptable auxiliaries. These include, inter alia, carriers (e.g. microcrystalline cellulose, lactose, mannitol), solvents (e.g. liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (e.g. sodium lauryl sulfate, polyoxysorbitan oleate), binders (e.g. polyvinylpyrrolidone), synthetic and natural polymers (e.g. albumin), stabilizers (e.g. antioxidants, such as ascorbic acid), colorants (e.g. inorganic pigments, such as iron oxide) and aroma and/or odor masking agents.

The invention further provides medicaments comprising at least one compound according to the invention, usually in combination with one or more inert, non-toxic, pharmaceutically acceptable auxiliaries and their use for the stated purposes.

In general, it has proven advantageous to administer the drug in an intravenous dose of about 0.001 to 10mg/kg, preferably about 0.01 to 5mg/kg of body weight to achieve effective results, while the dose administered orally is about 0.01 to 25mg/kg, preferably 0.1 to 10mg/kg of body weight.

But may deviate from the amounts as required, i.e. depending on body weight, route of administration, individual response to the active compound, mode of formulation and time or interval at which administration takes place. Therefore, it may be sufficient in some cases to lower than the aforementioned minimum amount, while in other cases the upper limit must be exceeded. In the case of larger amounts to be administered, it may be advisable to divide these amounts into a plurality of individual doses per day.

Unless otherwise indicated, the percentage data in the following tests and examples are in weight percent; the parts are weight parts. The solvent ratio, dilution ratio and concentration data of the liquid/liquid solution are in each case based on volume.

A. Examples of the embodiments

Abbreviations:

ca. about

BINAP 2, 2 '-bis (diphenylphosphino) -1, 1' -binaphthyl

CDCl₃Deuterated chloroform

DC thin layer chromatography

DCI direct chemical ionization (in MS)

DCM dichloromethane

DIEA N, N-diisopropylethylamine

DMSO dimethyl sulfoxide

DMF N, N-dimethylformamide

Th theoretical value

EE acetic acid ethyl ester

EI Electron impact ionization (in MS)

ESI electrospray ionization (in MS)

Fp. melting Point

ges. saturation

h hours

HPLC high pressure, high performance liquid chromatography

Concentration of konz

LC-MS liquid chromatography-coupled mass spectrometry

LDA lithium diisopropylamide

min for

MS Mass Spectrometry

MTBE methyl tert-butyl ether

NMR nuclear magnetic resonance spectroscopy

Pd-C Palladium on carbon

pro z

RP-HPLC reversed phase HPLC

RT Room temperature

R_tResidence time (in HPLC)

THF tetrahydrofuran

General LC-MS and HPLC methods:

method 1 (analytical HPLC): column: kromasil C1860 mm × 2 mm; temperature: 30 ℃; flow rate: 0.75 ml/min; mobile phase A: 0.005M HClO₄And a mobile phase B: acetonitrile; gradient: → 0.5min 98% A, → 4.5min 10% A, → 6.5min 10% A.

Method 2 (preparative HPLC): column: GromSil C18, 250 mm. times.30 mm; flow rate: 50 ml/min; operating time: 38 min; and (3) detection: 210 nm; mobile phase A: water, mobile phase B: acetonitrile; gradient: 10% B (3min) → 90% B (31min) → 90% B (34min) → 10% B (34.01 min).

Method 3 (LC-MS): column: GromSil 120 ODS-4 HE, 50 mm. times.2.0 mm, 3 μm; mobile phase A: 1l of water +1ml of 50% strength formic acid, mobile phase B: 1l acetonitrile +1ml 50% strength formic acid; gradient: 0.0min 100% A → 0.2min 100% A → 2.9min 30% A → 3.1min 10% A → 4.5min 10% A; furnace: 55 ℃ is carried out; flow rate: 0.8 ml/min; and (4) UV detection: 208-400 nm.

Method 4 (preparative HPLC, separation of enantiomers, carboxylic acid): column: the filler chiral silica gel selector, KBD8361(420mm x 100mm), is based on the selector poly (N-methacryloyl-L-leucine-1-menthylamide); temperature: 23 ℃; mobile phase: methyl tert-butyl ether; flow rate: 100 ml/min; the compound was dissolved in methyl tert-butyl ether/acetate (9: 1).

Method 5 (preparative HPLC): column: GromSil C18, 250 mm. times.30 mm; flow rate: 50 ml/min; operating time: 38 min; and (3) detection: 210 nm; mobile phase A: water with 0.1% formic acid, mobile phase B: acetonitrile; gradient: 10% B (3min) → 90% B (31min) → 90% B (34min) → 10% B (34.01 min).

Method 6 (analytical HPLC): the instrument comprises the following steps: HP 1100 detected using DAD; column: kromasil RP-18, 60 mm. times.2 mm, 3.5 μm; mobile phase A: 5ml HClO₄Water/l, mobile phase B: acetonitrile; gradient: 0min 2% B, 0.5min 2% B, 4.5min 90% B, 9min 90% B; flow rate: 0.75 ml/min; temperature: 30 ℃; and (3) detection: UV 210 nm.

Method 7 (LC-MC): the instrument comprises the following steps: MicromassPlatform LCZ from HPLC Agilent 1100 series was used; column: from-SIL 120 ODS-4 HE, 50 mm. times.2.0 mm, 3/μm; mobile phase A: 1l of water +1ml of 50% strength formic acid, mobile phase B: 1l acetonitrile +1ml 50% strength formic acid; gradient: 0.0min 100% A → 0.2min 100% A → 2.9min 30% A → 3.1min 10% A → 4.5min 10% A; furnace: 55 ℃ is carried out; flow rate: 0.8 ml/min; and (4) UV detection: 210 nm.

Method 8 (LC-MC): the instrument comprises the following steps: micromass Platform LCZ, HP 1100; column: symmetry C18, 50mm × 2.1mm, 3.5 μm; mobile phase A: acetonitrile + 0.1% formic acid, mobile phase B: water + 0.1% formic acid; gradient: 0.0min 10% A → 4.0min 90% A → 6.0min 90% A; furnace: 40 ℃; flow rate: 0.5 ml/min; and (4) UV detection: 208-400 nm.

Method 9 (LC-MC): MS instrument: micromass ZQ; HPLC apparatus: WatersAlliance 2795; column: merck Chromolith Speed ROD RP-18e 50 mm. times.4.6 mm; mobile phase A: water + 500. mu.l of 50% strength formic acid/l, mobile phase B: acetonitrile + 500. mu.l of 50% strength formic acid/l; gradient: 0.0min 10% B → 3.0min 95% B → 4.0min 95% B; furnace: 35 ℃ is carried out; flow rate: 0.0min 1.0ml/min → 3.0min 3.0ml/min → 4.0min 3.0 ml/min; and (4) UV detection: 210 nm.

Method 10 (LC-MC): MS instrument: mieromass ZQ; HPLC apparatus: HP 1100 series; UV DAD; column: from-Sil 120 ODS-4 HE 50mm × 2mm, 3.0 μm; mobile phase A: water + 500. mu.l of 50% strength formic acid/l, mobile phase B: acetonitrile + 500. mu.l 50% strength formic acid/l; gradient: 0.0min 0% B → 2.9min 70% B → 3.1min 90% B → 4.5min 90% B; furnace: 50 ℃; flow rate: 0.8 ml/min; and (4) UV detection: 210 nm.

Method 11 (preparative HPLC, separation of enantiomers): column: the filler chiral silica gel selector KBD8361 (250mm × 20mm) is based on the selector poly (N-methacryloyl-L-leucine-1-menthylamide); temperature: 23 ℃; mobile phase: methyl tert-butyl ether + 5% ethyl acetate; flow rate: 25 ml/min.

Method 12 (preparative HPLC, separation of enantiomers): column: the filler chiral silica gel selector KBD 5326(250mm × 20mm) is based on the selector poly (N-methacryloyl-L-leucine-dicyclopropylmethylamide); temperature: 23 ℃; mobile phase: methyl tert-butyl ether + 5% ethyl acetate; flow rate: 25 ml/min.

Method 13 (preparative HPLC, separation of enantiomers): column: the filler chiral silica gel selector KBD8361 (250mm × 20mm) is based on the selector poly (N-methacryloyl-L-leucine-1-menthylamide); temperature: 23 ℃; mobile phase: methyl tert-butyl ether; flow rate: 25 ml/min.

Method 14 (preparative HPLC, separation of enantiomers, ester): column: the filler chiral silica gel selector, KBD8361(420mm x 100mm), is based on the selector poly (N-methacryloyl-L-leucine-1-menthylamide); temperature: 23 ℃; mobile phase: isohexane/ethyl acetate 85/15 v/v; flow rate: 100 ml/min; the compound was dissolved in isohexane/ethyl acetate (85: 15).

Method 15 (preparative HPLC, separation of enantiomers, ester): column: filler chiral silica gel selector KBD8361(420mm x 100mm) based on selector poly (N-methacryloyl-L-leucine-1-menthylamide); temperature: 23 ℃; mobile phase: methyl tert-butyl ether; flow rate: 100 ml/min; the compound was dissolved in methyl tert-butyl ether.

Method 16 (LC-MS): the instrument comprises the following steps: MicromassPlatform LCZ from HPLC Agilent 1100 series was used; column: from-SIL 120 ODS-4 HE, 50 mm. times.2.0 mm, 3 μm; mobile phase A: 1l of water +1ml of 50% strength formic acid, mobile phase B: 1l acetonitrile +1ml 50% strength formic acid; gradient: 0.0min 100% A → 0.2min 100% A → 2.9min 30% A → 3.1min 10% A → 4.5min 10% A; furnace: 55 ℃ is carried out; flow rate: 0.8 m/min; and (4) UV detection: 208-400 nm.

Method 17 (LC-MS): MS instrument type: micromass ZQ; HPLC instrument type: waters Alliance 2790; column: from-Sil 120 ODS-4 HE 50mm × 2mm, 3.0 μm; mobile phase A: water + 500. mu.l of 50% strength formic acid/l, mobile phase B: acetonitrile + 500. mu.l 50% strength formic acid/l; gradient: 0.0min 0% B → 0.2min 0% B → 2.9min 70% B → 3.1min 90% B → 4.5min 90% B; furnace: 45 degrees centigrade; flow rate: 0.8 ml/min; and (4) UV detection: 210 nm.

Starting materials

General procedure [ A]: synthesis of substituted 2-substituted anilines by Heck coupling of 2-halogen substituted anilines Aminocinnamic acid derivatives

In a one-neck flask, 1.0 equivalent of aryl halide was charged with 1.6 equivalents of methyl acrylate or t-butyl acrylate, 2.0 equivalents of triethylamine, 0.03 equivalents of palladium (II) acetate and 0.03 equivalents of tri-o-tolylphosphine in acetonitrile (ca. 1M solution). The mixture was stirred at reflux for 48 hours. After the reaction has ended (the reaction is detected by DC), the solvent is removed. The residue was purified by chromatography on silica gel using cyclohexane/ethyl acetate 8: 2 v/v.

Example 1A

(2E) -3- [ 2-amino-3-fluorophenyl ] acrylic acid methyl ester

Starting from 42.00g (221.04mmol) of 2-bromo-6-fluoroaniline, the general procedure [ A ] gave 29.66g (68% of theory) of product.

HPLC (method 1): r_t＝4.14min

MS(ESI-pos)：m/z＝196(M+H)⁺

Example 2A

2-amino-3- [ (1E) -3-methoxy-3-oxo-1-propenyl ] benzoic acid methyl ester

Starting from 2.00g (8.69mmol) of methyl 2-amino-3-bromobenzoate, general procedure [ A ] gave 1.29g (60% of theory) of product.

HPLC (method 1): r_t＝4.42min

MS(ESI-pos)：m/z＝236(M+H)⁺

Example 3A

(2E) -3- (2-amino-3, 5-difluorophenyl) -2-propenoic acid methyl ester

Starting from 3.00g (14.42mmol) of 2-bromo-4, 6-difluoroaniline, 1.41g (45% of theory) of product are obtained by general procedure [ A ].

HPLC (method 1): r_t＝4.23min

MS(ESI-pos)：m/z＝214(M+H)⁺

Example 4A

4-amino-3- [ (1E) -3-methoxy-3-oxo-1-propenyl ] benzoic acid methyl ester

Starting from 25.00g (90.23mmol) of methyl 4-amino-3-iodobenzoate, the general procedure [ A ] gives 24.31g (92% of theory) of product.

HPLC (method 1): r_t＝4.71min

MS(ESI-pos)：m/z＝278(M+H)⁺

Example 5A

(2E) -3- [ 2-amino-5-cyanophenyl ] -2-propenoic acid methyl ester

Starting from 1.90g (9.64mmol) of 3-bromo-4-aminobenzonitrile, general procedure [ A ] gave 1.28g (50% of theory) of product.

HPLC (method 1): r_t＝2.85min

MS(DCI-pos)：m/z＝220(M+NH₄)⁺

General procedure [ B]: by means of a Wittig-Horner reaction of 2-halogen-substituted benzaldehydes Substituted 2-nitro cinnamic acid derivatives

In a 100ml one-necked flask, 27.5mmol of methyldiethylphosphonoacetate, 25.0mmol of benzaldehyde and 27.5mmol of lithium hydroxide were suspended in tetrahydrofuran. After the reaction had ended (the reaction was detected by DC), the reaction mixture was mixed with the same volume of water. The aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution and dried over sodium sulfate, and the solvent was removed. The product was dried under high vacuum at RT without further purification. If the product is very impure, it is purified as required by column chromatography on silica gel using cyclohexane/ethyl acetate.

Example 6A

(2E) -3- (3-methoxy-2-nitrophenyl) -2-propenoic acid methyl ester

Starting from 2.00g (11.04mmol) of 3-methoxy-2-nitrobenzaldehyde, according to general procedure [ B ] 2.46g (92% of theory) of product are obtained.

HPLC (method 1): r_t＝4.37min

MS(ESI-pos)：m/z＝238(M+H)⁺

Example 7A

(2E) -3- (5-fluoro-2-nitrophenyl) -2-propenoic acid methyl ester

Starting from 20.0g (118.3mmol) of 5-fluoro-2-nitrobenzaldehyde, according to general procedure [ B ] 7.25g (27% of theory) of product are obtained.

MS(DCI)：m/z＝243(M+NH₄)⁺

General procedure [ C]: preparation of 2-nitrobenzaldehyde from benzyl halide

10.0mmol of benzyl halide are suspended with 4.1g of molecular sieve 4. ANG. and 20.0mmol of N-methylmorpholine-N-oxide in 45ml of acetonitrile. The mixture was stirred at RT until reaction (reaction detected by DC). After the reaction had ended, the molecular sieves were filtered off, the solvent was removed and the residue was taken up again in ethyl acetate. The solution was washed initially with 1N hydrochloric acid and subsequently with saturated sodium chloride solution. The organic phase is separated off and subsequently dried over sodium sulfate, and the solvent is removed again. Analysis showed that the crude product was sufficiently pure and was directly available for further reaction.

Example 8A

2-fluoro-6-nitrobenzaldehyde

Starting from 2.00g (8.55mmol) of 3-fluoro-6-nitrobenzyl bromide, general procedure [ C ] gives 1.09g (75% of theory) of product.

HPLC (method 1): r_t＝3.58min

General procedure [ D]: reduction of nitro group of 2-nitrocinnamic acid derivative

25mmol of nitro compound and 125mmol of tin (II) chloride dihydrate are initially charged in 60ml of absolute ethanol under argon in a 250ml two-necked flask. The suspension was stirred at reflux for 30 minutes to form a clear solution. The solution was then cooled to room temperature and then poured onto ice water. The pH was adjusted to pH 7-8 using solid sodium bicarbonate or saturated sodium carbonate solution. 60ml of ethyl acetate were then added and the precipitated tin salt was filtered off through celite (layer thickness approx.1 cm). The organic phase was separated off and the aqueous phase was extracted again with ethyl acetate. The organic phases are combined, washed once with saturated sodium chloride solution and dried over sodium sulfate, and the solvent is concentrated to about half. Activated carbon corresponding to 1% by weight of nitro compound was then added and the mixture was heated at reflux for 30 minutes (color change of solution). The activated carbon was filtered off and the solvent was concentrated.

The residue obtained is an oil and is dried under high vacuum at RT to form crystals. The product was used directly in the next step without further purification.

Example 9A

3- [ 2-amino-6-fluorophenyl ] acrylic acid methyl ester

Starting from 7.25g (32.2mmol) of the nitro compound from example 7A, 5.0g (58% of theory) of the product are obtained by general procedure [ D ].

HPLC (method 1): r_t＝3.33min

General procedure [ E]: synthesis of iminophosphoranes by the Appel reaction of substituted anilines

In a 50ml one-necked flask, 10.0mmol of amine of 2-aminocinnamate, 20.0mmol of triphenylphosphine, 100.0mmol of carbon tetrachloride and 100.0mmol of triethylamine were dissolved in 20ml of acetonitrile. The mixture was stirred at room temperature for 2 hours. After the reaction had ended (reaction detected by DC or analytical HPLC), the solvent was removed in vacuo and the residue was purified by column chromatography on silica gel using cyclohexane/ethyl acetate 7: 3.

Example 10A

(2E) -3- { 3-fluoro-2- [ (triphenylphospinylidene) amino ] phenyl } acrylic acid methyl ester

Starting from 29.3g (150.1mmol) of the amine compound from example 1A, 55.0g (80% of theory) of the product are obtained by general procedure [ E ].

HPLC (method 1): r_t＝4.46min

MS(ESI-pos)：m/z＝456(M+H)⁺

Example 11A

(2E) -3- { 5-fluoro-2- [ (triphenylphospinylidene) amino ] phenyl } acrylic acid methyl ester

Starting from 50.0g (256.2mmol) of the amine compound from example 9A, the general procedure [ E ] gives 89.6g (77% of theory) of product.

HPLC (method 1): r_t＝4.36min

MS(ESI-pos)：m/z＝456(M+H)⁺

Example 12A

(2E) -3- { 5-cyano-2- [ (triphenylphospinylidene) amino ] phenyl } propenoic acid methyl ester

Starting from 1.24g (4.60mmol) of the amine compound from example 5A, 2.12g (92% of theory) of the product are obtained by general procedure [ E ].

HPLC (method 1): r_t＝4.42min

MS(ESI-pos)：m/z＝463(M+H)⁺

General procedure [ F]: synthesis of phenylpiperazines by Buchwald-Hartwig reaction

To prepare the reaction, the reaction flask was heated well under high vacuum and filled with argon gas. 1.0 equivalent of bromoaryl compound and 6.0 equivalents of piperazine in absolute toluene were charged to the flask (0.2-0.3M solution of bromine compound). 0.01 equivalents of tris (dibenzylideneacetone) dipalladium and 0.03 equivalents of BINAP were then added. The reaction mixture was stirred at reflux for 16 h. The mixture was then extracted once with water, the organic phase was extracted twice with 1N hydrochloric acid and the aqueous phase was adjusted to pH 8 using 1N aqueous sodium hydroxide solution and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and filtered, the solvent was removed in vacuo and the product was dried under high vacuum overnight.

Example 13A

N- (4-fluoro-3-methylphenyl) piperazine

Starting from 5.0g (26.5mmol) of 4-fluoro-3-methyl-1-bromobenzene, general procedure [ F ] gave 4.52g (83% of theory) of product.

HPLC (method 1): r_t＝3.54min

MS(ESI pos)：m/z＝195(M+H)⁺

Example 14A

N- (4-fluorophenyl) -3-methylpiperazine

Starting from 1.0g (5.71mmol) of 4-fluoro-3-methyl-1-bromobenzene, by general procedure [ F ] 0.57g (49% of theory) of product is obtained.

HPLC (method 1): r_t＝3.37min

MS(DCI pos)：m/z＝195(M+H)⁺

Example 15A

1- (3-fluorophenyl) piperazine

1g (5.71mmol) of 3-fluorobromobenzene and 2.95g (34.29mmol) of piperazine were dissolved in 20ml of toluene, and 0.77g (8mmol) of sodium tert-butoxide was added. The mixture was stirred at reflux overnight in the presence of 0.11g (0.17mmol) of BINAP and 0.05g (0.06mmol) of tris (dibenzylideneacetone) dipalladium. After cooling, ethyl acetate was added and the mixture was washed with water. The mixture was then extracted with 1N hydrochloric acid and the aqueous phase was washed with ethyl acetate. The pH was adjusted to 8-9 and the mixture was subsequently extracted with dichloromethane. The organic phase is dried over magnesium sulfate and the solvent is removed to give the title compound.

Yield: 0.8g (78% of theory)

HPLC (method 1): r_t＝3.4min

MS(ESI-pos)：m/z＝181(M+H)⁺

Example 16A

1- (3, 4-difluorophenyl) piperazine

In 100ml of toluene, 5g (25.91mmol) of 3, 4-difluorobromobenzene and 13.39g (155.45mmol) of piperazine, 3.49g (36.27mmol) of sodium tert-butoxide, 0.24g (0.26mmol) of tris (dibenzylideneacetone) dipalladium and 0.48g (0.78mmol) of BINAP were stirred at reflux overnight. Ethyl acetate was added, the mixture was subsequently washed with water and the organic phase was extracted with 1N hydrochloric acid. The aqueous phase was then washed with ethyl acetate and then adjusted to pH 8 the product was extracted from the aqueous phase using dichloromethane. The extract was then dried over magnesium sulfate, the solvent was removed and the target compound was dried in vacuo.

Yield: 3.85g (75% of theory)

HPLC (method 1): r_t＝3.4min

MS(DCI)：m/z＝199(M+H)⁺

Example 17A

2-isocyanato-1-methoxy-4- (trifluoromethyl) benzene

3g (15.69mmol) of 2-methoxy-5-trifluoromethylaniline are dissolved in 100ml of dichloromethane and 6.73g (31.39mmol) of 1, 8-bis (dimethylamino) naphthalene are added. 2.24g (11.3mmol) of trichloromethyl chloroformate dissolved in 50ml of dichloromethane are added dropwise at 0-5 ℃ and the mixture is stirred at 0 ℃ for 30min and subsequently at room temperature for 60 min. The mixture was washed with 1N hydrochloric acid, ice water and sodium bicarbonate solution at 0 ℃. Drying over magnesium sulfate and removal of the solvent by distillation gave the product. The isocyanate was subsequently used in the subsequent reaction without further purification.

Yield: 3.00g (88% of theory)

Example 18A

(2E) -3- { 3-fluoro-2- [ ({ [ 2-methoxy-5- (trifluoromethyl) phenyl ] imino } methylene) amino ] phenyl } -2-propenoic acid methyl ester

5.0g (10.98mmol) of methyl (2E) -3- { 3-fluoro-2- [ (triphenylphosphorylidene) amino ] phenyl } -2-propenoate (example 10A) are taken up in 50ml of dichloromethane and stirred with 2.5g (11.53mmol) of 2-isocyanato-1-methoxy-4- (trifluoromethyl) benzene (example 17A) at room temperature overnight. The solvent was removed by distillation and the product was subsequently purified by chromatography on silica gel (isohexane/dichloromethane 2: 1; 1: 1) and recrystallized from isohexane.

Yield: 2.69g (62% of theory)

HPLC (method 1): r_t＝5.6min

MS(ESI-pos)：m/z＝395(M+H)⁺

General procedure [ G]: reaction of iminophosphoranes with isocyanates and subsequent amines to give bis Hydroquinazoline derivatives

1.0 equivalent of iminophosphorane is dissolved in 20ml of dichloromethane (0.1-0.2M solution). 1.05 equivalents of substituted isocyanate were then added and the mixture was stirred at RT until the reaction was complete. The reaction was detected by DC or by analytical HPLC.

1.0 equivalent of amine and a spatula tip of silica gel were then added to the resulting carbodiimide solution in dichloromethane and the mixture was stirred at room temperature until the reaction had been completed. After the reaction had ended (reaction detected by DC or HPLC), the mixture was concentrated and purified by preparative HPLC in the RP phase.

In some cases, NMR showed the presence of different proportions of non-cyclized reaction product. In those cases, the mixture of cyclized and non-cyclized products was taken up in dioxane, a spatula tip of silica gel was added and the mixture was stirred under reflux for 30min to 16 h. The silica gel was filtered off and the solution was used for further reaction.

If it is desired to produce an enantiomerically pure compound, chromatographic separation is carried out at this stage.

Example 19A

{ 8-fluoro-2- [4- (4-fluorophenyl) -1-piperazinyl ] -3- [3- (trifluoromethyl) phenyl ] -3, 4-dihydro-4-quinazolinyl } acetic acid methyl ester

Starting from 92.5mg (0.2mmol) of the iminophosphane of example 10A, according to general procedure [ G ] 50mg (45% of theory) of the product are obtained.

HPLC (method 1): r_t＝4.81min

Example 20A

{ 8-fluoro-2- [4- (4-fluorophenyl) -1-piperazinyl ] -3- [3- (trifluoromethyl) phenyl ] -3, 4-dihydro-4-quinazolinyl } acetic acid methyl ester

This compound is obtained as enantiomer a after separation of 3.84g of the enantiomer of example 19A (715mg, 14% of theory).

HPLC (method 1): r_t＝4.81min

MS(ESI-pos)：m/z＝544.9(M+H)⁺

Example 21A

{ 6-fluoro-2- [4- (4-fluorophenyl) -1-piperazinyl ] -3- [3- (trifluoromethyl) phenyl ] -3, 4-dihydro-4-quinazolinyl } acetic acid methyl ester

Starting from 100mg (0.28mmol) of the iminophosphane of example 1A, the general procedure [ G ] gives 58mg (39% of theory) of the product.

HPLC (method 1): r_t＝4.80min

Example 22A

{ 6-fluoro-2- [4- (4-fluorophenyl) -1-piperazinyl ] -3- [3- (trifluoromethyl) phenyl ] -3, 4-dihydro-4-quinazolinyl } acetic acid methyl ester

This compound is obtained as enantiomer a after separation of 832mg of the enantiomer of example 21A (368mg, 17% of theory).

HPLC (method 1): r_t＝4.77min

MS(ESI-pos)：m/z＝544.9(M+H)⁺

Example 23A

{ 8-fluoro-2- [4- (3-methylphenyl) -1-piperazinyl ] -3- [3- (trifluoromethyl) phenyl ] -3, 4-dihydro-4-quinazolinyl } acetic acid methyl ester

Starting from 93mg (0.2mmol) of the iminophosphane of example 10A, according to general procedure [ G ] 43mg (39% of theory) of product are obtained.

HPLC (method 1): r_t＝4.80min

MS(ESI-pos)：m/z＝541.0(M+H)⁺

Example 24A

{ 8-fluoro-2- [4- (3-methylphenyl) -1-piperazinyl ] -3- [3- (trifluoromethyl) phenyl ] -3, 4-dihydro-4-quinazolinyl } acetic acid methyl ester

This compound is obtained as enantiomer A after separation of 3.31g of the enantiomer of example 23A (1.18g, 22% of theory).

HPLC (method 1): r_t＝4.80min

MS(ESI-pos)：m/z＝541.0(M+H)⁺

Example 25A

{ 8-fluoro-2- [4- (3-methoxyphenyl) -1-piperazinyl ] -3- [3- (trifluoromethyl) phenyl ] -3, 4-dihydro-4-quinazolinyl } acetic acid methyl ester

Starting from 93mg (0.2mmol) of the iminophosphane of example 10A, general procedure [ G ] gives 51mg (45% of theory) of the product.

HPLC (method 1): r_t＝4.62min

MS(ESI-pos)：m/z＝556.7(M+H)⁺

Example 26A

{ 8-fluoro-2- [4- (3-methoxyphenyl) -1-piperazinyl ] -3- [ 3-trifluoromethyl ] phenyl ] -3, 4-dihydro-4-quinazolinyl } acetic acid methyl ester

This compound is obtained as enantiomer A after separation of 5.11g of the enantiomer of example 25A (0.49g, 9% of theory).

HPLC (method 1): r_t＝4.71min

MS(ESI-pos)：m/z＝556.8(M+H)⁺

Example 27A

{ 8-fluoro-2- [4- (4-fluoro-3-methylphenyl) -1-piperazinyl ] -3- [ 6-methoxy-3- (trifluoromethyl) phenyl ] -3, 4-dihydro-4-quinazolinyl } acetic acid methyl ester

Starting from 1.0g (2.2mmol) of the iminophosphane of example 10A, 500mg (2.31mmol) of 2-isocyanato-1-methoxy-4- (trifluoromethyl) benzene (example 17A) and 427mg (2.2mmol) of the phenylpiperazine of example 13A, 1.03g (79% of theory) of the crude product are obtained after filtration through silica gel (cyclohexane/ethyl acetate 2: 1 (v/v)). The product was reacted further without further purification.

LC-MS (method 3): r_t＝2.55min，2.66min

MS(ESI-pos)：m/z＝589.3(M+H)⁺

Example 28A

{ 8-fluoro-2- [4- (4-fluoro-3-methylphenyl) -1-piperazinyl ] -3- [ 6-methoxy-3-methylphenyl ] -3, 4-dihydro-4-quinazolinyl } acetic acid methyl ester

Starting from 0.60g (1.76mmol) of the A iminophosphane of example 10, 376mg (2.31mmol) of 2-methoxy-5-methylphenyl isocyanate and 342mg (1.76mmol) of the phenylpiperazine of example 13A, 183mg (16% of theory) of the product are obtained after purification by preparative HPLC.

HPLC (method 1): r_t＝4.77min

MS(ESI-pos)：m/z＝535.2(M+H)⁺

Example 29A

{ 8-fluoro-2- [4- (4-fluorophenyl) -1-piperazinyl ] -3- [ 6-methoxy-3-chlorophenyl ] -3, 4-dihydro-4-quinazolinyl } acetic acid methyl ester

Starting from 1.0g (2.2mmol) of the iminophosphorane of example 10A, 423mg (2.31mmol) of 2-methoxy-5-chlorophenylisocyanate and 396mg (2.2mmol) of 4-fluorophenylpiperazine, 621mg (52% of theory) of the product are obtained after purification by preparative HPLC.

HPLC (method 1): r_t＝4.75min

MS(ESI-pos)：m/z＝541.2(M+H)⁺

Example 30A

{ 8-fluoro-2- [4- (4-fluorophenyl) -1-piperazinyl ] -3- [ 2-methoxy-5- (trifluoromethyl) phenyl ] -3, 4-dihydro-4-quinazolinyl } acetic acid methyl ester

550mg (1.39mmol) of methyl (2E) -3- { 3-fluoro-2- [ ({ [ 2-methoxy-5- (trifluoromethyl) phenyl ] -imino } methylene) amino ] phenyl } -2-propenoate (example 18A) and 251mg (1.39mmol) of 1- (4-fluorophenyl) piperazine were stirred in the presence of a spatula tip of silica gel in 15ml of dichloromethane for 1 hour. After stirring at reflux for 90 hours, the product was purified by chromatography on silica gel (dichloromethane, dichloromethane/ethyl acetate 10: 1).

Yield: 769mg (96% of theory)

HPLC (method 1): r_t＝4.8min

MS(ESI-pos)：m/z＝575(M+H)⁺

Example 31A

{ 8-fluoro-2- [4- (3-methoxyphenyl) -1-piperazinyl ] -3- [ 2-methoxy-5- (trifluoromethyl) -phenyl ] -3, 4-dihydro-4-quinazolinyl } acetic acid methyl ester

700mg (1.78mmol) of methyl (2E) -3- { 3-fluoro-2- [ ({ [ 2-methoxy-5- (trifluoromethyl) phenyl ] -imino } methylene) amino ] phenyl } -2-propenoate (example 18A), 341mg (1.78mmol) of 1- (3-methoxyphenyl) piperazine and a spatula tip of silica gel were stirred in 20ml of dichloromethane at room temperature for 1 hour and subsequently under reflux for 35 hours. The expected compound is obtained after purification on silica gel (dichloromethane, dichloromethane/ethyl acetate 10: 1).

Yield: 1012mg (97% of theory)

HPLC (method 6): r_t＝4.8min

MS(ESI-pos)：m/z＝587(M+H)⁺

Example 32A

{ 8-fluoro-2- [4- (3, 4-difluorophenyl) -1-piperazinyl ] -3- [ 2-methoxy-5- (trifluoromethyl) -phenyl ] -3, 4-dihydro-4-quinazolinyl } acetic acid methyl ester

700mg (1.78mmol) of methyl (2E) -3- { 3-fluoro-2- [ ({ [ 2-methoxy-5- (trifluoromethyl) phenyl ] -imino } methylene) amino ] phenyl } -2-propenoate (example 18A), 352mg (1.78mmol) of 1- (3, 4-difluorophenyl) piperazine (example 16A) and a spatula tip of silica gel were stirred in 20ml of dichloromethane at room temperature for 1 hour and subsequently under reflux for 20 hours. The target compound is subsequently purified by chromatography on silica gel (dichloromethane, dichloromethane/ethyl acetate 10: 1).

Yield: 1027mg (97% of theory)

HPLC (method 1): r_t＝4.8min

MS(ESI-pos)：m/z＝593(M+H)⁺

Example 33A

{ 8-fluoro-2- [4- (3-methylphenyl) -1-piperazinyl ] -3- [ 2-methoxy-5- (trifluoromethyl) phenyl ] -3, 4-dihydro-4-quinazolinyl } acetic acid methyl ester

11.5g (29.16mmol) methyl (2E) -3- { 3-fluoro-2- [ ({ [ 2-methoxy-5- (trifluoromethyl) phenyl ] -imino } methylene) amino ] phenyl } -2-propenoate (example 18A), 5.14g (29.16mmol)1- (3-methylphenyl) piperazine and a spatula tip of silica gel were stirred in 300ml dichloromethane at room temperature for 1h and subsequently under reflux for 20 h. The product is obtained after chromatography on silica gel (dichloromethane, dichloromethane/ethyl acetate 10: 1, 5: 1).

Yield: 15.8g (95% of theory)

HPLC (method 1): r_t＝4.8min

MS(ESI-pos)：m/z＝571(M+H)⁺

Example 34A

{ 8-fluoro-2- [4- (3-fluorophenyl) -1-piperazinyl ] -3- [ 2-methoxy-5- (trifluoromethyl) phenyl ] -3, 4-dihydro-4-quinazolinyl } acetic acid methyl ester

100mg (0.25mmol) of methyl (2E) -3- { 3-fluoro-2- [ ({ [ 2-methoxy-5- (trifluoromethyl) phenyl ] -imino } methylene) amino ] phenyl } -2-propenoate (example 18A), 45.7mg (0.25mmol) of 1- (3-fluorophenyl) piperazine (example 15A) and a spatula tip of silica gel were stirred in 15ml of dichloromethane at room temperature for 1 hour and subsequently under reflux for 20 hours. The title compound is obtained after chromatography on silica gel (dichloromethane, dichloromethane/ethyl acetate 10: 1).

Yield: 139.2mg (96% of theory)

HPLC (method 1): r_t＝4.8min

MS(ESI-pos)：m/z＝575(M)⁺

Example 35A

{ 8-fluoro-2- [4- (3-chlorophenyl) -1-piperazinyl ] -3- [3- (trifluoromethyl) phenyl ] -3, 4-dihydro-4-quinazolinyl } acetic acid methyl ester

Starting from 93mg (0.2mmol) of the iminophosphane of example 10A, general procedure [ G ] gives 51mg (45% of theory) of the product.

LC-MS (method 3): r_t＝4.78min

MS(ESI-pos)：m/z＝561(M+H)⁺

Example 36A

{ 8-fluoro-2- [4- (1, 3-benzodioxol-5-yl) -1-piperazinyl ] -3- [3- (trifluoromethyl) phenyl ] -3, 4-dihydro-4-quinazolinyl } acetic acid methyl ester

Starting from 4.19G (9.2mmol) of the iminophosphane of example 10A, 3.67G (70% of theory) of the product are obtained by general procedure [ G ].

HPLC (method 1): r_t＝4.67min

MS(ESI-pos)：m/z＝571(M+H)⁺

Example 37A

4-amino-3- [ (1E) -3-tert-butoxy-3-oxoprop-1-en-1-yl ] benzoic acid methyl ester

Starting from 25.0g (90.2mmol) of methyl 4-amino-3-iodobenzoate, the general procedure [ A ] was followed to give 24.3g (88% of theory) of product.

HPLC (method 1): r_t＝4.71min

MS(DCI-pos)：m/z＝295(M+NH₄)⁺

Example 38A

(2E) -3- (4-cyano-2-nitrophenyl) -2-propenoic acid methyl ester

Starting from 3.00g (17.0mmol) of 4-cyano-2-nitrobenzaldehyde, the general procedure [ B ] and recrystallization from methanol gave 2.51g (63% of theory) of the product.

HPLC (method 1): r_t＝4.06min

MS(ESI-pos)：m/z＝233(M+H)⁺

Example 39A

3- [ 2-amino-7-cyanophenyl ] acrylic acid methyl ester

Starting from 1.0g (4.31mmol) of the nitro compound from example 38A, the general procedure [ D ], but without boiling on activated carbon, gives 793mg (89% of theory) of the product.

HPLC (method 1): r_t＝3.99min

Example 40A

(2E) -3- { 6-cyano-2- [ (triphenylphospinylidene) amino ] phenyl } propenoic acid methyl ester

Starting from 0.75g (3.71mmol) of the amine compound from example 39A, 1.09g (62% of theory) of the product are obtained by general procedure [ E ].

HPLC (method 1): r_t＝4.30min

MS(ESI-pos)：m/z＝463(M+H)⁺

Example 41A

3- [ (1E) -3-tert-butoxy-3-oxoprop-1-en-1-yl ] -4- [ (triphenylphosp-rophy-l) amino ] -benzoic acid methyl ester

Starting from 19.0g (68.5mmol) of the amine compound from example 37A, 31.4g (85% of theory) of product are obtained by general procedure [ E ].

HPLC (method 1): r_t＝4.69min

MS(ESI-pos)：m/z＝538(M+H)⁺

Example 42A

{ 8-fluoro-2- [4- (4-fluorophenyl) -1-piperazinyl ] -3- [ 2-methoxy-5- (trifluoromethyl) phenyl ] -3, 4-dihydro-4-quinazolinyl } acetic acid methyl ester

This compound was obtained as enantiomer a by chromatographic separation of the racemate from example 30A into the enantiomers according to method 15. Starting from 231g of racemate, 120g of the expected product are obtained and are reacted further directly.

MS(ESI-pos)：m/z＝575(M+H)⁺

Example 43A

{ 8-fluoro-2- [4- (3-methoxyphenyl) -1-piperazinyl ] -3- [ 2-methoxy-5- (trifluoromethyl) -phenyl ] -3, 4-dihydro-4-quinazolinyl } acetic acid methyl ester

This compound was obtained as enantiomer a by chromatographic separation of the racemate from example 31A into the enantiomers according to method 15. Starting from 231g of racemate, 111g (48% of theory) of the expected product are obtained.

MS(ESI-pos)：m/z＝587(M+H)⁺

Example 44A

{ 6-cyano-2- [4- (4-fluorophenyl) -1-piperazinyl ] -3- [ 3-trifluoromethyl ] phenyl ] -3, 4-dihydro-4-quinazolinyl } acetic acid methyl ester

Starting from 400mg (0.6mmol) of the iminophosphane of example 12A, the general procedure [ G ] gives 166mg (48% of theory) of the product.

HPLC (method 1): r_t＝4.65min

MS(ESI-pos)：m/z＝552(M+H)⁺

Example 45A

{ 7-cyano-2- [4- (4-fluorophenyl) -1-piperazinyl ] -3- [3- (trifluoromethyl) phenyl ] -3, 4-dihydro-4-quinazolinyl } acetic acid methyl ester

Starting from 1.0G (2.16mmol) of the iminophosphane of example 40A, general procedure [ G ] gives 1.07G (98% of theory) of product.

HPLC (method 1): r_t＝4.72min

MS(ESI-pos)：m/z＝552(M+H)⁺

Example 46A

4- (2-tert-butoxy-2-oxoethyl) -2- [4- (4-fluorophenyl) piperazin-1-yl ] -3- [3- (trifluoromethyl) phenyl ] -3, 4-dihydroquinazoline-6-carboxylic acid methyl ester

Starting from 4.2G (9.3mmol) of the iminophosphane of example 41A, by general procedure [ G ] 3.9G (51% of theory) of the product are obtained.

HPLC (method 1): r_t＝5.03min

MS(ESI-pos)：m/z＝627(M+H)⁺

Example 47A

{ 8-fluoro-2- [4- (4-fluorophenyl) -1-piperazinyl ] -3- [3- (trifluoromethyl) phenyl ] -3, 4-dihydro-4-quinazolinyl } acetic acid methyl ester

This compound is obtained as enantiomer A after separation of 3.5g of the enantiomer of example 46A (1.4mg, 20% of theory).

HPLC (method 1): r_t＝4.91min

MS(ESI-pos)：m/z＝627(M+H)⁺

Example 48A

4- (2-tert-butoxy-2-oxoethyl) -2- [4- (4-fluorophenyl) piperazin-1-yl ] -3- [3- (trifluoromethyl) phenyl ] -3, 4-dihydroquinazoline-6-carboxylic acid

1.3g (2.0mmol) of the methyl carboxylate of example 47A are dissolved in 12ml of dioxane, 2.4ml of a 1N aqueous solution of potassium hydroxide are added and the mixture is stirred at 60 ℃ for 5 hours. The pH was adjusted to 4 using 1N aqueous hydrochloric acid and the reaction mixture was concentrated and purified by preparative HPLC. This gives 580mg (48% of theory) of product.

HPLC (method 1): r_t＝4.85min

MS(ESI-pos)：m/z＝613(M+H)⁺

Example 49A

{6- (aminocarbonyl) -2- [4- (4-fluorophenyl) piperazin-1-yl ] -3- [3- (trifluoromethyl) phenyl ] -3, 4-dihydroquinazolin-4-yl } acetic acid tert-butyl ester

560mg (0.9mmol) of the carboxylic acid from example 48A with 2.6mmol of aluminum chloride, 1.1mmol of 1-hydroxy-1H-benzotriazole hydrate and 1.1mmol of N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide are suspended in DMF. 2.6mmol of N, N-diisopropylamine were added, and the mixture was stirred at room temperature for 16 hours. 20ml of ethyl acetate was added to the reaction mixture, followed by washing with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution. The combined aqueous phases were adjusted to pH 8 and extracted with ethyl acetate. The combined organic phases were finally washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated. This gives 548mg (97% of theory) of product.

HPLC (method 1): r_t＝4.73min

MS(ESI-pos)：m/z＝612(M+H)⁺

Examples 50A to 112A of Table 1 can be prepared from the corresponding starting materials by the general procedures [ A ] to [ G ].

TABLE 1

Examples

General procedure [ H ]: hydrolysis of quinazolinyl acetates

1.0 equivalent of quinazolinyl acetate was dissolved in dioxane and 5.0 equivalents of 1N aqueous sodium hydroxide solution was added. The mixture was stirred at 80 degrees celsius for 16 hours and after the reaction had ended (the reaction was monitored by analytical HPLC), the mixture was concentrated. The residue was then taken up in water and adjusted to pH 5 using 1N hydrochloric acid. The resulting precipitate was filtered off, washed with a small amount of water and diethyl ether and dried under high vacuum at room temperature. Alternatively, the precipitate can be filtered off through an Extrelut cartridge, followed by washing with ethyl acetate, and then concentrating the filtrate. If the purity of the product is not high enough, the product is purified by preparative HPLC on RP phase (method 2 or method 5) or on silica gel using the mixture cyclohexane/ethyl acetate.

Example 1

{ 8-fluoro-2- [4- (4-fluorophenyl) -1-piperazinyl ] -3- [3- (trifluoromethyl) phenyl ] -3, 4-dihydro-4-quinazolinyl } acetic acid

Starting from 37mg (0.07mmol) of the methyl ester of example 19A, the general procedure [ H ] gives 29mg (80% of theory) of the product.

HPLC (method 1): r_t＝4.49min

MS(ESI-pos)：m/z＝530.7(M+H)⁺

¹H-NMR(400MHz，CD₃CN)：δ[ppm]＝7.59(s，1H)；7.45(t，1H)；7.37(t，2H)；7.02-6.95(m，3H)；6.93-6.85(m，4H)；5.24(dd，1H)；2.98(d_b，4H)；2.91(d_b，4H)；2.73(dd，1H)；2.54(dd，1H)。

Example 2

{ 8-fluoro-2- [4- (4-fluorophenyl) -1-piperazinyl ] -3- [3- (trifluoromethyl) phenyl ] -3, 4-dihydro-4-quinazolinyl } acetic acid

Starting from 695mg (1.27mmol) of the methyl ester of example 20A, general procedure [ H ] gives 488mg (64% of theory) of the product.

HPLC (method 1): r_t＝4.59min

MS(ESI-pos)：m/z＝530.8(M+H)⁺

¹H-NMR(400MHz，CD₃CN)：δ[ppm]＝7.60(s，1H)；7.47-7.40(m，3H)；7.03-6.86(m，7H)；5.26-5.23(m，1H)；3.60-3.52(m，4H)；2.99-2.90(m，4H)；2.75(dd，1H)；2.56(dd，1H)。

Example 3

{ 8-fluoro-2- [4- (3-methylphenyl) -1-piperazinyl ] -3- [3- (trifluoromethyl) phenyl ] -3, 4-dihydro-4-quinazolinyl } acetic acid

Starting from 34mg (0.06mmol) of the methyl ester of example 23A, 30mg (90% of theory) of the product are obtained by general procedure [ H ].

HPLC (method 1): r_t＝4.56min

MS(ESI-pos)：m/z＝526.9(M+H)⁺

¹H-NMR(200MHz，DMSO-d₆)：δ[ppm]＝7.64(s，1H)；7.53(t，1H)；7.44-7.34(m，2H)；7.11-6.90(m，3H)；6.72-6.59(m，4H)；5.33-5.25(m，1H)；3.52(d_b，4H)；3.02(d_b4H); 2.69-2.55(m, 2H, partially hidden by DMSO signal); 2.23(s, 3H).

Example 4

{ 8-fluoro-2- [4- (3-methoxyphenyl) -1-piperazinyl ] -3- [3- (trifluoromethyl) phenyl ] -3, 4-dihydro-4-quinazolinyl } acetic acid

Starting from 36mg (0.07mmol) of the methyl ester of example 25A, the general procedure [ H ] and chromatography (method 2) give 28mg (77% of theory) of product.

HPLC (method 1): r_t＝4.46min

MS(ESI-pos)：m/z＝542.9(M+H)⁺

¹H-NMR(200MHz，DMSO-d₆)：δ[ppm]＝7.67(s，1H)；7.54(t，1H)；7.45-7.38(m，2H)；7.14-6.94(m，3H)；6.51-6.35(m，4H)；5.35-5.25(m，1H)；3.69(s，3H)；3.50(d_b，4H)；3.06(d_b，4H)；2.58-2.52(m，2H)。

Example 5

{ 8-fluoro-2- [4- (3-chlorophenyl) -1-piperazinyl ] -3- [3- (trifluoromethyl) phenyl ] -3, 4-dihydro-4-quinazolinyl } acetic acid

Starting from 38mg (0.07mmol) of the methyl ester of example 35A, the general procedure [ H ] gives 25mg (66% of theory) of the product.

HPLC (method 1): r_t＝4.64min

MS(ESI-pos)：m/z＝546.9(M+H)⁺

¹H-NMR(200MHz，DMSO-d₆)：δ[ppm]＝7.66(s，1H)；7.52(t，1H)；7.38(dd，2H)；7.20(t，1H)；7.10-6.78(m，6H)；5.33-5.26(m，1H)；3.51(d_b，4H)；3.11(d_b，4H)；2.61-2.55(m，2H)。

Example 6

{ 8-fluoro-2- [4- (1, 3-benzodioxol-5-yl) -1-piperazinyl ] -3- [3- (trifluoromethyl) phenyl ] -3, 4-dihydro-4-quinazolinyl } acetic acid

Starting from 173mg (0.30 mmol) of the methyl ester of example 36A, 79mg (46% of theory) of product are obtained according to general procedure [ H ].

HPLC (method 1): r_t＝4.44min

MS(ESI-pos)：m/z＝557.2(M+H)⁺

¹H-NMR(300MHz，CDCl₃)：δ[ppm]＝7.47(s，1H)；7.42-7.34(m，3H)；7.03-6.89(m，2H)；6.79(d，1H)；6.64(d，1H)；6.41(d，1H)；6.22(dd，1H)；5.87(s，2H)；5.20-5.15(m，1H)；3.59(s_b，3H)；2.94-2.85(m，5H)；2.59(dd，1H)。

Example 7

{ 6-fluoro-2- [4- (4-fluorophenyl) -1-piperazinyl ] -3- [3- (trifluoromethyl) phenyl ] -3, 4-dihydro-4-quinazolinyl } acetic acid

Starting from 42mg (0.08mmol) of the methyl ester of example 21A, 34mg (76% of theory) of the product are obtained by general procedure [ H ].

HPLC (method 1): r_t＝4.63min

MS(ESI-pos)：m/z＝530.9(M+H)⁺

Example 8

{ 6-fluoro-2- [4- (4-fluorophenyl) -1-piperazinyl ] -3- [3- (trifluoromethyl) phenyl ] -3, 4-dihydro-4-quinazolinyl } acetic acid hydrochloride

Starting from 350mg (0.64mmol) of the ester of example 22A, 284mg (83% of theory) of product are obtained by general procedure [ H ].

HPLC (method 1): r_t＝4.53min

MS(ESI-pos)：m/z＝530.8(M+H-HCl)⁺

¹H-NMR(400MHz，CD₃CN)：δ[ppm]＝7.62(s，1H)；7.51-7.48(m，1H)；7.43-7.41(d，1H)；7.26-7.23(m，1H)；7.04-6.95(m，2H)；6.91-6.85(m，3H)；5.23(dd，1H)；3.55(s_b，3H)；3.02-2.99(m，1H)；2.94(s_b，4H)；2.80(dd，1H)。

Example 9

{ 8-fluoro-2- [4- (3-methylphenyl) -1-piperazinyl ] -3- [3- (trifluoromethyl) phenyl ] -3, 4-dihydro-4-quinazolinyl } acetic acid hydrochloride

Starting from 1.10g (1.93mmol) of the ester of example 24A, general procedure [ H ] gives 1.04g (91% of theory) of product. After separation of the enantiomers by method 4, the product is obtained as enantiomer a.

HPLC (method 1): r_t＝4.68min

MS(ESI-pos)：m/z＝526.9(M+H-HCl)⁺

¹H-NMR(400MHz，CD₃CN)：δ[ppm]＝7.61(s，1H)；7.49-7.38(m，3H)；7.10-6.89(m，4H)；6.71-6.65(m，3H)；5.26(dd，1H)；3.60-3.52(m，4H)；3.03-2.95(m，4H)；2.76(dd，1H)；2.57(dd，1H)；2.25(s，3H)。

Example 10

{ 8-fluoro-2- [4- (3-methoxyphenyl) -1-piperazinyl ] -3- [3- (trifluoromethyl) phenyl ] -3, 4-dihydro-4-quinazolinyl } acetic acid hydrochloride

Starting from 437mg (0.79mmol) of the ester of example 26A, according to general procedure [ H ] 344mg (72% of theory) of the product are obtained.

HPLC (method 1): r_t＝4.48min

MS(ESI-pos)：m/z＝543.0(M+H-HCl)⁺

¹H-NMR(400MHz，CD₃CN)：δ[ppm]＝7.61(s，1H)；7.49-7.38(m，3H)；7.14-6.89(m，4H)；6.47-6.39(m，3H)；5.26(dd，1H)；3.72(s，1H)；3.60-3.54(m，4H)；3.07-3.00(m，4H)；2.77(dd，1H)；2.57(dd，1H)。

Example 11

{ 8-fluoro-2- [4- (4-fluoro-3-methylphenyl) -1-piperazinyl ] -3- [ 6-methoxy-3- (trifluoromethyl) phenyl ] -3, 4-dihydro-4-quinazolinyl } acetic acid hydrochloride

Starting from 1.03g (1.75mmol) of the crude ester of example 27A, 283mg (22% of theory) of the hydrochloride salt are obtained after general step [ H ] and chromatography according to method 5 and subsequent absorption of the product in methanol/1N hydrochloric acid and subsequent evaporation of the solvent.

HPLC (method 1): r_t＝4.58min

MS(ESI-pos)：m/z＝575.2(M+H-HCl)⁺

¹H-NMR(400MHz，CD₃CN)：δ[ppm]＝8.17(s，0.66H)；7.69(d，1H)；7.55-7.30(m，1H)；7.27-7.24(m，2H)；7.16(d，0.6H)；7.09-7.04(m，2H)；5.33-5.27，5.12-5.06(2x m，1H)；4.08-3.35(m，4H)；3.69(s，3H)；3.30-3.22(m，1H)；2.80-2.76(m，1H)；2.25(s，3H)。

Example 12

{ 8-fluoro-2- [4- (4-fluoro-3-methylphenyl) -1-piperazinyl ] -3- [ 6-methoxy-3- (trifluoromethyl) phenyl ] -3, 4-dihydro-4-quinazolinyl } acetic acid hydrochloride

Before the separation of the enantiomers, 268mg of the hydrochloride salt from example 11 were taken up in dichloromethane and the organic phase was extracted twice with saturated sodium bicarbonate solution. The combined aqueous phases were extracted once with dichloromethane, the combined organic phases were dried over sodium sulfate and filtered and the solvent was removed in vacuo. This gives 204mg (86% of theory) of the free base. Thus, after separation of the enantiomer (method 4), re-purification by preparative HPLC (method 5) and subsequent absorption of the product in methanol/1N hydrochloric acid and re-evaporation of the solvent, 80mg (78% of theory) of enantiomer A are obtained.

HPLC (method 6): r_t＝4.66min

MS(ESI-pos)：m/z＝575.2(M+H-HCl)⁺

¹H-NMR(400MHz，CD₃CN)：δ[ppm]＝8.17(s，0.66H)；7.69(d，1H)；7.45-7.30(m，1H)；7.24(d，2H)；7.15(d，0.7H)；7.08-7.01(m，2H)；5.32-5.27，5.11-5.07(2x m，1H)；4.06-3.50(m，4H)；3.68(s，3H)；3.33-3.24(m，1H)；2.77-2.72(m，1H)；2.24，2.23(2x s，3H)。

Example 13

{ 8-fluoro-2- [4- (4-fluoro-3-methylphenyl) -1-piperazinyl ] -3- [ 6-methoxy-3-methylphenyl ] -3, 4-dihydro-4-quinazolinyl } acetic acid hydrochloride

Starting from 183mg (0.34mmol) of the crude ester of example 28A, after general step [ H ] and chromatography according to method 5 and dissolution of the product in methanol/1N hydrochloric acid and re-evaporation of the solvent, 135mg (67% of theory) of the hydrochloride salt are obtained.

HPLC (method 1): r_t＝4.67min

MS(ESI-pos)：m/z＝521.2(M+H-HCl)⁺

¹H-NMR(400MHz，CD₃CN)：δ[ppm]＝7.69-7.42(m，4H)；7.25-7.06(m，5H)；6.93-6.78(m，1H)；5.24-5.21，5.06-5.03(2x m，1H)；4.00-3.35(m，8H)；3.21-3.08(m，1H)；3.01-2.77(m，1H)；2.34，2.20(2x s，3H)；2.26(s，3H)。

Example 14

{ 8-fluoro-2- [4- (3-methoxyphenyl) -1-piperazinyl ] -3- [ 2-methoxy-5- (trifluoromethyl) phenyl ] -3, 4-dihydro-4-quinazolinyl } acetic acid

179.6mg (4.49mmol) of sodium hydroxide are added to 878mg (1.5mmol) of methyl { 8-fluoro-2- [4- (3-methoxyphenyl) -1-piperazinyl ] -3- [ 2-methoxy-5- (trifluoromethyl) phenyl ] -3, 4-dihydro-4-quinazolinyl } acetate (example 31A) in 40ml of dioxane at room temperature, and the mixture is stirred at 50 ℃ for 2 hours. The pH is subsequently adjusted to 4-5. The product was filtered off, washed with water and dried in vacuo.

Yield: 801mg (93% of theory)

HPLC (method 1): r_t＝4.5min

MS(ESI-pos)：m/z＝573(M+H)⁺

Example 15

{ 8-fluoro-2- [4- (3-methoxyphenyl) -1-piperazinyl ] -3- [ 2-methoxy-5- (trifluoromethyl) phenyl ] -3, 4-dihydro-4-quinazolinyl } acetic acid

After enantiomeric separation (method 11) of 500mg of the racemate (example 14), the crude product is purified by chromatography on silica gel and subsequently dissolved in 1N aqueous sodium hydroxide solution and extracted with diethyl ether. After acidification with 1N hydrochloric acid, the product was filtered off and dried in vacuo.

Yield: 105mg (21% of theory)

MS(ESI-pos)：m/z＝573(M+H)⁺

¹H-NMR(300MHz，DMSO-d₆)：δ[ppm]＝2.4-2.5(m，1H)；2.7-3.1(m，5H)；3.3-3.6(m，4H)；3.7(s，3H)；3.7-3.9(s_b，3H)；4.8-5.05(s_b，1H)；6.3-6.4(m，2H)；6.4-6.5(m，1H)；6.8-7.65(m，6H)；12.5(s_b，1H)。

Alternatively, the desired product was obtained by reacting the enantiomerically pure ester of example 43A according to general procedure [ H ]. Starting from 111g (0.19mol) of ester, 69g (63% of theory) of the desired product are obtained.

Example 16

{ 8-fluoro-2- [4- (3, 4-difluorophenyl) -1-piperazinyl ] -3- [ 2-methoxy-5- (trifluoromethyl) phenyl ] -3, 4-dihydro-4-quinazolinyl } acetic acid

881mg (1.49mmol) of methyl { 8-fluoro-2- [4- (3, 4-difluorophenyl) -1-piperazinyl ] -3- [ 2-methoxy-5- (trifluoromethyl) phenyl ] -3, 4-dihydro-4-quinazolinyl } acetate (example 32A) and 178mg (4.46mmo1) sodium hydroxide in 40ml dioxane were stirred at 50 ℃ for 2 hours. After acidification with 1N hydrochloric acid, the product is filtered off with suction, washed with water and dried in vacuo.

Yield: 775mg (90% of theory)

HPLC (method 1): r_t＝4.5min

MS(ESI-pos)：m/z＝579(M+H)⁺

Example 17

{ 8-fluoro-2- [4- (3, 4-difluorophenyl) -1-piperazinyl ] -3- [ 2-methoxy-5- (trifluoromethyl) phenyl ] -3, 4-dihydro-4-quinazolinyl } acetic acid

After enantiomeric separation (method 12) of 500mg (0.86mmol) of the racemate (example 16), the crude product is purified by chromatography on silica gel (dichloromethane, dichloromethane/methanol 20: 1, 10: 1), dissolved in 1N aqueous sodium hydroxide solution and extracted with diethyl ether. The aqueous phase was adjusted to pH4-5 using 1N hydrochloric acid, and the product was filtered off, washed with water and dried in vacuo.

Yield: 86mg (17% of theory)

MS(ESI-pos)：m/z＝579(M+H)⁺

¹H-NMR(300MHz，DMSO-d₆)：δ[ppm]＝2.6-3.1(m，6H)；3.25-3.6(m，4H)；3.75(s_b，3H)；4.85(s_b，1H)；6.6-6.7(m，1H)；6.7-7.7(m，9H)；12.5(s_b，1H)。

Example 18

{ 8-fluoro-2- [4- (4-fluorophenyl) -1-piperazinyl ] -3- [ 2-methoxy-5- (trifluoromethyl) phenyl ] -3, 4-dihydro-4-quinazolinyl } acetic acid

15g (26.11mmol) of methyl { 8-fluoro-2- [4- (4-fluorophenyl) -1-piperazinyl ] -3- [ 2-methoxy-5- (trifluoromethyl) phenyl ] -3, 4-dihydro-4-quinazolinyl } acetate (example 30A) and 3.13g (78.32mmol) of sodium hydroxide are stirred in 800ml of dioxane at 50 ℃ for 4 hours. After removal of the solvent by distillation, the residue is dissolved in 500ml of water and acidified and the precipitate is filtered off with suction. The product was washed with water and dried in vacuo.

Yield: 14.5g (99% of theory)

HPLC (method 1): r_t＝4.5min

MS(ESI-pos)：m/z＝561(M+H)₊

Example 19

{ 8-fluoro-2- [4- (4-fluorophenyl) -1-piperazinyl ] -3- [ 2-methoxy-5- (trifluoromethyl) phenyl ] -3, 4-dihydro-4-quinazolinyl } acetic acid

14.2g (25.33mmol) of the racemate (example 18) are isolated (method 13). The crude product was dissolved in 250ml of 0.5N sodium hydroxide solution and subsequently purified by extraction with diethyl ether. After acidification of the aqueous phase with hydrochloric acid, the product was filtered off, washed with water and dried in vacuo.

Yield: 5.85g (41% of theory)

MS(ESI-pos)：m/z＝561(M+H)⁺

HPLC (method 1): r_t＝4.5min

¹H-NMR(400MHz，DMSO-d₆)：δ[ppm]＝2.6-3.0(m，6H)；3.3-3.6(m，4H)；3.6-4.0(s_b，3H)；4.8-5.2(s_b，1H)；6.7-7.75(m，10H)；12.2-12.8(s_b，1H)。

Alternatively, the desired product was obtained by reacting the enantiomerically pure ester of example 42A according to general procedure [ H ]. Starting from 120g (0.21mol) of ester, 96g (81% of theory) of the desired product are obtained.

Example 20

{ 8-fluoro-2- [4- (3-methylphenyl) -1-piperazinyl ] -3- [ 2-methoxy-5- (trifluoromethyl) phenyl ] -3, 4-dihydro-4-quinazolinyl } acetic acid

892mg (1.56mmol) of methyl { 8-fluoro-2- [4- (3-methylphenyl) -1-piperazinyl ] -3- [ 2-methoxy-5- (trifluoromethyl) phenyl ] -3, 4-dihydro-4-quinazolinyl } acetate (example 33A) and 187.6mg (4.69mmol) of sodium hydroxide are stirred in 40ml of dioxane at 50 ℃ for 2 hours. After removal of the solvent, the residue was taken up in water and adjusted to pH4-5 using 1N hydrochloric acid. The product was filtered off and then washed with water and dried in vacuo.

Yield: 788mg (91% of theory)

MS(ESI-pos)：m/z＝557(M+H)⁺

HPLC (method 6): r_t＝4.5min

Example 21

{ 8-fluoro-2- [4- (3-methylphenyl) -1-piperazinyl ] -3- [ 2-methoxy-5- (trifluoromethyl) phenyl ] -3, 4-dihydro-4-quinazolinyl } acetic acid

The separation of the enantiomers (method 13) is carried out using 500mg (0.9mmol) of the racemate (example 20). The crude product is then dissolved in 1N aqueous sodium hydroxide solution, the solution is extracted with diethyl ether and the aqueous phase is adjusted to pH4-5 using 1N hydrochloric acid. The product is filtered off with suction, washed with water and dried in vacuo.

Yield: 104mg (21% of theory)

MS(ESI-pos)：m/z＝557(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ[ppm]＝2.2(s_b，3H)；2.35-2.5(m，1H)；2.6-3.1(m，5H)；3.3-3.6(m，4H)；3.8(s_b，3H)；4.9(s_b，1H)；6.5-6.7(m，3H)；6.8-7.7(m，7H)；12.6(s_b，1H)。

Example 22

{ 8-fluoro-2- [4- (4-fluorophenyl) -1-piperazinyl ] -3- [ 6-methoxy-3-chlorophenyl ] -3, 4-dihydro-4-quinazolinyl } acetic acid hydrochloride

Starting from 621mg (1.15mmol) of the ester of example 29A, purification by preparative HPLC (method 5) and coevaporation with methanol/1N hydrochloric acid according to general procedure [ H ] gives 330mg (51% of theory) of the product.

HPLC (method 1): r_t＝4.58min

MS(ESI-pos)：m/z＝527.0(M+H-HCl)⁺

Example 23

{ 8-fluoro-2- [4- (4-fluorophenyl) -1-piperazinyl ] -3- [ 6-methoxy-3-chlorophenyl ] -3, 4-dihydro-4-quinazolinyl } acetic acid hydrochloride

Starting from 320mg (0.06mmol) of the racemate from example 22, the chromatographic enantiomers are separated (method 4) and the product is subsequently taken up in methanol/1N hydrochloric acid and the solvent is evaporated, giving 174mg (50% of theory) of the hydrochloride salt.

HPLC (method 1): r_t＝4.51min

MS(ESI-pos)：m/z＝527.1(M+H-HCl)⁺

¹H-NMR(400MHz，CD₃CN)：δ[ppm]＝7.29(dd，1H)；7.19-7.11(m，2H)；7.01-6.94(m，4H)；6.87-6.83(m，2H)；5.08(t，1H)；3.67(s，3H)；3.56(s，4H)；3.03-2.92(m，5H)；2.72(dd，1H)。

Example 24

{ 8-fluoro-2- [4- (3-fluorophenyl) -1-piperazinyl ] -3- [ 2-methoxy-5- (trifluoromethyl) phenyl ] -3, 4-dihydro-4-quinazolinyl } acetic acid

117mg (0.2mmol) of methyl { 8-fluoro-2- [4- (3-fluorophenyl) -1-piperazinyl ] -3- [ 2-methoxy-5- (trifluoromethyl) phenyl ] -3, 4-dihydro-4-quinazolinyl } acetate (example 34A) are mixed with 0.61ml of 1N aqueous sodium hydroxide in 15ml of dioxane, and the mixture is stirred at 50 ℃ for 3 hours. After removal of the solvent, the residue was taken up in water and the mixture was adjusted to pH3-4 using 1N hydrochloric acid. The precipitate is filtered off with suction, washed with water and dried in vacuo.

Yield: 76mg (67% of theory)

HPLC (method 1): r_t＝4.6min

MS(ESI-pos)：m/z＝561(M+H)⁺

Example 25

{ 8-fluoro-2- [4- (3-fluorophenyl) -1-piperazinyl ] -3- [ 2-methoxy-5- (trifluoromethyl) phenyl ] -3, 4-dihydro-4-quinazolinyl } acetic acid

52mg (0.09mmol) of the racemate (example 24) are separated into the enantiomers (method 13). The crude product is then purified by chromatography on silica gel (acetic acid, dichloromethane/methanol 10: 1) and dried in vacuo.

Yield: 12.3mg (24% of theory)

LC-MS (method 7): r_t＝2.50min

MS(ESI-pos)：m/z＝561(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ[ppm]＝2.35-2.5(m，1H)；2.7-3.1(m，5H)；3.3-3.6(m，4H)；3.8(s_b，3H)；4.8-4.9(m，1H)；6.45-6.6(m，1H)；6.6-6.7(m，2H)；6.8-6.9(m，2H)；6.98-7.1(m，1H)；7.1-7.6(m，4H)：12.4(s_b，1H)。

Examples 26 to 34 and 36 to 89 of table 2 can be prepared from the corresponding starting materials using the general procedures [ a ] to [ H ], and example 35 can be prepared as described later in table 2.

TABLE 2

Example 35

{2- [4- (4-fluorophenyl) piperazin-1-yl ] -8-hydroxy-3- [3- (trifluoromethyl) phenyl ] -3, 4-dihydroquinazolin-4-yl } acetic acid

80mg (0.14mmol) of methyl ether (example 89) are dissolved in 2ml of dichloromethane and a 1M solution of 0.41mmol of boron tribromide in dichloromethane is added at 0 ℃. The mixture was stirred at room temperature for 16 hours and an additional 0.82mmol boron tribromide solution was added, followed by an additional 1.23mmol after 24 hours. The reaction mixture was stirred at room temperature for 24 hours and then poured onto ice, and 5ml of 1N aqueous hydrochloric acid solution was added. The mixture was extracted with 25ml of ethyl acetate. The organic phase is washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, concentrated and purified by preparative HPLC. This gives 50mg (63% of theory) of product.

HPLC (method 1): r_t＝4.47min

MS(ESI-pos)：m/z＝529(M+H-HCl)⁺

Example 90

{ 7-hydroxycarbonyl-2- [4- (4-fluorophenyl) -1-piperazinyl ] -3- [5- (trifluoromethyl) phenyl ] -3, 4-dihydro-4-quinazolinyl } acetic acid

100mg (0.16mmol) of the ester of example 45A are suspended in semi-concentrated hydrochloric acid and the reaction mixture is stirred at 90 ℃ for 42 hours. After cooling, the mixture is adjusted to pH4 using 20% strength aqueous sodium hydroxide solution and the precipitate formed is filtered off, washed with water and dried in vacuo.

Yield: 64mg (66% of theory)

HPLC (method 1): r_t＝4.38min

MS(ESI-pos)：m/z＝557(M+H)⁺

Example 91

{6- (aminocarbonyl) -2- [4- (4-fluorophenyl) piperazin-1-yl ] -3- [3- (trifluoromethyl) phenyl ] -3, 4-dihydroquinazolin-4-yl } acetate hydrochloride

500mg (0.8mmol) of tert-butyl ester from example 49A were suspended with 8ml of a 4M solution of hydrogen chloride in dioxane and the reaction mixture was stirred at room temperature for 16 hours. The suspension was concentrated and dried in vacuo.

Yield: 564mg (99% of theory)

HPLC (method 1): r_t＝4.25min

MS(ESI-pos)：m/z＝556(M+H-HCl)⁺

¹H-NMR(300MHz，DMSO-d₆)：δ[ppm]＝12.94(brs，1H)；8.11(s，1H)；8.03-7.95(m，2H)；7.92-7.65(m，4H)；7.09-6.91(m，4H)；5.50(dd，1H)；4.38-4.12(m，4H)；3.17-3.06(m，5H)；2.81(dd，1H)。

B. Evaluation of physiological Activity

The in vitro effect of the compounds of the invention can be given in the following assays:

anti-HCMV (anti-human cytomegalovirus) cytopathic test

The test compounds were used as a 50 millimolar (mM) solution in dimethyl sulfoxide (DMSO). GanciclovirPhosphoformic acidAnd cidofovirUsed as reference compound. After in each case 2. mu.l of 50, 5, 0.5 and 0.05mM DMSO stock solutions were added to 98. mu.l of cell culture medium in rows A-H for replication assays, 1: 2 dilutions were made up to row 11 of 96 well plates using 50. mu.l of medium. The wells in rows 1 and 12 each contain 50 μ l of medium. 150. mu.l of 1X 10⁴Cells (human foreskin fibroblast [ NHDF)]) The suspension of (a) was pipetted into each well (row 1 ═ cell control) and in rows 2-12 HCMV-infected and uninfected NHDF cells (m.o.i.: 0.001-0.002) were added, i.e. 1-2 infected cells/1000 uninfected cells. Row 12 (no material) was used as a virus control group. The final assay concentration was 250-0.0005. mu.M. The plates were placed at 37 deg.C/5% CO₂Incubate for 6 days until all cells are infected in the virus control group (100% cytopathic effect [ CPE ]]). The wells were then fixed and stained by adding a mixture of formalin and Giemsa dye (30 minutes), washed with double distilled water and dried in a drying oven at 50 degrees celsius. The plates were then visually evaluated using an overhead microscope (plane Multiplier from Technomara).

The following data can be obtained from the test panels:

CC₅₀(NHDF) ═ concentration of substance at which no cytopathic effect was evident on cells by comparison with untreated cell controls, μ M;

EC₅₀(HCMV) ═ substance concentration at which CPE (cytopathic effect) is 50% inhibited, pM, compared to untreated virus controls;

SI (Selectivity index) ═ CC₅₀(NHDF)/EC₅₀(HCMV)。

Representative in vitro data for the effect of the compounds of the invention are given in table a:

TABLE A

Example No. 2	NHDFCC[μM]	HCMVEC[μM]	SIHCMV
				2	12	0.016	750
9	15	0.02	750
				15	31	0.002	15500
19	17	0.002	8947
				23	24	0.002	12632
29	47	0.07	671

The suitability of the compounds of the invention for the treatment of HCMV infection can be given in the following animal models:

HCMV Xenograft-Gelfoam model (model)

Animals:

female immunodeficient mice at 3-4 weeks (16-18g), Fox Chase SCID or Fox Chase SCID-NOD or SCID-biege were purchased from commercial breeders (Taconic M + B, Jackson USA). Animals were housed in isolators under sterile conditions (including bedding and feed).

And (3) virus growth:

human Cytomegalovirus (HCMV), Davis or AD169 strains grow in vitro on human embryonic foreskin fibroblasts (NHDF cells). After NHDF cells have been infected with multiple infections (m.o.i.)0.01-0.03, virus-infected cells are harvested after 5-10 days and stored at 40 degrees celsius in the presence of Minimal Essential Medium (MEM), 10% Fetal Calf Serum (FCS) with 10% DMSO. After serial 10-step dilutions of virus-infected cells, titer values were determined for 24-well plates of confluent NHDF cells after staining with neutral red vital.

Preparation, transplantation, treatment and evaluation of sponges:

collagen sponge (Gelfoam) of 1X 1cm size；Peasel&Lorey, Inc., order No. 407534; k.t. chong et al, abstract of antimicrobial and chemotherapy cross-science conference at 39, 1999, p.439) was initially wetted with Phosphate Buffered Saline (PBS), entrained air bubbles were removed by degassing and subsequently stored in MEM + 10% FCS. 1X 10⁶Virally infected NHDF cells (infected with HCMV Davis or HCMV AD169 m.o.i. ═ 0.03) were isolated 3 hours after infection and wet sponges were added at 20 μ l mem, 10% FCS per drop. After about 16 hours, the sponge loaded with infected cells was incubated with 25 μ l PBS/0.1% BSA/1mM DTT with 5ng/μ l basic fibroblast growth factor (bFGF). For transplantation, immunodeficient mice were anesthetized with either avertin or ketamine/xylazine/azin mixtures, the fur on the back was removed using a razor, the epidermis was opened 1-2cm, the load was removed and the wet sponge was transplanted under the back skin. The surgical wound was sealed with tissue glue. The mice can be treated for the first time 6 hours after transplantation (one treatment on the day of surgery). On subsequent days, rats were orally administered three times a day (7.00 and 14.00 and 19.00) and two times a day (8.00 and 19.00) over a period of 8 days18.00 o 'clock) or once a day (14.00 o' clock) with a substance. The daily dose is, for example, 3 or 10 or 30 or 60 or 100mg/kg body weight, the administration volume is 10ml/kg body weight. The substances are formulated in the form of a suspension of either Tylose at a concentration of 0.5% or Tylose at a concentration of 0.5% with 2% DMSO. Animals were painlessly slaughtered and sponges removed 9 days after transplantation and 16 hours after the last substance administration. Virus infected cells were released from the sponge by collagenase digestion (330U/1.5ml) and stored in the presence of MEM, 10% fetal bovine serum, 10% DMSO at-140 degrees celsius. Evaluation was performed after serial 10-step dilutions of virus-infected cells: titration values on 24-well plates of confluent NHDF cells were determined after vital staining with neutral red. The number of infected cells or infected virus particles was determined in substance treatment compared to placebo treated control groups (infection center analysis).

CYP inhibition assay

To investigate the mechanistic (irreversible) inhibition of CYP3A4, different concentrations of test substance were incubated at 37 ℃ with human liver microsomes (2mg/ml microsome protein) in potassium phosphate buffer (pH7.4) with the addition of NADPH-generating system (NADP +, glucose-6-phosphate dehydrogenase). At various time points, 2 aliquots were removed from the culture.

The first aliquot was incubated in a new incubation solution (phosphate buffer, NADPH-producing system and 10. mu.M midazolam) at 37 degrees Celsius (1: 50) for another 10 min. The incubation was then stopped using acetonitrile on ice, the protein was pelleted at 15000g in a centrifuge and the supernatant was analyzed for 1' -hydroxymidazolam formation using standard HPLC/MS methods.

The second aliquot was stopped using acetonitrile on ice and the remaining test substance was analyzed using HPLC/UV/MS.

From these two sets of analytical data, the parameters (k) typical for irreversible inhibition were determined_inact，K_iAnd distribution ratio r), and using these data to evaluate the test substanceQualitative (see a.madan et al, a.d.rodrigues (editions) "drug-drug interactions", "drug and drug science", vol.116, ISBN 0-8247-0283.2, Marcel Dekker inc., New York, 2002).

C. Embodiments of the pharmaceutical composition

The compounds of the invention can be converted into pharmaceutical preparations in the following manner:

and (3) tablet preparation:

consists of the following components:

100mg of the compound according to example 1, 50mg of lactose (monohydrate), 50mg of corn starch (native), 10mg of polyvinylpyrrolidone (PVP 25) (from BASF, Ludwigshafen, Germany) and 2mg of magnesium stearate.

Tablet weight 212 mg. The diameter is 8mm, and the curvature radius is 12 mm.

Production:

the mixture of active ingredient, lactose and starch was granulated using a 5% strength solution (m/m) of PVP in water. The granules were then dried and mixed with magnesium stearate for 5 min. The mixture is compressed using a conventional tablet press (see above for the form of tablets). The standard for the compressive force for compression is 15 kN.

Orally administrable suspensions:

consists of the following components:

1000mg of the compound of example 1, 1000mg of ethanol (96%), 400mg of Rhodigel (xanthan gum from FMC, Pennsylvania, USA) and 99g of water.

10ml of an oral suspension corresponds to a single dose of 100mg of a compound of the invention.

Production:

rhodigel is suspended in ethanol and the active ingredient is added to the suspension. Water was added with stirring. The mixture was stirred for about 6h until swelling of the Rhodigel was complete.

Intravenously administrable solutions:

consists of the following components:

10-500mg of the compound of example 1, 15g of polyethylene glycol 400 and 250g of water are used for injection.

Production:

the compound of example 1 was dissolved in water with polyethylene glycol 400 under stirring. The solution was sterile filtered (pore diameter 0.22 μm) and dispensed under sterile conditions into heat sterilized infusion bottles. The latter is sealed with an infusion plug and a trim cover.

Claims (21)

1. A compound of the formula:

wherein

Ar represents C which may be substituted by 1 to 3 substituents₆-C₁₄Aryl, wherein the substituents are independently of one another selected from C₁-C₆Alkyl radical, C₁-C₆Alkoxy, formyl, carboxy, C₁-C₆Alkylcarbonyl group, C₁-C₆Alkoxycarbonyl, trifluoromethyl, halogen, cyano, hydroxy, amino, C₁-C₆Alkylamino, aminocarbonyl and nitro groups,

wherein the alkyl group may be substituted with 1 to 3 substituents, wherein the substituents are independently from each other selected from halogen, amino, C₁-C₆Alkylamino, hydroxy and C₆-C₁₄An aryl group, a heteroaryl group,

or two substituents on the aryl radical together with the carbon atom to which they are attached form a 1, 3-dioxolane, cyclopentane or cyclohexane ring, and the third substituent, if present, is independently selected from C₁-C₆Alkyl radical, C₁-C₆Alkoxy, formyl, carboxyl, C₁-C₆Alkylcarbonyl group, C₁-C₆Alkoxycarbonyl, trifluoromethyl, halogen, cyano, hydroxy, amino, C₁-C₆Alkylamino, aminocarbonyl and nitro groups,

wherein the alkyl group may be substituted with 1 to 3 substituents, wherein the substituents are independently from each other selected from halogen, amino, C₁-C₆Alkylamino, hydroxy and C₆-C₁₄An aryl group, a heteroaryl group,

R¹represents hydrogen, amino, C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₁-C₆Alkylamino radical, C₁-C₆Alkylthio, cyano, halogen, nitro or trifluoromethyl,

R²represents hydrogen, C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₁-C₆Alkylthio, cyano, halogen, nitro or trifluoromethyl,

R³represents amino, C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₁-C₆Alkylamino radical, C₁-C₆Alkylthio, cyano, halogen, nitro, trifluoromethyl, C₁-C₆Alkylsulfonyl or C₁-C₆An alkylaminosulfonyl group, an alkyl amino group,

or

Radical R¹、R²And R³One represents hydrogen and C₁-C₆Alkyl radical, C₁-C₆Alkoxy, cyano, halogen, nitro or trifluoromethyl, and the other two together with the carbon atom to which they are attached form a 1, 3-dioxolane, cyclopentane-or cyclohexane ring,

R⁴represents hydrogen or C₁-C₆An alkyl group, a carboxyl group,

R⁵represents hydrogen or C₁-C₆An alkyl group, a carboxyl group,

or

Radicals R in the piperazine ring⁴And R⁵Attached to the carbon atom in the 2, 5-or 3, 6-position and forming a methylene bridge optionally substituted with 1 or 2 methyl groups,

R⁶is represented by C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₁-C₆Alkylthio, formyl, carboxy, aminocarbonyl, C₁-C₆Alkylcarbonyl group, C₁-C₆Alkoxycarbonyl, trifluoromethyl, halogen, cyano, hydroxy or nitro,

R⁷represents hydrogen, C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₁-C₆Alkylthio, formyl, carboxy, C₁-C₆Alkylcarbonyl group, C₁-C₆Alkoxycarbonyl, trifluoromethyl, halogen, cyano, hydroxy or nitro,

and

R⁸represents hydrogen, C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₁-C₆Alkylthio, formyl, carboxy, C₁-C₆Alkylcarbonyl group, C₁-C₆Alkoxycarbonyl, trifluoromethyl, halogen, cyano, hydroxy or nitro.

2. A compound according to claim 1, characterized in that:

ar represents phenyl which may be substituted by 1 to 3 substituents, wherein the substituents are independently from each other selected from C₁-C₆Alkyl radical, C₁-C₆Alkoxy, carboxyl, C₁-C₆-alkylcarbonyl group, C₁-C₆Alkoxycarbonyl, trifluoromethyl, fluoro, chloro, bromo, cyano, hydroxy, amino, C₁-C₆-an alkylamino group and a nitro group,

or two substituents on the phenyl radical together with the carbon atom to which they are attached form a 1, 3-dioxolane and the third substituent, if present, is independently selected from C₁-C₆Alkyl radical, C₁-C₆Alkoxy, carboxyl, C₁-C₆-alkylcarbonyl group, C₁-C₆Alkoxycarbonyl, trifluoromethyl, fluoro, chloro, bromo, cyano, hydroxy, amino, C₁-C₆-an alkylamino group and a nitro group,

R¹represents hydrogen, C₁-C₃Alkyl radical, C₁-C₃-alkoxy, C₁-C₃-alkylthio, fluoro or chloro,

R²represents hydrogen, C₁-C₃Alkyl radical, C₁-C₃-alkoxy, C₁-C₃-alkylthio, fluoro or chloro,

R³is represented by C₁-C₄Alkyl, cyano, fluoro, chloro, nitro, trifluoromethyl or C₁-C₃-an alkylsulfonyl group,

or a radical R¹、R²And R³One represents hydrogen and C₁-C₃Alkyl radical, C₁-C₃-alkoxy, cyano, halogen, nitro or trifluoromethyl, and the other two together with the carbon atom to which they are attached form a cyclopentane or cyclohexane ring,

R⁴represents hydrogen or a methyl group,

R⁵represents hydrogen, and is represented by the formula,

R⁶is represented by C₁-C₃Alkyl radical, C₁-C₃-alkoxy, carboxyl, aminocarbonyl, trifluoromethyl, fluorine, chlorine, cyano, hydroxyl or nitro,

R⁷represents hydrogen, C₁-C₃Alkyl radical, C₁-C₃-alkanesOxy, fluoro, chloro, cyano or hydroxy,

and

R⁸represents hydrogen, C₁-C₃Alkyl radical, C₁-C₃-alkoxy, fluoro, chloro, cyano or hydroxy.

3. A compound according to claim 1, characterized in that:

ar represents phenyl which may be substituted by 1 or 2 substituents, wherein the substituents are independently from each other selected from the group consisting of methyl, methoxy, fluoro and chloro,

R¹represents hydrogen, methyl, methoxy, methylthio, fluoro or chloro,

R²represents hydrogen, and is represented by the formula,

R³represents methyl, isopropyl, tert-butyl, cyano, fluoro, chloro, nitro or trifluoromethyl,

R⁴represents hydrogen, and is represented by the formula,

R⁵represents hydrogen, and is represented by the formula,

R⁶represents aminocarbonyl, fluorine, chlorine, cyano or hydroxy,

R⁷represents hydrogen, and

R⁸represents hydrogen, fluorine or chlorine.

4. A compound according to claim 1, characterized in that R¹Represents hydrogen, methyl, methoxy or fluorine.

5. A compound according to one of claims 1 to 4, characterized in that R¹Represents a methoxy group.

6. A compound according to one of claims 1 to 4, characterized in that R¹Attached to the phenyl ring at a position adjacent to the point of attachment of the phenyl ring to the nitrogen atom of the dihydroquinazoline.

7. A compound according to one of claims 1, 2 and 4, characterized in thatCharacterized by R²Represents hydrogen.

8. A compound according to one of claims 1 to 4, characterized in that R³Represents trifluoromethyl, chlorine, methyl, isopropyl or tert-butyl.

9. A compound according to one of claims 1 to 4, characterized in that R³Represents trifluoromethyl, chlorine or methyl.

10. A compound according to one of claims 1 to 4, characterized in that R¹Attached to the phenyl ring by a position adjacent to the point of attachment of the phenyl ring to the nitrogen atom of the dihydroquinazoline, R³The point of attachment to the nitrogen atom of the dihydroquinazoline through the phenyl ring is meta and is to R¹The opposite position is attached to the phenyl ring.

11. A compound according to one of claims 1, 2 and 4, characterized in that R⁴And R⁵Represents hydrogen.

12. A compound according to one of claims 1 to 4, characterized in that R⁶Represents fluorine.

13. A compound according to one of claims 1, 2 and 4, characterized in that R⁷Represents hydrogen.

14. A compound according to one of claims 1, 2 and 4, characterized in that R⁸Represents hydrogen, methyl or fluorine.

15. A compound according to one of claims 1, 2 and 4, characterized in that Ar represents phenyl which may be substituted by 1 or 2 substituents, wherein the substituents are independently from each other selected from the group consisting of methyl, methoxy, fluoro and chloro.

16. A process for the preparation of a compound of formula (I) according to claim 1, characterized in that a compound of formula:

wherein Ar, R¹、R²、R³、R⁴、R⁵、R⁶、R⁷And R⁸As defined in claim 1, R⁹Is represented by C₁-C₆An alkyl group.

17. The method according to claim 16, wherein said R is⁹Represents methyl or ethyl or tert-butyl.

18. A medicament comprising a compound according to any one of claims 1 to 15 in combination with inert, non-toxic pharmaceutically acceptable auxiliary substances.

19. Use of a compound according to one of claims 1 to 15 for the preparation of a medicament for the treatment and/or prophylaxis of viral infections.

20. Use according to claim 19, characterized in that the viral infection is an infection with human cytomegalovirus or another representative herpes virus.

21. Use of an antiviral effective amount of at least one compound according to one of claims 1 to 15, a medicament according to claim 18 or a medicament obtained according to claim 19 or 20 for the preparation of a medicament for controlling viral infections in humans and animals.