# Patent

## Title
Metabotropic glutamate receptor antagonists

## Abstract

The present invention concerns compounds of formula. In a preferable embodiment, X represents O; R1 represents C1-6alkyl; cycloC3-12alkyl or (cycloC3-12alkyl)C1-6alkyl, wherein one or more hydrogen atoms in a C1-6alkyl-moiety or in a cycloC3-12alkyl-moiety optionally may be replaced by C1-6alkyloxy, aryl, halo or thienyl; R2 represents hydrogen; halo; C1-6alkyl or amino; R3 and R4 each independently represent hydrogen or C1-6alkyl; or R2 and R3 may be taken together to form —R2—R3—, which represents a bivalent radical of formula -Z4-CH2—CH2—CH2— or -Z4-CH2—CH2— with Z4 being O or NR11 wherein R11 is C1-6alkyl; and wherein each bivalent radical is optionally substituted with C1-6alkyl; or R3 and R4 may be taken together to form a bivalent radical of formula —CH2—CH2—CH2—CH2—; R5 represents hydrogen; Y represents O; and aryl represents phenyl optionally substituted with halo. The invention also relates to the use of a compound according to the invention as a medicament and in the manufacture of a medicament for treating or preventing glutamate-induced diseases of the central nervous system, as well as formulations comprising such a compound and processes for preparing such a compound.

## Background
CROSS REFERENCE TO RELATED APPLICATIONS
This application is a divisional of application Ser. No. 10/381,987, now allowed, which is a National Stage application under 35 U.S.C. §371 of PCT/EP01/11135 filed Sep. 25, 2001, which claims priority from EP 00203419.7, filed Oct. 2, 2000.


The present invention is concerned with quinoline and quinolinone derivatives showing metabotropic glutamate receptor antagonistic activity and their preparation; it further relates to compositions comprising them, as well as their use as a medicine.
The neurotransmitter glutamate is considered to be the major excitatory neurotransmitter in the mammalian central nervous system. The binding of this neurotransmitter to metabotropic glutamate receptors (mGluRs), which are a subfamily of the G-protein-coupled receptors and which comprise 8 distinct subtypes of mGluRs, namely mGluR1 through mGluR8, activates a variety of intracellular second messenger systems. The mGluRs can be divided into 3 groups based on amino acid sequence homology, the second messenger system utilized by the receptors and the pharmacological characteristics. Group I mGluRs, which comprises mGluR subtype 1 and 5, couple to phospholipase C and their activation leads to intracellular calcium-ion mobilization. Group II mGluRs (mGluR2 and 3) and group III mGluRs (mGluR4, 6, 7 and 8) couple to adenyl cyclase and their activation causes a reduction in second messenger cAMP and as such a dampening of the neuronal activity. Treatment with Group I mGluR antagonists has been shown to translate in the presynapse into a reduced release of neurotransmitter glutamate and to decrease the glutamate-mediated neuronal excitation via postsynaptic mechanisms. Since a variety of pathophysiological processes and disease states affecting the central nervous system are thought to be due to excessive glutamate induced excitation of the central nervous system neurons, Group I mGluR antagonists could be therapeutically beneficial in the treatment of central nervous system diseases.
WO 99/26927 discloses antagonists of Group I mGlu receptors for treating neurological diseases and disorders, based—among others—on a quinoline structure.
WO 99/03822 discloses bicyclic metabotropic glutamate receptor ligands, none of them based on a quinoline or quinolinone structure.
The present invention concerns compounds of formula




an N-oxide form, a pharmaceutically acceptable addition salt, a quatenary amine and a stereochemically isomeric form thereof, wherein

    X represents O; C(R6)2 with R6 being hydrogen, aryl or C1-6alkyl optionally substituted with amino or mono- or di(C1-6alkyl)amino; S or N—R7 with R7 being amino or hydroxy;
    R1 represents C1-6alkyl; aryl; thienyl; quinolinyl; cycloC3-12alkyl or (cycloC3-12alkyl)C1-6alkyl, wherein the cycloC3-12alkyl moiety optionally may contain a double bond and wherein one carbon atom in the cycloC3-12alkyl moiety may be replaced by an oxygen atom or an NR8-moiety with R8 being hydrogen, benzyl or C1-6alkyloxycarbonyl; wherein one or more hydrogen atoms in a C1-6alkyl-moiety or in a cycloC3-12alkyl-moiety optionally may be replaced by C1-6alkyl, hydroxyC1-6alkyl, haloC1-6alkyl, aminoC1-6alkyl, hydroxy, C1-6alkyloxy, arylC1-6alkyloxy, halo, C1-6alkyloxycarbonyl, aryl, amino, mono- or di(C1-6alkyl)amino, C1-6alkyloxycarbonylamino, halo, piperazinyl, pyridinyl, morpholinyl, thienyl or a bivalent radical of formula —O—, —O—CH2—O or —O—CH2—CH2—O—;
    
        or a radical of formula (a-1)
    
    






    
    
        
        
            wherein
            
                Z1 is a single covalent bond, O, NH or CH2;
                Z2 is a single covalent bond, O, NH or CH2;
                n is an integer of 0, 1, 2 or 3;
                and wherein each hydrogen atom in the phenyl ring independently may optionally be replaced by halo, hydroxy, C1-6alkyl, C1-6alkyloxy or hydroxyC1-6alkyl;
            
            
        
        
    
    
    or X and R1 may be taken together with the carbon atom to which X and R1 are attached to form a radical of formula (b-1), (b-2) or (b-3);






    R2 represents hydrogen; halo; cyano; C1-6alkyl; C1-6alkyloxy; C1-6alkylthio; C1-6alkylcarbonyl; C1-6alkyloxycarbonyl; C1-6alkylcarbonyloxyC1-6alkyl; C2-6alkenyl; hydroxyC2-6alkenyl; C2-6alkynyl; hydroxyC2-6alkynyl; tri(C1-6alkyl)silaneC2-6alkynyl; amino; mono- or di(C1-6alkyl)amino; mono- or di(C1-6alkyloxyC1-6alkyl)amino; mono- or di(C1-6alkylthioC1-6alkyl)amino; aryl; arylC1-6alkyl; arylC2-6alkynyl; C1-6alkyloxyC1-6alkylaminoC1-6alkyl; aminocarbonyl optionally substituted with C1-6alkyl, C1-6alkyloxyC1-6alkyl, C1-6alkyloxycarbonylC1-6alkyl or pyridinylC1-6alkyl;
    
        a heterocycle selected from thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, isothiazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, piperidinyl and piperazinyl, optionally N-substituted with C1-6alkyloxyC1-6alkyl, morpholinyl, thiomorpholinyl, dioxanyl or dithianyl;
        a radical —NH—C(═O)R9 wherein R9 represents
        
            C1-6alkyl optionally substituted with cycloC3-12alkyl, C1-6alkyloxy, C1-6alkyloxycarbonyl, aryl, aryloxy, thienyl, pyridinyl, mono- or di(C1-6alkyl)amino, C1-6alkylthio, benzylthio, pyridinylthio or pyrimidinylthio;
            cycloC3-12alkyl; cyclohexenyl; amino; arylcycloC3-12alkylamino; mono-or-di(C1-6alkyl )amino; mono- or di(C1-6alkyloxycarbonylC1-6alkyl)amino; mono- or di(C1-6alkyloxycarbonyl)amino; mono-or di(C2-6alkenyl)amino; mono- or di(arylC1-6alkyl)amino; mono- or diarylamino; arylC2-6alkenyl; furanylC2-6alkenyl; piperididinyl; piperazinyl; indolyl; furyl; benzofuryl; terahydrofuryl; indenyl; adamantyl; pyridinyl; pyrazinyl; aryl; arylC1-6alkylthio or a radical of formula (a-1);
        
        
        a sulfonamid —NH—SO2—R10 wherein R10 represents C1-6alkyl, mono- or poly haloC1-6alkyl, arylC1-6alkyl, arylC2-6alkenyl, aryl, quinolinyl, isoxazolyl or di(C1-6alkyl)amino;
    
    
    R3 and R4 each independently represent hydrogen; halo; hydroxy; cyano; C1-6alkyl; C1-6alkyloxy; C1-6alkyloxyC1-6alkyl; C1-6alkylcarbonyl; C1-6alkyloxycarbonyl; C2-6alkenyl; hydroxyC2-6alkenyl; C2-6alkynyl; hydroxyC2-6alkynyl; tri(C1-6alkyl)silaneC2-6alkynyl; amino; mono- or di(C1-6alkyl)amino; mono- or di(C1-6alkyloxyC1-6alkyl)amino; mono- or di(C1-6alkylthioC1-6alkyl)amino; aryl; morpholinylC1-6alkyl or piperidinylC1-6alkyl; or
    R2 and R3 may be taken together to form —R2—R3—, which represents a bivalent radical of formula —(CH2)3—, —(CH2)4—, —(CH2)5—, —(CH2)6—, —CH═CH—CH═CH—, -Z4-CH═CH—, —CH═CH-Z4-, -Z4-CH2—CH2—CH2—, —CH2-Z4-CH2—CH2—, —CH2—CH2-Z4-CH2—, —CH2—CH2—CH2-Z4-, -Z4-CH2—CH2—, —CH2-Z4-CH2— or —CH2—CH2-Z4-, with Z4 being O, S, SO2 or NR11 wherein R11 is hydrogen, C1-6alkyl, benzyl or C1-6alkyloxycarbonyl; and wherein each bivalent radical is optionally substituted with C1-6alkyl.
    or R3 and R4 may be taken together to form a bivalent radical of formula —CH═CH—CH═CH— or —CH2—CH2—CH2—CH2—;
    R5 represents hydrogen; cycloC3-12alkyl; piperidinyl; oxo-thienyl; tetrahydrothienyl, arylC1-6alkyl; C1-6alkyloxyC1-6alkyl; C1-6alkyloxycarbonylC1-6alkyl or C1-6alkyl optionally substituted with a radical C(═O)NRxRy, in which Rx and Ry, each independently are hydrogen, cycloC3-12alkyl, C2-6alkynyl or C1-6alkyl optionally substituted with cyano, C1-6alkyloxy, C1-6alkyloxycarbonyl, furanyl, pyrrolidinyl, benzylthio, pyridinyl, pyrrolyl or thienyl;
    Y represents O or S;
    or Y and R5 may be taken together to form ═Y—R5— which represents a radical of formula

—CH═N—N═  (c-1);

—N═N—N═  (c-2); or

—N—CH═CH—  (c-3);

    aryl represents phenyl or naphthyl optionally substituted with one or more substituents selected from halo, hydroxy, C1-6alkyl, C1-6alkyloxy, phenyloxy, nitro, amino, thio, C1-6alkylthio, haloC1-6alkyl, polyhaloC1-6alkyl, polyhaloC1-6alkyloxy, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl, aminoC1-6alkyl, mono- or di(C1-6alkyl)amino; mono- or di(C1-6alkyl)aminoC1-6alkyl, cyano, —CO—R12, —CO—OR13, —NR13SO2R12, —SO2—NR13R14, —NR13C(O)R12, —C(O)NR13R14, —SOR12, —SO2R12; wherein each R12, R13 and R14 independently represent C1-6alkyl; cycloC3-6alkyl; phenyl; phenyl substituted with halo, hydroxy, C1-6alkyl, C1-6alkyloxy, haloC1-6alkyl, polyhaloC1-6alkyl, furanyl, thienyl, pyrrolyl, imidazolyl, thiazolyl or oxazolyl;

and when the R1—C(═X) moiety is linked to another position than the 7 or 8 position, then said 7 and 8 position may be substituted with R15 and R16 wherein either one or both of R15 and R16 represents C1-6alkyl, C1-6alkyloxy or R15 and R16 taken together may form a bivalent radical of formula —CH═CH—CH═CH—.



As used in the foregoing definitions and hereinafter C1-6alkyl as a group or part of a group encompasses the straight and branched chain saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, pentyl or hexyl; C2-6alkenyl as a group or part of a group encompasses the straight and branched chain hydrocarbon radicals having from 2 to 6 carbon atoms and having a double bond such as ethenyl, propenyl, butenyl, pentenyl, hexenyl, 3-methylbutenyl and the like; C2-6alkynyl as a group or part of a group defines straight or branched chain hydrocarbon radicals having from 2 to 6 carbon atoms and having a triple bond such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, 3-methylbutynyl and the like; cycloC3-6alkyl encompasses monocyclic alkyl ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; cycloC3-12alkyl encompasses mono-, bi- or tricyclic alkyl ring structures and is generic to for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornanyl, adamantyl.
The term halo is generic to fluoro, chloro, bromo and iodo. As used in the foregoing and hereinafter, polyhaloC1-6alkyl as a group or part of a group is defined as mono- or polyhalosubstituted C1-6alkyl, in particular methyl with one or more fluoro atoms, for example, difluoromethyl or trifluoromethyl. In case more than one halogen atoms are attached to an alkyl group within the definition of polyhaloC1-6alkyl, they may be the same or different.
When any variable, e.g. aryl, occurs more than one time in any constituent, each definition is independent.
When any bond is drawn into a ring structure, it means that the corresponding substituent may be linked to any atom of said ring structure. This means for instance that the R1—C(═X) moiety may be linked to the quinoline or quinolinone moiety in position 5, 6, 7, 8 but also position 3 or position 4.
For therapeutic use, salts of the compounds of formula (I-A) and (I-B) are those wherein the counterion is pharmaceutically acceptable. However, salts of acids and bases which are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not are included within the ambit of the present invention.
The pharmaceutically acceptable addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid addition salt forms which the compounds of formula (I-A) and (I-B) are able to form. The latter can conveniently be obtained by treating the base form with such appropriate acids as inorganic acids, for example, hydrohalic acids, e.g. hydrochloric, hydrobromic and the like; sulfuric acid; nitric acid; phosphoric acid and the like; or organic acids, for example, acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, 2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids. Conversely the salt form can be converted by treatment with alkali into the free base form.
The compounds of formula (I-A) and (I-B) containing acidic protons may be converted into their therapeutically active non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases. Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. primary, secondary and tertiary aliphatic and aromatic amines such as methylamine, ethylamine, propylamine, isopropylamine, the four butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyridine, quinoline and isoquinoline, the benzathine, N-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)-1,3-propanediol, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like. Conversely the salt form can be converted by treatment with acid into the free acid form.
The term addition salt also comprises the hydrates and solvent addition forms which the compounds of formula (I-A) and (I-B) are able to form. Examples of such forms are e.g. hydrates, alcoholates and the like.
The term “quaternary amine” as used hereinbefore defines the quaternary ammonium salts which the compounds of formula (I-A) and (I-B) are able to form by reaction between a basic nitrogen of a compound of formula (I-A) or (I-B) and an appropriate quaternizing agent, such as, for example, an optionally substituted alkylhalide, arylhalide or arylalkylhalide, e.g. methyliodide or benzyliodide. Other reactants with good leaving groups may also be used, such as alkyl trifluoromethanesulfonates, alkyl methanesulfonates, and alkyl p-toluenesulfonates. A quaternary amine has a positively charged nitrogen. Pharmaceutically acceptable counterions include chloro, bromo, iodo, trifluoroacetate and acetate. The counterion of choice can be introduced using ion exchange resins.
It will be appreciated that some of the compounds of formula (I-A) and (I-B) and their N-oxides, salts, quaternary amines and stereochemically isomeric forms may contain one or more centers of chirality and exist as stereochemically isomeric forms.
The term “stereochemically isomeric forms” as used hereinbefore defines all the possible stereoisomeric forms which the compounds of formula (I-A) and (I-B), and their N-oxides, salts, quaternary amines or physiologically functional derivatives may possess. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereoisomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure as well as each of the individual isomeric forms of formula (I-A) and (I-B) and their N-oxides, salts, solvates or quaternary amines substantially free, i.e. associated with less than 10%, preferably less than 5%, in particular less than 2% and most preferably less than 1% of the other isomers. Stereochemically isomeric forms of the compounds of formula (I-A) and (I-B) are obviously intended to be embraced within the scope of the present invention. The same applies to the intermediates as described herein, used to prepare end products of formula (I-A) and (I-B).
The terms cis and trans are used herein in accordance with Chemical Abstracts nomenclature.
In some compounds of formula (I-A) and (I-B) and in the intermediates used in their preparation, the absolute stereochemical configuration has not been determined. In these cases, the stereoisomeric form which was first isolated is designated as “A” and the second as “B”, without further reference to the actual stereochemical configuration. However, said “A” and “B” stereoisomeric forms can be unambiguously characterized by physicochemical characteristics such as their optical rotation in case “A” and “B” have an enantiomeric relationship. A person skilled in the art is able to determine the absolute configuration of such compounds using art-known methods such as, for example, X-ray diffraction. In case “A” and “B” are stereoisomeric mixtures, they can be further separated whereby the respective first fractions isolated are designated “A1” and “B1” and the second as “A2” and “B2”, without further reference to the actual stereochemical configuration.
The N-oxide forms of the present compounds are meant to comprise the compounds of formula (I-A) and (I-B) wherein one or several nitrogen atoms are oxidized to the so-called N-oxide.
Some of the compounds of formula (I-A) and (I-B) may also exist in their tautomeric form. Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention.
Whenever used hereinafter, the term “compounds of formula (I-A) and (I-B)” is meant to also include their N-oxide forms, their salts, their quaternary amines and their stereochemically isomeric forms. Of special interest are those compounds of formula (I-A) and (I-B) which are stereochemically pure.
An interesting group of compounds are those compounds of formula (I-A) and (I-B) wherein

    X represents O; C(R6)2 with R6 being hydrogen or aryl; or N—R7 with R7 being amino or hydroxy;
    R1 represents C1-6alkyl, aryl; thienyl; quinolinyl; cycloC3-12alkyl or (cycloC3-12alkyl)C1-6alkyl, wherein the cycloC3-12alkyl moiety optionally may contain a double bond and wherein one carbon atom in the cycloC3-12alkyl moiety may be replaced by an oxygen atom or an NR8-moiety with R8 being benzyl or C1-6alkyloxycarbonyl; wherein one or more hydrogen atoms in a C1-6alkyl-moiety or in a cycloC3-12alkyl-moiety optionally may be replaced by C1-6alkyl, haloC1-6alkyl, hydroxy, C1-6allyloxy, arylC1-6alkyloxy, halo, aryl, mono- or di(C1-6alkyl)amino, C1-6alkyloxycarbonylamino, halo, piperazinyl, pyridinyl, morpholinyl, thienyl or a bivalent radical of formula —O— or —O—CH2—CH2—O—;
    
        or a radical of formula (a-1)
    
    






    
    
        
        
            wherein
            
                Z1 is a single covalent bond, O or CH2;
                Z2 is a single covalent bond, O or CH2;
                n is an integer of 0, 1, or 2;
                and wherein each hydrogen atom in the phenyl ring independently may optionally be replaced by halo or hydroxy;
            
            
        
        
        or X and R1 may be taken together with the carbon atom to which X and R1 are attached to form a radical of formula (b-1), (b-2) or (b-3);
    
    






    R2 represents hydrogen; halo; cyano; C1-6alkyl; C1-6alkyloxy; C1-6alkylthio; C1-6alkylcarbonyl; C1-6alkyloxycarbonyl; C2-6alkenyl; hydroxyC2-6alkenyl; C2-6alkynyl; hydroxyC2-6alkynyl; tri(C1-6alkyl)silaneC2-6alkynyl; amino; mono- or di(C1-6alkyl)amino; mono- or di(C1-6alkyloxyC1-6alkyl)amino; mono- or di(C1-6alkylthioC1-6alkyl)amino; aryl; arylC1-6alkyl; arylC2-6alkynyl; C1-6alkyloxyC1-6alkylaminoC1-6alkyl; aminocarbonyl optionally substituted with C1-6alkyloxycarbonylC1-6alkyl; a heterocycle selected from thienyl, furanyl, thiazolyl and piperidinyl, optionally N-substituted with morpholinyl or thiomorpholinyl; a radical —NH—C(═O)R9 wherein R9 represents C1-6alkyl optionally substituted with cycloC3-12alkyl, C1-6alkyloxy, C1-6alkyloxycarbonyl, aryl, aryloxy, thienyl, pyridinyl, mono- or di(C1-6alkyl)amino, C1-6alkylthio, benzylthio, pyridinylthio or pyrimidinylthio; cycloC3-12alkyl; cyclohexenyl; amino; arylcycloC3-12alkylamino; mono-or-di(C1-6alkyl)amino; mono- or di(C1-6alkyloxycarbonylC1-6alkyl)amino; mono- or di(C1-6alkyloxycarbonyl)amino; mono-or di(C2-6alkenyl)amino; mono- or di(arylC1-6alkyl)amino; mono- or diarylamino; arylC2-6alkenyl; furanylC2-6alkenyl; piperididinyl; piperazinyl; indolyl; furyl; benzofuryl; tetrahydrofuryl; indenyl; adamantyl; pyridinyl; pyrazinyl; aryl or a radical of formula (a-1); a sulfonamid —NH—SO2—R10 wherein R10 represents C1-6alkyl, mono- or poly haloC1-6alkyl, arylC6alkyl or aryl;
    R3 and R4 each independently represent hydrogen; C1-6alkyl; C1-6alkyloxyC1-6alkyl; C1-6alkyloxycarbonyl; or
    R2and R3 may be taken together to form —R2—R3—, which represents a bivalent radical of formula —(CH2)4—, —(CH2)5—, -Z4-CH═CH—, -Z4-CH2—CH2—CH2— or -Z4-CH2—CH2—, with Z4 being O, S, SO2 or NR11 wherein R11 is hydrogen, C1-6alkyl, benzyl or C1-6alkyloxycarbonyl; and wherein each bivalent radical is optionally substituted with C1-6alkyl;
    or R3 and R4 may be taken together to form a bivalent radical of formula —CH═CH—CH═CH— or —CH2—CH2—CH2—CH2—;
    R5 represents hydrogen; piperidinyl; oxo-thienyl; tetrahydrothienyl, arylC1-6alkyl; C1-6alkyloxycarbonylC1-6alkyl or C1-6alkyl optionally substituted with a radical C(═O)NRxRy, in which Rx and Ry, each independently are hydrogen, cycloC3-12alkyl, C2-6alkynyl or C1-6alkyl optionally substituted with cyano, C1-6alkyloxy or C1-6alkyloxycarbonyl;
    Y represents O or S;
    or Y and R5 may be taken together to form ═Y—R5— which represents a radical of formula

—CH═N—N═  (c-1); or

—N═N—N═  (c-2);

    aryl represents phenyl or naphthyl optionally substituted with one or more substituents selected from halo, C1-6alkyloxy, phenyloxy, mono-or di(C1-6alkyl)amino and cyano;

and when the R1—C(═X) moiety is linked to another position than the 7 or 8 position, then said 7 and 8 position may be substituted with R15 and R16 wherein either one or both of R15 and R16 represents C1-6alkyl or R15 and R16 taken together may form a bivalent radical of formula —CH═CH—CH═CH—.



A further most interesting group of compounds comprises those compounds of formula (I-A) and (I-B) wherein X represents O;

    R1 represents C1-6alkyl; cycloC3-12alkyl or (cycloC3-12alkyl)C1-6alkyl, wherein one or more hydrogen atoms in a C1-6alkyl-moiety or in a cycloC3-12alkyl-moiety optionally may be replaced by C1-6alkyloxy, aryl, halo or thienyl;
    R2 represents hydrogen; halo; C1-6alkyl or amino;
    R3 and R4 each independently represent hydrogen or C1-6alkyl; or
    R2 and R3 may be taken together to form —R2—R3—, which represents a bivalent radical of formula -Z4-CH2—CH2—CH2— or -Z4-CH2—CH2— with Z4 being O or NR11 wherein R11 is C1-6alkyl; and wherein each bivalent radical is optionally substituted with C1-6alkyl;
    
        or R3 and R4 may be taken together to form a bivalent radical of formula —CH2—CH2—CH2—CH2—;
    
    
    R5 represents hydrogen;
    Y represents O; and
    aryl represents phenyl optionally substituted with halo.


A further interesting group of compounds comprises those compounds of formula (I-A) and (I-B) wherein the R1—C(═X) moiety is linked to the quinoline or quinolinone moiety in position 6.
In order to simplify the structural representation of some of the present compounds and intermediates in the following preparation procedures, the quinoline or the quinolinone moiety will hereinafter be represented by the symbol Q.




The compounds of formula (I-A) or (I-B), wherein X represents O, said compounds being represented by formula (IA/B-a), can be prepared by oxidizing an intermediate of formula (II) in the presence of a suitable oxidizing agent, such as potassium permanganate, and a suitable phase-transfer catalyst, such as tris(dioxa-3,6-heptyl)amine, in a suitable reaction-inert solvent, such as for example dichloromethane.




Compounds of formula (IA/B-a) may also be prepared by reacting an intermediate of formula (III) with an intermediate of formula (IV), wherein W1 represents a halo atom, e.g. bromo, in the presence of butyl lithium and a suitable reaction-inert solvent, such as for example tetrahydrofuran.




Alternatively, compounds of formula (IA/B-a) may also be prepared by reacting an intermediate of formula (V) with an intermediate of formula (IV) in the presence of butyl lithium and a suitable reaction-inert solvent, such as for example tetrahydrofuran.




Compounds of formula (IA/B-a), wherein the R1 substituent is linked to the carbonyl moiety via an oxygen atom, said R1 substituent being represented by O—R1a and said compounds by formula (IA/B-a-1), can be prepared by reacting an intermediate of formula (VI) with an intermediate of formula (VII) in the presence of a suitable acid, such as sulfuric acid.




Compounds of formula (I-A), wherein R2 represents methylcarbonyl, said compounds being represented by formula (I-A-1), can be prepared by reacting an intermediate of formula (VIII) in the presence of a suitable acid, such as hydrochloric acid, and a suitable reaction-inert solvent, such as for example tetrahydrofuran.




The compounds of formula (I) may also be converted into each other following art-known transformations.
Compounds of formula (I-A) wherein R2 is a halo atom, such as chloro, can be converted into a compound of formula (I-A), wherein R2 is another halo atom, such as fluoro or iodo, by reaction with a suitable halogenating agent, such as for example potassium fluoride or sodium iodide, in the presence of a suitable reaction-inert solvent, e.g. dimethyl sulfoxide or acetonitrile and optionally in the presence of acetyl chloride.
Compounds of formula (I-A), wherein R2 is a suitable leaving group, such as a halo atom, e.g. chloro, iodo, said leaving group being represented by W2 and said compounds by (I-A-2), can be converted into a compound of formula (I-A) wherein R2 is cyano, said compound being represented by formula (I-A-3), by reaction with a suitable cyano-introducing agent, such as for example trimethylsilanecarbonitrile, in the presence of a suitable base such as N,N-diethylethanamine and a suitable catalyst, such as for example tetrakis(triphenylphosphine)palladium.
Compounds of formula (I-A-2) can also be converted into a compound of formula (I-A-4) by reaction with C2-6alkynyltri(C1-6alkyl)silane in the presence of CuI, an appropriate base, such as for example N,N-ethylethanamine, and an appropriate catalyst, such as for example tetrakis(triphenylphosphine)palladium. Compounds of formula (I-A-4) can on their turn be converted into a compound of formula (I-A-5) by reaction with potassium fluoride in the presence of a suitable acid such as acetic acid, or by reaction with a suitable base, such as potassium hydroxide, in the presence of a suitable reaction-inert solvent, such as an alcohol, e.g. methanol and the like.
Compounds of formula (I-A-2) can also be converted into a compound of formula (I-A-6) by reaction with an intermediate of formula (IX) in the presence of CuI, a suitable base, such as for example N,N-diethylethanamine, and a suitable catalyst such as tetrakis(triphenylphosphine)palladium.
Compounds of formula (I-A-2) can also be converted into a compound wherein R2 is C1-6alkyl, said compound being represented by formula (I-A-8) in the presence of a suitable alkylating agent, such as for example Sn(C1-6alkyl)4, or into a compound wherein R2 is C2-6alkenyl, said compound being represented by formula (I-A-9) in the presence of a suitable alkenylating agent, such as for example Sn(C2-6alkenyl)(C1-6alkyl)3, both reactions in the presence of a suitable catalyst, such as for example tetrakis(triphenylphosphine)palladium and a reaction-inert solvent, such as for example toluene or dioxane.
Compounds of formula (I-A-2) can also be converted into a compound of formula (I-A-7) wherein Z represents O or S, by reaction with an intermediate of formula (X) optionally in the presence of a suitable base such as dipotassium carbonate and a reaction-inert solvent, such as N,N-dimethyl formamide.
Compounds of formula (I-A-2) can also be converted into a compound of formula (I-A), wherein R2 is C1-6alkyloxycarbonyl, said compound being represented by formula (I-A-10) and a compound of formula (I-A), wherein R2 is hydrogen, said compound being represented by formula (I-A-11), by reaction with a suitable alcohol of formula
C1-6alkylOH and CO in the presence of a suitable catalyst, such as for example palladium(II)acetate, triphenylphosphine, a suitable base such as dipotassium carbonate and a reaction-inert solvent, such as N,N-dimethylformamide.
Compounds of formula (I-A-11) can also be prepared by reacting a compound of formula (I-A-2) with Zn in the presence of a suitable acid such as acetic acid.
Compounds of formula (I-A-2) can also be converted into a compound of formula (I-A), wherein R2 is aminocarbonyl substituted with C1-6alkyloxycarbonylC1-6alkyl, said compound being represented by formula (I-A-12), by reaction with an intermediate of formula H2N—C1-6alkyl-C(═O)—O—C1-6alkyl in the presence of CO, a suitable catalyst such as tetrakis(triphenylphosphine)palladium, a suitable base, such as for example N,N-diethylethanamine, and a suitable reaction-inert solvent, such as for example toluene.




Compounds of formula (I-A-2) can also be converted into a compound of formula (I-A) wherein R2 is aryl or a heterocycle selected from the group described in the definition of R2 hereinabove, said R2 being represented by R2a and said compound by formula (I-A-13) by reaction with an intermediate of formula (XI), (XII) or (XIII) in the presence of a suitable catalyst such as for example tetrakis(triphenylphosphine)palladium and a suitable reaction-inert solvent, such as for example dioxane.




Compounds of formula (I-A-2) can also be converted into a compound of formula (I-B), wherein Y and R5 are taken together to form a radical of formula (b-1) or (b-2), said compound being represented by formula (I-B-1) or (I-B-2), by reaction with hydrazincarboxaldehyde or sodium azide in a suitable reaction-inert solvent, such as an alcohol, e.g. butanol, or N,N-diethylformamide.




Compounds of formula (I-A-11) can be converted into the corresponding N-oxide, represented by formula (I-A-14), by reaction with a suitable peroxide, such as 3-chloro-benzenecarboperoxoic acid, in a suitable reaction-inert solvent, such as for example methylene chloride. Said compound of formula (I-A-14) can further be converted into a compound of formula (I-B), wherein R5 is hydrogen, said compound being represented by formula (I-B-3), by reaction with 4-methyl-benzene sulfonyl chloride in the presence of a suitable base, such as for example dipotassium carbonate and a suitable reaction-inert solvent, such as for example methylene chloride.




Compounds of formula (I-B-3) can also be prepared from a compound of formula (I-A), wherein R2 is C1-6alkyloxy, said compound being represented by formula (I-A-15), by reaction with a suitable acid, such as hydrochloric acid, in the presence of a suitable reaction-inert solvent, such as for example tetrahydrofuran.




Compounds of formula (I-B-3) can be converted into a compound of formula (I-B), wherein R5 represents C1-6alkyl, said compound being represented by formula (I-B-4), by reaction with an appropriate alkylating agent, such as for example an intermediate of formula (XIV), wherein W3 represents a suitable leaving group such as a halo atom e.g. iodo, in the presence of potassium tert. butoxide and in the presence of a suitable reaction-inert solvent, such as for example tetrahydrofuran.




Compounds of formula (I-B-3) can also be converted into a compound of formula (I-B), wherein R5 is C1-6alkyloxycarbonylC1-6alkyl or arylC1-6alkyl, said R5 being represented by R5a and said compound being represented by formula (I-B-5), by reaction with an intermediate of formula (XV), wherein W4 represents a suitable leaving group, such as a halo atom, e.g. bromo, chloro and the like, in the presence of a suitable base, such as for example sodium hydride and a suitable reaction-inert solvent, such as for example N,N-dimethylformamide.




Compounds of formula (I-A-2) can also be converted into a compound of formula (I-B), wherein R5 is hydrogen and Y is S, said compound being represented by formula (I-B-6), by reaction with H2N—C(═S)—NH2 in the presence of a suitable base, such as potassium hydroxide, and a suitable reaction-inert solvent, such as an alcohol, for example ethanol, or water. Compounds of formula (I-B-6) can further be converted into a compound of formula (I-A), wherein R2 is C1-6alkylthio, said compound being represented by formula (I-A-16), by reaction with a suitable C1-6alkylhalide, such as for example C1-6alkyliodide, in the presence of a suitable base, such as dipotassium carbonate, and a suitable solvent, such as for example acetone.




Compounds of formula (IA/B-a) can be converted into a compounds of formula (I-A) or (I-B), wherein X is N—R7, said compound being represented by formula (IA/B-b), by reaction with an intermediate of formula (XVI), optionally in the presence of a suitable base, such as for example N,N-diethylethanamine, and in the presence of a suitable reaction-inert solvent, such as an alcohol, e.g. ethanol.




As already indicated in the preparation procedure of compounds of formula (I-A-13) described above, the compounds of formula (I) may also be converted to the corresponding N-oxide forms following art-known procedures for converting a trivalent nitrogen into its N-oxide form. Said N-oxidation reaction may generally be carried out by reacting the starting material of formula (I) with an appropriate organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal or earth alkaline metal peroxides, e.g. sodium peroxide, potassium peroxide; appropriate organic peroxides may comprise peroxy acids such as, for example, benzenecarboperoxoic acid or halo substituted benzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, e.g. peroxoacetic acid, allylhydroperoxides, e.g. tert-butyl hydroperoxide. Suitable solvents are, for example, water, lower alkanols, e.g. ethanol and the like, hydrocarbons, e.g. toluene, ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g. dichloromethane, and mixtures of such solvents.
Some of the intermediates and starting materials used in the above reaction procedures are commercially available, or may be synthesized according to procedures already described in the literature.
Intermediates of formula (II) may be prepared by reacting an intermediate of formula (XVII) with an intermediate of formula (XVIII), wherein W5 represents a suitable leaving group such as a halo atom, e.g. chloro, bromo and the like, in the presence of magnesium, diethylether and a suitable reaction-inert solvent, such as diethylether.




Intermediates of formula (XVII) may be prepared by oxidizing an intermediate of formula (XIX) in the presence of a suitable oxidizing agent, such as MnO2, and a suitable reaction-inert solvent, such as methylene chloride.




Intermediates of formula (XIX) can be prepared by reducing an intermediate of formula (XX) in the presence of a suitable reducing agent such as lithium aluminium hydride, and a suitable reaction-inert solvent, such as tetrahydrofuran.




Intermediates of formula (XX), wherein Q represents a quinoline moiety optionally substituted in position 3 with C1-6alkyl and wherein the carbonyl moiety is placed in position 6, said intermediates being represented by formula (XX-a), can be prepared by reacting an intermediate of formula (XXI) with an intermediate of formula (XXII) in the presence of sodium 3-nitro-benzene sulfonate, a suitable acid, such as sulfuric acid, and a suitable alcohol, e.g. methanol, ethanol, propanol, butanol and the like.




Alternatively, intermediates of formula (II) can also be prepared by reacting an intermediate of formula (XXIII) with an intermediate of formula (XXIV), wherein W6 is a suitable leaving group, such as a halo atom, e.g. bromo, chloro and the like, in the presence of a suitable agent, such as butyl lithium and a suitable reaction-inert solvent, such as tetrahydrofuran.




Intermediates of formula (XXIII) can be prepared by oxidizing an intermediate of formula (XXV) using the Moffatt Pfitzner or Swern oxidation (dimethylsulfoxide adducts with dehydrating agents e.g. DCC, Ac2O, SO3, P4O10, COCl2 or Cl—CO—COCl) in an inert solvent such as methylene chloride.




Intermediates of formula (XXV) can be prepared by reducing an intermediate of formula (XXVI) in the presence of a suitable reducing agent, such as for example lithium aluminium hydride and a suitable reaction-inert solvent, such as benzene.




Intermediates of formula (XXVI) can be prepared from an intermediate of formula (XXVII) by esterification in the presence of a suitable alcohol, such as methanol, ethanol, propanol, butanol and he like, and a suitable acid, such as sulfuric acid.




Intermediates of formula (XXVII), wherein R1 represents a radical of formula (a-1) with Z1 being O, Z2 being CH2 and n being 1, said intermediates being represented by formula (XXVII-a), can be prepared by reducing an intermediate of formula (XXVIII) in the presence of a suitable reducing agent such as hydrogen, and a suitable catalyst, such as palladium on charcoal, and a suitable acid such as acetic acid. When R1 of intermediate (XXVII) represents an optionally substituted phenyl moiety, it can also be converted into an optionally substituted cyclohexyl moiety by reduction in the presence of a suitable reducing agent such as rhodium on Al2O3, and a suitable reaction-inert solvent, such as tetrahydrofuran.




Intermediates of formula (IV), wherein Q represents a quinoline moiety substituted in position 2 with halo,e.g. chloro, said intermediates being represented by formula (IV-a), can be prepared by reacting an intermediate of formula (IV), wherein Q represents a quinolinone moiety with R5 being hydrogen, said intermediate being represented by formula (IV-b), in the presence of POCl3.




Intermediates of formula (IV-a), wherein R4 is hydrogen, said intermediates being represented by formula (IV-a-1), can also be prepared by reacting an intermediate of formula (XXIX) with POCl3 in the presence of N,N-diethylformamide (Vilsmeier-Haack formylation followed by cyclization).




Intermediates of formula (XXIX) may be prepared by reacting an intermediate of formula (XXX) with an intermediate of formula (XXXI), wherein W7 represents a suitable leaving group, such as a halo atom, e.g. chloro, in the presence of a suitable base, such as for example N,N-diethylethanamine, and a suitable reaction-inert solvent, such as methylene chloride.




Intermediates of formula (IV-a) can be converted into an intermediate of formula (IV-c) by reaction with an intermediate of formula (XXXII) in the presence of a suitable reaction-inert solvent, such as an alcohol, e.g. methanol and the like.




Intermediates of formula (IV-a) can also be converted into an intermediate of formula (IV-d-1) by reaction with a suitable amine of formula (XXXIII-a), wherein Z3 and Z4 each independently represent hydrogen, C1-6alkyl, C1-6alkyloxyC1-6alkyl, C1-6alkylthioC1-6alkyl or into an intermediate of formula (IV-d-2) by reaction with a suitable amine of formula (XXXIII-b), wherein Z3 and Z4 are taken together to form a heterocycle as defined hereinabove in the definition of R2 provided that the heterocycle comprises at least one nitrogen atom, in the presence of a suitable base, such as for example dipotassium carbonate, and a reaction-inert solvent, such as N,N-dimethylformamide.




Intermediates of formula (IV-a), wherein R3 represents CH2—CH2—CH2—Cl, said intermediates being represented by formula (IV-a-2), can also be converted into an intermediate of formula (IV), wherein R2 and R3 are taken together to form a bivalent radical of formula —O—CH2—CH2—CH2—, said intermediate being represented by formula (IV-e-1), by reaction with a suitable acid, such as hydrochloric acid and the like. Intermediates of formula (IV-a-2) can also be converted into an intermediate of formula (IV), wherein R2 and R3 are taken together to form a bivalent radical of formula —S—CH2—CH2—CH2—, said intermediate being represented by formula (IV-e-2), by reaction with H2N—C(═S)—NH2 in the presence of a suitable reaction-inert solvent, such as an alcohol, e.g. ethanol.




Intermediates of formula (V) may be prepared by reacting an intermediate of formula (XXVII) with an intermediate of formula CH3—NH—O—CH3 in the presence of 1,1′-carbonyldiimidazole and a suitable reaction-inert solvent, such as methylene chloride.




Intermediates of formula (VII), wherein Q represents a quinoline moiety, in particular a quinoline moiety wherein R2 is ethyl, R3 is methyl and R4 is hydrogen, and the carboxyl moiety is placed in position 6, said intermediates being represented by formula (VII-a), can be prepared by reaction an intermediate of formula (XXXIV) in the presence of a suitable aldehyde, such as CH3—CH2—CH(═O), (CH2O)n, ZnCl2, FeCl3 and a suitable reaction-inert solvent, such as an alcohol, for example ethanol.




Intermediates of formula (VIII) can be prepared by reacting an intermediate of formula (XXXV) with an intermediate of formula (XXXVI) in the presence of a suitable catalyst, such as for example tetrakis(triphenylphosphine)palladium and a suitable reaction-inert solvent, such as for example dioxane.




Still some other preparations can be devised, some of them are disclosed further in this application with the Examples.
Pure stereoisomeric forms of the compounds and the intermediates of this invention may be obtained by the application of art-known procedures. Diastereomers may be separated by physical separation methods such as selective crystallization and chromatographic techniques, e.g. liquid chromatography using chiral stationary phases. Enantiomers may be separated from each other by the selective crystallization of their diastereomeric salts with optically active acids. Alternatively, enantiomers may be separated by chromato-graphic techniques using chiral stationary phases. Said pure stereoisomeric forms may also be derived from the corresponding pure stereoisomeric forms of the appropriate starting materials, provided that the reaction occurs stereo-selectively or stereospecifically. Preferably, if a specific stereoisomer is desired, said compound will be synthesized by stereoselective or stereospecific methods of preparation. These methods will advantageously employ chirally pure starting materials. Stereoisomeric forms of the compounds of formula (I) are obviously intended to be included within the scope of the invention.
A stereoisomer of a compound of formula (I-A) or (I-B) such as a cis form, may be converted into another stereoisomer such as the corresponding trans form by reacting the compound with a suitable acid, such as hydrochloric acid, in the presence of a suitable reaction-inert solvent, such as for example tetrahydrofuran.
The compounds of formula (I-A) and (I-B), the N-oxides, the pharmaceutically acceptable addition salts, the quaternary amines and the stereochemically isomeric forms thereof show mGluR antagonistic activity, more in particular Group I mGluR antagonistic activity. The Group I mGluR specifically antagonized by the present compounds is the mGluR1.
The mGluR1 antagonistic activity of the present compounds can be demonstrated in the Signal transduction on cloned rat mGluR1 in CHO cells test and the Cold allodynia test in rats with a Bennett ligation, as described hereinafter.
Due to their mGluR antagonistic activity, more in particular their Group I mGluR antagonistic activity and even more in particular, their mGluR1 antagonistic activity, the compounds of formula (I-A) or (I-B), their N-oxides, pharmaceutically acceptable addition salts, quaternary amines and stereochemically isomeric forms are useful in the treatment or prevention of glutamate-induced diseases of the central nervous system. Diseases in which a role for glutamate has been demonstrated include drug addiction or abstinence (dependence, opioid tolerance, opioid withdrawal), hypoxic, anoxic and ischemic injuries (ischemic stroke, cardiac arrest), pain (neuropathic pain, inflammatory pain, hyperalgesia), hypoglycemia, diseases related to neuronal damage, brain trauma, head trauma, spinal cord injury, myelopathy, dementia, anxiety, schizophrenia, depression, impaired cognition, amnesia, bipolar disorders, conduct disorders, Alzheimer's disease, vascular dementia, mixed (Alzheimer's and vascular) dementia, Lewy Body disease, delirium or confusion, Parkinson's disease, Huntington's disease, Down syndrome, epilepsy, aging, Amyotrophic Lateral Sclerosis, multiple sclerosis, AIDS (Acquired Immune Deficiency Syndrome) and AIDS related complex (ARC).
In view of the utility of the compounds of formula (I-A) and (I-B), there is provided a method of treating warm-blooded animals, including humans, suffering from glutamate-induced diseases of the central nervous system. Said method comprises the administration, preferably oral administration, of an effective amount of a compound of formula (I-A) or (I-B), a N-oxide form, a pharmaceutically acceptable addition salt, a quaternary amine or a possible stereoisomeric form thereof, to warm-blooded animals, including humans.
In view of the above described pharmacological properties, the compounds of formula (I-A) and (I-B) or any subgroup thereof, their N-oxides, pharmaceutically acceptable addition salts, quaternary amines and stereochemically isomeric forms, may be used as a medicine. In particular, the use of a compound of formula (I-A) and (I-B) in the manufacture of a medicament for treating or preventing glutamate-induced diseases of the central nervous system is provided. More in particular, the present compounds may be used as neuroprotectants, analgesics or anticonvulstants.
The present invention also provides compositions for treating or preventing glutamate-induced diseases of the central nervous system comprising a therapeutically effective amount of a compound of formula (I-A) or (I-B) and a pharmaceutically acceptable carrier or diluent.
Therefore, the compounds of the present invention or any subgroup thereof may be formulated into various pharmaceutical forms for administration purposes. As appropriate compositions there may be cited all compositions usually employed for systemically administering drugs. To prepare the pharmaceutical compositions of this invention, a therapeutically effective amount of a particular compound, in base or addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for administration orally, rectally, topically, percutaneously or by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, emulsions, elixirs and solutions: or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations. As appropriate compositions for topical application there may be cited all compositions usually employed for topically administering drugs e.g. creams, gel, dressings, shampoos, tinctures, pastes, ointments, salves, powders and the like. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause a significant deleterious effect to the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment.
It is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. Unit dosage form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, suppositories, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.
The therapeutically effective dose or frequency of administration depends on the particular compound of formula (I-A) or (I-B) used, the particular condition being treated, the severity of the condition being treated the age, weight, sex, fed or fasted state, and the general physical condition of the particular patient as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that said therapeutically effective dose or the effective daily dose may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention. It may be appropriate to administer the required dose as two, three, four or more sub-doses at appropriate intervals throughout the day. Said sub-doses may be formulated as unit dosage forms.
The following examples are intended to illustrate the present invention.


EXPERIMENTAL PART
Hereinafter, “DMF” is defined as N,N-dimethylformamide, “DIPE” is defined as diisopropylether, “DMSO” is defined as dimethylsulfoxide, “BHT” is defined as 2,6-bis(1,1-dimethylethyl)-4-methylphenol, and “THF” is defined as tetrahydrofuran.
Preparation of the Intermediates
EXAMPLE A1
Preparation of




A mixture of 4-(1-methylethoxy)benzoic acid (0.083 mol) and Rh/Al2O3 5% (10 g) in THF (220 ml) was hydrogenated at 50° C. (under 3 bar pressure of H2) for 1 night. The mixture was filtered over celite, washed with THF and evaporated. Yield: 16 g of intermediate 1 (100%).
EXAMPLE A2
Preparation of 2-ethyl-3-methyl-6-quinolinecarboxylic acid (interm. 2)
A mixture of 4-aminobenzoic acid (0.299 mol) in ethanol (250 ml) was stirred at room temperature. ZnCl2 (0.0367 mol) and (CH2O)n (10 g) were added. FeCl3.6H2O (0.5 mol) was added portionwise and the temperature rised till 60-65° C. Propanal (30 ml) was added dropwise over a 2 hours period. The mixture was refluxed for 2 hours and kept at room temperature for 12 hours. The mixture was poured into water and filtered through celite. The filtrate was acidified till pH=7 with HCl 6N and the mixture was evaporated till dryness. The residue was used without further purification. Yield: 56.1 g of 2-ethyl-3-methyl-6-quinolinecarboxylic acid (interm. 2).
EXAMPLE A3
Preparation of




Pentanoyl chloride (0.2784 mol) was added at 5° C. to a mixture of 4-bromobenzenamine (0.232 mol) and N,N-ethylethanamine (0.2784 mol) in CH2Cl2 (400 ml). The mixture was stirred at room temperature overnight, poured out into water and extracted with CH2Cl2. The organic layer was separated, washed with a concentrated NH4OH solution and water, dried (MgSO4), filtered and the solvent was evaporated. The residue (60 g) was crystallized from diethylether. The precipitate was filtered off and dried. The residue (35 g, 63%) was taken up in CH2Cl2. The organic layer was separated, washed with a 10% K2CO3 solution, washed with water, dried (MgSO4), filtered and the solvent was evaporate Yield: 30 g of intermediate (3) (54%).
EXAMPLE A4
Preparation of




A mixture of 6-bromo-2(1H)-quinolinone (0.089 mol) in POCl3 (55 ml) was stirred at 60° C. overnight, then at 100° C. for 3 hours and the solvent was evaporated. The residue was taken up in CH2Cl2, poured out into ice water, basified with NH4OH conc., filtered over celite and extracted with CH2Cl2. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. Yield. 14.5 g of intermediate (4) (67%).
EXAMPLE A5
a) Preparation of




DMF (37 ml) was added dropwise at 10° C. under N2 flow to POCl3 (108 ml). After complete addition, the mixture was allowed to warm to room temperature. N-(4-bromophenyl)butanamide (0.33 mol) was added portionwise. The mixture was stirred at 85° C. overnight, then allowed to cool to room temperature and poured out on ice (exothermic reaction). The precipitate was filtered off, washed with a small amount of water and dried (vacuum). The residue was washed with EtOAc/diethyl ether and dried. Yield: 44.2 g of intermediate (5) (50%).
b) Preparation of




A mixture of intermediate (5) (0.162 mol) in methanol (600 ml), and a solution of methanol sodium salt in methanol at 35% (154 ml) was stirred and refluxed overnight. The mixture was poured out on ice. The precipitate was filtered off, washed with a small amount of water and taken up in CH2Cl2, K2CO3 10% was added and the mixture was extracted with CH2Cl2. The organic layer was separated, washed with water, dried (MgSO4), filtered and the solvent was evaporated. Yield: 31.9 g of intermediate (6) (74%).
EXAMPLE A6
Preparation of




1,1′-Carbonylbis-1H-imidazole (0.074 mol) was added portionwise to a mixture of 4-methoxycyclohexanecarboxylic acid (0.063 mol) in CH2Cl2 (200 ml). The mixture was stirred at room temperature for 1 hour. Then N-methoxymethanamine (0.074 mol) was added. The mixture was stirred at room temperature overnight, poured out into H2O and extracted with CH2Cl2. The organic layer was separated, washed several times with H2O, drized (MgSO4), filtered and the solvent was evaporated. Yield: 12.6 g of interm. 7.
EXAMPLE A7
a) A mixture of 6-fluoro-4-oxo-4H-1-benzopyran-2-carboxylic acid (0.30 mol) in acetic acid (400 ml) was hydrogenated with Pd/C (3 g) as a catalyst. After uptake of H2 (3 equiv), the catalyst was filtered off. The filtrate was evaporated. The residue was stirred in petroleum ether. The precipitate was filtered off and dried (vacuum; 70° C.). After recrystallization from CHCl3/CH3OH, the precipitate was filtered off and dried (vacuum; 80° C. and high vacuum; 85° C.). Yield: 8.8 g of 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (interm. 8) (15.0%).
b) A mixture of intermediate (8) (0.255 mol) in ethanol (400 ml) and H2SO4 (5 ml) was stirred and refluxed for 8 hours. The solvent was evaporated till dryness. The residue was dissolved in CH2Cl2. The organic layer was separated, washed with K2CO3 10%, dried (MgSO4), filtered and the solvent was evaporated. Yield: 45 g of ethyl 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylate (interm. 9) (79%).
c) Reaction under N2. A mixture of sodium bis(2-methoxyethoxy)aluminumhydride, 70 wt % solution in methylbenzene 3.4 M (0.44 mol) in benzene (150 ml) (reflux) was added dropwise during 1 hour to a refluxed mixture of interm. 9 (0.22 mol) and benzene (600 ml). After stirring for 2.5 hours at reflux temperature, the mixture was cooled to ±15° C. The mixture was decomposed by adding dropwise ethanol (30 ml) and water (10 ml). This mixture was poured out onto ice/water and this mixture was acidified with concentrated hydrochloric acid. This mixture was extracted with diethyl ether (500 ml). The separated organic layer was washed with water, dried, filtered and the solvent was evaporated. The residue was purified by column chromotoghaphy over silica gel (eluent: CHCl3). The desired fraction was collected and the eluent was evaporated. Yield. 34 g of 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol (interm. 10) (85%).
d) Reaction under N2. To a stirred and cooled (−60° C.; 2-propanone/CO2 bath) mixture of ethanedioyl dichloride (0.1 mol) in CH2Cl2 (350 ml) was added sulfinylbis[methane] (30 ml) during 10 minutes. After stirring 10 minutes, a mixture of interm. 10 in CH2Cl2 (90 ml) was added during 5 minutes. After stirring for 15 minutes, N,N-diethylethanamine (125 ml) was added. When the mixture was warmed up to room temperature, it was poured out in water. The product was extracted with CH2Cl2. The organic layer was washed with water, HCl (1 M), water, NaHCO3 (10%) and water, dried and evaporated. The residue was dissolved in diethyl ether, washed with water, dried, filtered and evaporated. The residue was purified by column chromotoghaphy over silica gel (eluent: CHCl3). The desired fraction was collected and the eluent was evaporated. Yield: 21.6 g of 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxaldehyde (interm. 11)
e) Preparation of




nButyllithium 1.6 M (0.056 mol) was added slowly at −70° C. to a solution of intermediate (5) (0.046 mol) in THF (100 ml). The mixture was stirred at −70° C. for 30 minutes. A suspension of interm. 11 (0.056 mol) in THF (100 ml) was added slowly. The mixture was stirred at −70° C. for 1 hour, then brought to room temperature, poured out into H2O and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue (21 g) was purified by column chromatography over silica gel (eluent: cyclohexane/EtOAc 80/10; 15-35 μm). The pure fractions were collected and the solvent was evaporated. Yield: 9.5 g of interm. 12 (55%).
EXAMPLE A8
a) Preparation of




A mixture of intermediate (5) (0.1127 mol), 2-methoxyethanamine (0.2254 mol) and K2CO3 (0.2254 mol) in DMF (500 ml) was stirred at 120° C. for 15 hours and then cooled. The solvent was evaporated. The residue was taken up in CH2Cl2 and H2O. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated till dryness. The residue (33.53 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 99.5/0.5; 15-40 μm). Two fractions were collected and their solvents were evaporated. Yield: 5.7 g of interm. 14 (38%) and interm. 13 (34%).
b) Preparation of




A mixture of intermediate (5) (0.0751 mol), thiomorpholine (0.0891 mol) and K2CO3 (0.15 mol) in DMF (200 ml) was stirred at 120° C. for 12 hours. The solvent was evaporated till dryness. The residue was taken up in CH2Cl2 and H2O. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue (26 g) was purified by column chromatography over silica gel (eluent: cyclohexane/EtOAc 80/20; 20-45 μm). Two factions were collected and their solvents were evaporated. The two fractions were combined. Yield: 9.4 g of interm. 15 (37%); mp. 82° C.
EXAMPLE A9
a) 4-Aminobenzoic acid (0.219 mol) was added to a solution of sodium 3-nitrobenzenesulfonate (0.118 mol) in H2SO4 70% (230 ml) and the mixture was stirred and refluxed. 2-propene-1,1-diol, 2-methyl-, diacetate (0.216 mol) was added dropwise and the mixture was refluxed for 4 hours. Ethanol (200 ml) was added and the mixture was stirred at 80° C. for 48 hours. The mixture was evaporated, the residue was poured into ice water/NH4OH and extracted with CH2Cl2. The organic layer was dried (MgSO4) and evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/2-propanol 99/1). The pure fractions were collected and evaporated. Yield: 21 g of ethyl 3-methyl-6-quinolinecarboxylate (interm. 16) (45%).
b) Interm. 16 (0.098 mol) in THF (270 ml) was added at 0° C. to a solution of LiAlH4 (0.098 mol) in THF under N2. When the addition was complete, water (10 ml) was added. The precipitate was filtered off and washed with CH2Cl2. The organic layer was dried (MgSO4), filtered off and evaporated. The product was used without further purification. Yield: 16.71 g of 3-methyl-6-quinolinemethanol (interm. 17).
c) MnO2 (0.237 mol) was added to a solution of interm. 17 (0.096 mol) in CH2Cl2 (200 ml) and the mixture was stirred at room temperature for 12 hours. The mixture was filtered through celite and the filtrate was stirred again with MnO2 (20 g) for 12 hours. MnO2 (10 g) was added again. The mixture was stirred for 12 hours. The mixture was filtered through celite and evaporated. The product was used without further purification. Yield: 11.71 g of 3-methyl-6-quinolinecarboxaldehyde (71%) (interm. 18).
d) A solution of bromocyclohexyl (0.14 mol) in 1,1′-oxybisethane (50 ml) and Mg turnings (50 ml) was added at 10° C. to a mixture of THF (0.14 mol) in 1,1′-oxybisethane (10 ml). A solution of interm. 18 (0.07 mol) in Mg turnings (100 ml) was added carefully at 5° C., the mixture was poured into ice water and extracted with EtOAc. Yield: 11.34 g of (±)-α-cyclohexyl-3-methyl-6-quinolinemethanol (63%) (interm. 19).
EXAMPLE A10
Preparation of




A mixture of compound (5) (0.001507 mol), tributyl(1-ethoxyethenyl)stannane (0.00226 mol) and Pd(PPh3)4 (0.000151 mol) in 1,4-dioxane (5 ml) was stirred at 80° C. for 3 hours. Water was added. The mixture was extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. This product was used without further purification. Yield: 1.4 g of interm. 20.
EXAMPLE A11
Preparation of




A mixture of compound (45) (prepared according to B6) (0.00125 mol) in NaOH 3N (5 ml) and iPrOH (1.7 ml) was stirred at room temperature overnight, then poured out into H2O, acidified with HCl 3N and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue was taken up in diethyl ether. The precipitate was filtered off and dried. Yielding: 0.26 g of intermediate 23 (56%). (mp.: 232° C.)
EXAMPLE A12
a. Preparation of




A mixture of 5-bromo-1H-indole-2,3-dione (0.221 mol) in NaOH 3N (500 ml0 was stirred at 80° C. for 30 minutes, brought to room temperature and 2-pentanone (0.221 mol) was added. The mixture was stir and refluxed for 1 hour and 30 minutes and acidified with AcOH until pH=5. The precipitate was filtered, washed with water and dried. Yielding 52.3 g of intermediate 24 and intermediate 25. (Total yielding: 80%).
b. Preparation of




nBuLi 1.6 M (0.0816 mol) was added dropwise at −78° C. to a suspension of intermediate 25 (0.034 mol) and intermediate 26 (0.034 mol) in THF (300 ml) under N2 flow. The mixture was stirred at −78° C. for 30 minutes. nBuLi 1.6 M (0.0816 mol) was added dropwise. The mixture was stirred for 1 hour. A mixture of intermediate 9 (0.102 mol) in THF (250 ml) was added slowly. The mixture was stirred for −78° C. to −20° C., poured out into H2O/HCl 3N and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated till dryness. Yielding: 20.89 g of compound intermediate 26 and intermediate 27 (86%).
EXAMPLE A13
a. Preparation of




4-amino-3-methoxybenzoic acid (0.054 mol) was added portionwise at room temperature to a solution of 3-chloro-2-ethyl-2-butenal (0.065 mol) in AcOH (100 ml). The mixture was stirred and refluxed for 8 hours and evaporated to dryness. The residue was taken up in CH2Cl2, water was added and the solution was basified by Et3N. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue was crystallized from 2-propanone. The precipitate was filtered off and dried. Yielding: 2.5 g of interm. 26 (18%).
b. Preparation of




CDI (0.012 mol) was added at room temperature to a solution of interm. 26 (0.011 mol) in CH2Cl2 (30 ml). The mixture was sired at room temperature for 1 hour. methoxyaminomethyl (0.012 mol) was added and the mixture was stirred at room temperature for 8 hours. H2O was added. A precipitate was filtered off. The filtrate was extracted with CH2Cl2. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue was crystallized from diethyl ether. The precipitate was filtered off and dried. Yielding: 0.95 g of interm. 27 (31%) (mp.:148° C.).
EXAMPLE A14
Preparation of




4-Bromobenzenamine (0.034 mol) was added at room temperature to a solution of 3-chloride-2-ethyl-2-butanal (0.041 mol) in AcOH (60 ml). The mixture was stirred and refluxed for 8 hours, brought to room temperature and evaporated to dryness. The product was crystallized from EtOAc. The precipitate was filtered, washed with K2CO3 10% and taken up in CH2Cl2. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. Yielding: 4.6 g of interm. 28 (54%).
EXAMPLE A15
a. Preparation of




A solution of KOH (0.326 mol) in H2O (150 ml) was added slowly at 5° C. to a solution of 1,3-cyclohexanedione (0.268 mol) in H2O (150 ml). The temperature must not reach 12° C. KI (2 g) then 2-bromo-1-(4-nitrophenyl)ethanone (0.294 mol) were added portionwise. The mixture was stirred at room temperature for 48 hours. The precipitate was filtered, washed with H2O then with diethyl ether and dried. Yielding: 63 g (85%). A part of this fraction (1 g) was crystallized from EtOH. The precipitate was filtered off and dried. Yielding: 0.5 g of interm. 29 (42%) (mp.: 100° C.).
b. Preparation of




A mixture of interm. 29 (0.145 mol) in H2SO4 (40 ml) was stirred at room temperature for 1 hour, poured out into ice, basified with NH4OH and extracted with CH2Cl2. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue was crystallized from EtOH. The precipitate was filtered off and dried. Yielding: 31 g (58%). A part of this fraction (1 g) was crystallized from EtOH. The precipitate was filtered off and dried. Yielding: 0.7 g of interm. 30 (58%) (mp.:200° C.).
c. Preparation of




A mixture of interm. 30 (0.039 mol), Raney Ni (10 g) in EtOH (100 ml) was hydrogenated at room temperature under a 3 bar pressure for 1 hour. The mixture was filtered over celite and washed with CH2Cl2. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue (9.5 g) was crystallized from diethyl ether. The precipitate was filtered off and dried. Yielding: 4.6 g (52%). The filtrate was evaporated. The residue (2.7 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH; 99/1; 15-40 μm). Two fractions were collected and the solvent was evaporated. Yielding: 1.6 g F1 and 1.2 g F2. F2 was crystallized from EtOH. The precipitate was filtered off and dried. Yielding: 0.24 g of interm. 31 (2%) (mp.:202° C.).
d. Preparation of




Interm. 30 (0.02 mol) was added at room temperature to a solution of 3-chloro-2-ethyl-2-butenal (0.04 mol) in AcOH (50 ml). The mixture was stirred and refluxed for 4 hours. The solvent was evaporated till dryness. The residue was crystallized from EtOAc. The precipitate was filtered off and dried. The residue was taken up in CH2Cl2. The mixture was basified with K2CO3 10% and extracted with CH2Cl2. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue was crystallized from EtOH. The precipitate was filtered off and dried. Yielding: 2.5 g of interm. 32 (40%).
EXAMPLE A16
Preparation of




A mixture of 2-(4-nitrophenyl)-1-phenylethanone (0.083 mol) and Raney Ni (20 g) in EtOH (200 ml) was hydrogenated at room temperature for 1 hour under a 3 bar pressure, then filtered over celite, washed with CH2Cl2/CH3OH and dried. Yielding: 17.5 g of interm. 33 (97%).
B. Preparation of the Final Compounds
EXAMPLE B1
Preparation of




POCl3 (0.024 mol) was added slowly at 5° C. to DMF (0.024 mol). The mixture was stirred at room temperature for 30 minutes, then cooled to 5° C. 3-Oxo-butanoic acid ethyl ester (0.024 mol) was added slowly. The mixture was stirred at 5° C. for 30 minutes. 1-(4-aminophenyl)-2-phenylethanone (0.024 mol) was added portionwise. The mixture was stirred at 90° C. for 3 hours and dissolved in CH2Cl2. Ice water was added. The mixture was basified with NH4OH and extracted with CH2Cl2. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue was crystallized from 2-propanone/diethyl ether. The precipitate was filtered off and dried. Yielding: 0.9 g of compound 306 (11%) (mp.:136° C.).
EXAMPLE B2
Preparation of




KMnO4 (10 g) was added portionwise at room temperature to a solution of




(prepared according to example A7.e) (0.022 mol) in tris(dioxa-3,6-heptyl)amine (1 ml) and CH2Cl2 (100 ml). The mixture was stirred at room temperature for 8 hours, filtered over celite, washed with CH2Cl2 and dried. The residue (6 g, 100%) was crystallized from diethyl ether/petroleum ether. The precipitate was filtered off and dried. Yield: 2 g of compound (2) (33%); mp. 82° C.

EXAMPLE B3
a) Preparation of




nBuLi 1.6 M (0.07 mol) was added slowly at −70° C. to a solution of intermediate (5) (0.058 mol) in THF (150 ml). The mixture was stirred at −70° C. for 30 minutes. A solution of 2,3-dihydro-1H-Indene-2-carbonitrile (0.07 mol) in THF (100 ml) was added slowly. The mixture was stirred at −70° C. for 1 hour, brought slowly to room temperature, hydrolized with H2O and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue (22 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/cyclohexane 80/20 to 100; 15-35 μm). The pure fractions were collected and the solvent was evaporated. The second fraction was crystallized from 2-propanone/diethyl ether. The precipitate was filtered off and dried. Yield: 0.11 g of compound (3). The filtrate was concentrated. Yield: 0.55 g of compound (3); mp. 145° C.
b) Preparation of




nBuLi 1.6 M (0.022 mol) was added slowly at −70° C. to a solution of intermediate (5) (0.018 mol) in THF (50 ml). The mixture was stirred at −70° C. for 1 hour, brought to −40° C., then cooled to −70° C. A solution of interm. 7 (0.018 mol) in THF (40 ml) was added slowly. The mixture was stirred at −70° C. for 1 hour, then brought to −20° C., hydrolyzed with H2O and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue (6.5 g) was purified by column chromatography over silica gel (eluent: toluene/EtOAc 90/10; 15-40 μM). Two fractions (F1 and F2) were collected and the solvent was evaporated. F1 (2.4 g) was crystallized from diethyl ether. The precipitate was filtered off and dried. Yield: 1.8 g of compound (4) (29%); mp. 123° C. F2 (0.9 g) was crystallized from diethyl ether. The precipitate was filtered off and dried. Yield: 0.2 g of compound (5) (3%); mp. 120° C.
c) Preparation of




nBuLi 1.6 M in exane (0.107 mol) was added dropwise at −78° C. under N2 flow to a mixture of intermediate (6) (0.089 mol) in THF. The mixture was stirred at −78° C. for 1 hour. A mixture of interm. 7 (150 ml) was added at −78° C. under N2 flow. The mixture was stirred at −78° C. for 2 hours, brought to 0° C., poured out into H2O and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue (31 g) was purified by column chromatography over silica gel (eluent: cyclohexane/EtOAc 85/15; 20-45 μm). Two pure fractions were collected and their solvents were evaporated. Yielding: 11 g of compound (7) (38%) and 8.2 g of compound (8) (28%).
d) Preparation of




A solution of chloromethylbenzeen (0.0069 mol) in diethyl ether (8 ml) was added slowly to a suspension of Mg (0.0069 mol) in a small amount of diethyl ether. The mixture was stirred at room temperature for 30 minutes (disparition of Mg), then cooled to 5° C. A solution of interm. 27 (0.0027 mol) in THF (8 ml) was added slowly. The mixture was stirred at 5° C. for 15 minutes, then at room temperature for 2 hours, poured out into H2O and filtered over celite. The precipitate was washed with EtOAc. The filtrate was extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue (1 g) was purified by column chromatography over kromasil (eluent: CH2Cl2 100 to CH2Cl2/CH3OH 99/1; 15-40 μm). The pure fractions were collected and the solvent was evaporated. The residue (0.5 g, 56%) was crystallized from diethyl ether. The precipitate was filtered off and dried. Yielding: 0.14 g of compound 503 (15%).
EXAMPLE B4
Examples of Endgoup Modifications
a) Preparation of




A mixture of




(prepared according to example B3.c) (0.018 mol) in HCl 3N (60 ml) and THF (60 ml) was stirred at 60° C. overnight. The mixture was basified with a K2CO3 10% solution and extracted with CH2C2. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. Yield: 4.6 g of compound (156) (82%).

b) Preparation of




A mixture of




(prepared according to example B3.c) (0.0122 mol) in HCl 3N (40 ml) and THF (40 ml) was stirred and refluxed overnight, poured out into water, basified with K2CO3 10% and extracted with CH2Cl2. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: cyclohexane/EtOAc 40/60; 15-40 μm). The pure fractions were collected and the solvent was evaporated. Yield: 2 g of compound (9) (52%); mp. 226° C.

c) Preparation of




A mixture of compound (4) (0.0015 mol), 2-methoxyethanamine (0.003 mol) and K2CO3 (0.003 mol) in DMF (5 ml) was stirred at 140° C. for 48 hours. H2O was added. The mixture was extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue (1 g) was purified by column chromatography over silica gel (eluent: cyclohexane/EtOAc 60/40; 15-40 μm). Two fractions were collected and the solvent was evaporated. Both fractions were crystallized separately from pentane. The precipitate was filtered off and dried. Yield: 0.05 g of compound (10) (9%; mp. 115° C.) and 0.057 g of compound (11) (10%; mp. 107° C.).
d) Preparation of




A mixture of compound (4) (0.0015 mol) in 2-(methylthio)ethanamine (2 ml) was stirred at 120° C. for 8 hours. K2CO3 10% was added. The mixture was extracted with CH2Cl2. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue (2.2 g) was purified by column chromatography over silica gel (eluent: cyclohexane/EtOAc 70/30; 15-40 μm). Two fractions were collected and the solvent was evaporated. The first fraction was crystallized from diethyl ether/petroleum ether. The precipitate was filtered off and dried. Yield: 0.08 g of compound (12) (14%); mp. 120° C. The second fraction was crystallized from diethyl ether. The precipitate was filtered off and dried. Yield: 0.18 g of compound (13) (31%); mp. 125° C.
e) Preparation of




A mixture of compound (4) (0.001507 mol), ethynyltrimethylsilane (0.003013 mol), CuI (0.000151 mol) and Pd(PPh3)4 (0.000151 mol) in N,N-diethylethanamine (5 ml) was stirred at 100° C. for 24 hours. Water was added. The mixture was filtered over celite, washed with EtOAc and the filtrate was extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue (1.3 g) was purified by column chromatography over silica gel (eluent: cyclohexane/EtOAc 85/15; 15-40 μm). The pure fractions were collected and the solvent was evaporated. The residue (0.3 g) was crystallized from pentane. The precipitate was filtered off and dried. Yield: 0.11 g of compound (14) (18%); mp. 114° C.
f) Preparation of




A mixture of compound (14) (0.013 mol) and KF (0.038 mol) in acetic acid (50 ml) was stirred at room temperature for 2 hours. H2O was added and the mixture was extracted with diethyl ether. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue (4.4 g) was purified by column chromatography over silica gel (eluent: cyclohexane/EtOAc 70/30; 15-40 μm). One fraction was collected and the solvent was evaporated. This fraction (3 g, 73%) was crystallized from diethyl ether. The precipitate was filtered off and dried. Yield: 2.45 g of compound (15) (60%); mp. 132° C.
g) Preparation of




A mixture of




prepared according to example B.7.a) (0.0056 mol) in KOH [1M, H2O] (10 ml) and methanol (30 ml) was stirred at room temperature for 1 hour, poured out into water and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue (2.2 g) was purified by column chromatography over silica gel (eluent: cyclohexane/EtOAc 85/15 to 70/30; 15-40 μm). Two fractions were collected and the solvent was evaporated.

The first fraction was crystallized from diethyl ether. The precipitate was filtered off and dried. Yield: 0.2 g of compound (15) (11%); mp. 133° C.
The second fraction was crystallized from diethyl ether. The precipitate was filtered off and dried. Yield: 0.3 g of compound (17) (16%); mp. 128° C.
h) Preparation of




A mixture of compound (4) (0.001205 mol), 2-propyn-1-ol (0.002411 mol), Pd(PPh3)4 (0.000121 mol) and CuI (0.000121 mol) in N,N-diethylethanamine (5 ml) was stirred at 100° C. for 2 hours. Water was added. The mixture was filtered over celite, washed with EtOAc and extracted aith EtOAc. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue (0.7 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 98/2; 15-40 μm). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from petroleum ether and diethyl ether. The precipitate was filtered off and dried. Yield. 0.1 g of compound (18) (23%); mp. 113° C.
i) Preparation of




A mixture of compound (4) (0.006027 mol) and KF (0.024108 mol) in DMSO (20 ml) was stirred at 140° C. The solvent was evaporated till dryness. The residue was solidified in water and diethyl ether. The mixture was extracted with diethyl ether. The organic layer was separated, washed with diethyl ether, washed with a saturated solution of NaCl, dried (MgSO4), filtered and the solvent was evaporated. The residue (1.7 g) was purified by column chromatography over silica gel (eluent: cyclohexane/EtOAc 85/15; 15-40 μm). Three fractions were collected and their solvents were evaporated.
The first fraction was crystallized from petroleum ether. The precipitate was filtered off and dried. Yield: 0.21 g of compound (19) (11%); mp. 92° C.
The second fraction was crystallized from petroleum ether. The precipitate was filtered off and dried. Yield: 0.33 g of compound (20) (17%); mp. 114° C.
j) Preparation of




A mixture of compound (4) (0.003013 mol), acetyl chloride (0.003315 mol) and sodium iodide (0.006027 mol) in CH3CN (10 ml) was stirred and refluxed for 1 hour. K2CO3 10% was added. The mixture was extracted with CH2Cl2. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue (1 g) was purified by column chromatography over silica gel (eluent: cyclohexane/EtOAc 80/20; 15-40 μm). Two fractions were collected and their solvents were evaporated. The first fraction was crystallized from petroleum ether. The precipitate was filtered off and dried. Yield: 0.12 g of compound (21); mp. 110° C.
k) Preparation of




A mixture of compound (21) (0.000898 mol), trimethylsilanecarbonitrile (0.001347 mol) and Pd(PPh3)4 (0.00009 mol) in N,N-diethylethanamine (5 ml) was stirred at 100° C. for 2 hours. Water was added. The mixture was extracted with EtOAc. The organic layer was separated, dried (MgSO4). filtered and the solvent was evaporated. The residue (0.4 g) was purified by column chromatography over silica gel (eluent: cyclohexane/EtOAc 80/20; 15-40 μm). The pure fractions were collected and the solvent was evaporated. The residue (0.18 g, 62%) was crystallized from petroleum ether. The precipitate was filtered off and dried. Yield: 0.13 g of compound (22) (45%); mp. 138° C.
l) Preparation of




A mixture of compound (4) (0.00603 mol), Pd(OAc)2 (0.000603 mol), PPh3 (0.00904 mol) and K2CO3 (0.012054 mol) in CO (gas) and methanol (40 ml) was stirred at 90° C. for 8 hours under a 5 bar pressure of CO. H2O was added. The mixture was extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue (6 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 100/0 to 98/2; 15-35 μm). Four fractions (F1-F4) were collected and the solvent was evaporated. Yield: 0.13 g (cis) F1; 0.02 g F2 (cis, compound 25); 0.055 g F3 (trans, 3%) and 0.11 g F4 (trans; compound 26).
F1 was crystallized from petroleum ether. The precipitate was filtered off and dried. Yield: 0.03 g of compound (23) (1%); mp. 91° C.
F3 was crystallized from petroleum ether. The precipitate was filtered off and dried. Yield: 0.035 g of compound (24) (1%); mp. 99° C.
m) Preparation of




A mixture of compound (4) (0.009 mol) and Zn (0.027 mol) in acetic acid (30 ml) was stirred at 60° C. for 4 hours, filtered over celite, washed with CH2Cl2, evaporated till dryness, solubilized in CH2Cl2 and washed with K2CO3 10%. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue (4 g) was purified by column chromatography over silica gel (eluent: cyclohexane/EtOAc 75/25; 15-40 μm). One fraction was collected and the solvent was evaporated. This fraction (1 g 37%) was crystallized from petroleum ether. The precipitate was filtered off and dried. Yield: compound (25); mp. 88° C.
n) Preparation of




A mixture of compound (4) (0.001502 mol), Sn(CH3)4 (0.003004 mol) and Pd(PPh3)4 (0.00015 mol) in methylbenzene (5 ml) was stirred and refluxed for 3 hours. K2CO3 10% was added. The mixture was extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue (0.7 g) was purified by column chromatography over silica gel (eluent: cyclohexane/EtOAc 85/15; 15-40 μm). Two fractions (F1 and F2) were collected and their solvents were evaporated. Yield: 0.27 g (F 1, starting material) and 0.14 g (F2). F2 was crystallized from pentane and petroleum ether. The precipitate was filtered off and dried. Yield: 0.08 g of compound (27) (17%); mp. 110° C.
o) Preparation of




A mixture of compound (4) (0.001507 mol), tributylethenylstannane (0.002260 mol) and Pd(PPh3)4 (0.000151 mol) in dioxane (5 ml) was stirred at 80° C. for 8 hours. Water was added. The mixture was filtered over celite, washed with EtOAc and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue (0.65 g) was purified by column chromatography over silica gel (eluent: cyclohexane/EtOAc 90/10; 15-40 μm). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from petroleum ether. The precipitate was filtered off and dried. Yield: 0.07 g of compound (28) (14%); mp. 108° C.
p) Preparation of




A mixture of compound (5) (0.001507 mol), triphenyl(phenylmethyl)stannane (0.002260 mol) and Pd(PPh3)4 (0.000151 mol) in dioxane (5 ml) was stirred at 80° C. for 8 hours. Water was added. The mixture was extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue (1.4 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/EtOAc 96/4; 15-40 μm). The pure fractions were collected and the solvent was evaporated. The residue (0.38 g) was crystallized from petroleum ether. The precipitate was filtered off and dried. Yield: 0.16 g of compound (29) (28%); mp. 112° C.
q) Preparation of




A mixture of compound (4) (0.001507 mol), tributyl-2-thienylstannane (0.00226 mol) and Pd(PPh3)4 (0.0001507 mol) in dioxane (5 ml) was stirred at 80° C. for 8 hours. K2CO3 10% was added. The mixture was extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue (1.7 g) was purified by column chromatography over silica gel (eluent: cyclohexane/EtOAc 85/15; 15-40 μm). The pure fractions were collected and the solvent was evaporated. The residue (0.65 g) was crystallized from diethyl ether. The precipitate was filtered off and dried. Yield: 0.35 g of compound (30) (61%); mp. 142° C.
r) Preparation of




A mixture of compound (4) (0.0015 mol), 3-thienyl boronic acid (0.00226 mol), Pd(PPh3)4 (0.00015 mol) and dioxane was stirred and refluxed for 24 hours. K2CO3 10% was added. The mixture was extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue (0.8 g) was purified by column chromatography over silica gel (eluent: cyclohexane/EtOAc is 80/20; 15-40 μm). The pure fractions were collected and the solvent was evaporated. The residue (0.4 g, 70%) was crystallized from petroleum ether. The precipitate was filtered off and dried. Yield: 0.39 g of compound (31) (68%); mp. 113° C.
s) Preparation of




A mixture of compound (4) (0.003 mol), glycine methyl ester monohydrochloride (0.0066 mol) and Pd(PPh)4 (0.0003 mol) in Et3N (2 ml) and toluene (10 ml) was stirred at 100° C. under 5 bar pressure of CO for 8 hours, filtered over celite, washed with CH2Cl2 and evaporated. The residue (2 g) was purified by column chromatography over silica gel (eluent: cyclohexane/EtOAc 80/20; 75-35 μm). One fraction was collected and the solvent was evaporated. This fraction (1 g 80%) was crystallized from diethyl ether. The precipitate was filtered off and dried. Yielding: 0.46 g of compound (32) (37%).
t) Preparation of




A mixture of compound (4) (0.003 mol) and hydrazinecarboxaldehyde (0.0045 mol) in 1-butanol (15 ml) was stirred and refluxed overnight, poured out into water and extracted with CH2Cl2. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 95/5/0.1; 15-40 μm). Two fractions (F1 and F2) were collected and their solvents were evaporated. Yield: 0.3 g F1 and 0.3 g F2.
F1 was crystallized from CH3CN and diethyl ether. The precipitate was filtered off and dried. Yield: 0.102 g of compound (33); mp. 224° C.
F2 was crystallized from CH3CN and diethyl ether. The precipitate was filtered off and dried. Yield: 0.2 g of compound (34); mp. 185° C.
u) Preparation of




A mixture of compound 4 (0.015 mol) and NaN3 (0.045 mol) in DMF (50 ml) was stirred at 140° C. for 2 hours. K2CO310% was added and the mixture was extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue (6 g) was purified by column chromatography over silica gel (eluent: cyclohexane/EtOAc 60/40; 15-40 μm). The first fraction was collected and the solvent was evaporated. The residue was crystallized from diethyl ether. The precipitate was filtered off and dried. Yield: 1.26 g of compound (35) (24%); mp. 160° C.
v) Preparation of




A mixture of compound (4) (0.009 mol) and thiourea (0.0099 mol) in ethyl alcohol (30 ml) was stirred and refluxed for 12 hours and a solution of KOH (0.0149 mol) in H2O (5 ml) was added slowly. The mixture was stirred and refluxed for 1 hour, poured out into water and extracted with CH2Cl2. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (cyclohexane/EtOAc 70/30; 15-40 μm). The pure fractions were collected and the solvent was evaporated. Yielding: 1.1 g of F1 (37%) and 0.4 g of F2 (13%). F1 was crystallized from 2-propanone. The precipitate was filtered off and dried. Yielding: compound (36). F2 was crystallized from 2-propanone. The precipitate was filtered off and dried. Yielding: compound (37).
w) Preparation of




CH3I (0.0034 mol) was added slowly at room temperature to a solution of compound (36) (0.0015 mol), compound (37) (0.0015 mol) and K2CO3 (0.0034 mol) in acetone (15 ml). The mixture was stirred at room temperature for 8 hours. Water was added and the mixture was extracted with CH2Cl2. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue (1.2 g) was purified by column chromatography over silica gel (eluent: cyclohexane/EtOAc 85/15; 15-40 μm). The pure fractions were collected and the solvent was evaporated. Yielding: 0.6 g F1 (57%), and 0.18 g F2 (17%). F1 was crystallized from diethyl ether. The precipitate was filtered off and dried. Yielding: 0.28 g compound (38) (27%). F2 was crystallized from diethyl ether. The precipitate was filtered off and dried. Yielding: 0.065 g of compound (39) (6%).
x) Preparation of




A mixture of




prepared according to example B3b (0.0014 mol) in HCl 3N (5 ml) and THF (5 ml) was stirred and refluxed for a weekend, then poured out into H2O, basified with K2CO3 and extracted with CH2Cl2. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. Yielding: 0.5 g of F. This fraction F was crystallized from 2-propanone. The precipitate was filtered off and dried. Yielding: 0.35 g of compound (40) (74%).

y) Preparation of




A mixture of compound (5) (0.045 mol), acetamide (0.90013 mol) and K2CO3 (0.225 mol) was stirred and refluxed at 200° C. for 2 hours, cooled at room temperature, poured out into H2O/CH2Cl2; and extracted with CH2Cl2. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated till dryness. The residue (14.4 g) was crystallized from CH3OH. The precipitate was filtered off and dried. The filtrate was evaporated. The residue (11.27 g) was purified by column chromatography over silica gel (eluent CH2Cl2/CH3OH/NH4OH 96/4/0.1; 15-35 μm). The pure fractions were collected and the solvent was evaporated. Yielding: 4.2 g of compound (188) (65%).
z) Preparation of




A mixture of compound (188) (0.00032 mol), benzoic acid (1.5 equiv., 0.00048 mol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide. HCl (1:1) (1.5 equiv., 0.00048 mol), N-hydroxybenzotriazole (1.5 equiv., 0.00048 mol) and Et3N (1 equiv., 0.00032 mol) in CH2CL2 (2 ml) was stirred at room temperature for 15 hours. The solvent was evaporated. The residue was purified by HPLC and the product fractions were collected and the solvent was evaporated. Yield: 0.066 g of compound (205) (49.50%).
aa) Preparation of




A mixture of interm. 20 (0.001507 mol) in HCl 3N (10 ml) and THF (10 ml) was stirred at room temperature for 8 hours, basified with K2CO3 10% and extracted with CH2Cl2. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporate. The residue (1.2 g) was purified by column chromatography over silica gel (eluent: cyclohexane/EtOAc 85/15; 15-40 μm). The pure fractions were collected and the solvent was evaporated. The residue (0.4 g) was crystallized from petroleum ether. The precipitate was filtered off and dried. Yield: 0.3 g of compound (6) (58%); mp. 108° C.
ab) Preparation of




A mixture of compound 213 (prepared according to B4) (0.00305 mol) and CH3ONa (30% in CH3OH) (0.00916 mol) in CH3OH (25 ml) was stirred and refluxed for 15 hours then cooled to room temperature, poured out into H2O and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated till dryness. The residue (1.1 g) was purified by column chromatography over silica gel (eluent: cyclohexane/EtOAc; 40/60; 15-40 μm). Two fractions were collected and the solvent was evaporated. Yielding: 0.3 g F1 and 0.5 g F2 (50%) F2 was crystallized from diethyl ether/petroleum ether. The precipitate was filtered off and dried. Yielding: 0.26 g F1 was crystallized from pentane. The precipitate was filtered off and dried. Yielding: 0.19 g. This fraction was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH; 98/2; 15-40 μm). The pure fractions were collected and the solvent was evaporated. Yielding: 0.11 g. This fraction was purified by column chromatography over kromasil (eluent: CH3OH/H2O; 70/30). The pure fractions were collected and the solvent was evaporated. Yielding: 0.09 g. (9%) This fraction was crystallized from diethyl ether. The precipitate was filtered off and dried. Yielding: 0.08 g of compound 419 (8%).
EXAMPLE B5
Preparation of




Iodomethane (0.00456 mol) was added at 5° C. to a mixture of compound (9) (0.0019 mol), compound (8) (0.0019 mol) and tBuOK (0.00456 mol) in THF (30 ml) under N2 flow. The mixture was stirred at room temperature overnight, poured out into H2O and extracted with CH2Cl2. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: cyclohexane/EtOAc 65/35; 15-40 μm). Two fractions were collected and the solvent was evaporated. Yield: 0.35 g of compound (42) (30%; mp. 125° C.) and 0.35 g of compound (43) (30%; mp. 116° C.).
EXAMPLE B6
a) Preparation of




NaH 60% (0.01068 mol) was added at 0° C. under N2 flow to a mixture of compound (8) and compound (9) (0.0089 mol). The mixture was stirred for 30 minutes.
Ethyl bromoacetate (0.01068 mol) was added at 0° C. The mixture was stirred at room temperature for 1 hour, hydrolized with water and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: cyclohexane/EtOAc 60/40; 15-40 μm). The desired fractions (F1-F4) were collected and the solvent was evaporated. Yield: 0.11 g F1; 0.13 g F2; 0.75 g F3 and 0.8 g F4.
F3 was crystallized from diethyl ether. The precipitate was filtered off and dried. Yield: compound (44); mp. 152° C.
F4 was crystallized from diethyl ether. The precipitate was filtered off and dried. Yield: compound (45); mp. 147° C.
b) Preparation of




Bromomethylbenzene (0.007 mol) was added dropwise at 0° C. under N2 flow to a solution of compound (8) and compound (9) (0.0064 mol) and NaH 60% (0.007 mol) in DMF (40 ml). The mixture was stirred at room temperature for 1 hour, hydrolized with water and extracted with EtOAc. The organic layer was separated, washed with water, dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: cyclohexane/EtOAc 70/30; 15-40 μm). The desired fractions (F1-F4) were collected and the solvent was evaporated. Yield: 0.15 g F1, 0.1 g F2, 0.6 g F3 (23%) and 0.8 g F4.
F3 was crystallized from diethyl ether. The precipitate was filtered off and dried. Yield: 0.13 g of compound (46); mp. 137° C.
F4 was crystallized from DIPE and petroleum ether. The precipitate was filtered off and dried. Yield: compound (47); mp. 130° C.
EXAMPLE B7
a) 3-Chlorobenzenecarboperoxoic acid (0.088 mol) was added at 0° C. to a solution of compound (48) (prepared according to example B2) (0.044 mol) in CH2Cl2 (200 ml) and the mixture was stirred at room temperature for 12 hours. The mixture was washed with K2CO310%. The organic layer was dried (MgSO4), filtered off and evaporated. The residue was recrystallized from (C2H5)2O. Yield: 8.2 g of cyclohexyl(3-methyl-6-quinolinyl)methanone,1-oxide (compound 49) (69%).
b) 4-Methyl benzenesulfonyl chloride (0.043 mol) was added to a solution of compound (49) (0.028 mol) in K2CO3 (400 m) and CH2Cl2 (400 ml) and the mixture was stirred at room temperature for 1 hour. The mixture was extracted with CH2Cl2. The organic layer was dried (MgSO4), filtered off and evaporated. The residue was recrystallized from (C2H5)2O. Yield: 6.64 g of 6-(cyclohexylcarbonyl)-3-methyl-2(1H)-quinolinone (compound 50) (85%); mp. 256.1° C.
EXAMPLE B8
a) Preparation of




A mixture of compound (7) (0.0229 mol), hydroxylamine (0.0252 mol) and N,N-diethylethanamine (0.0252 mol) in ethanol (100 ml) was stirred and refluxed for 6 hours, poured out into water and extracted with CH2Cl2. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue was crystallized from CH3CN. The precipitate was filtered off and dried. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/EtOAc 80/20; 15-40 μm). Two fractions were collected and the solvent was evaporated. Yielding: 2.8 g of compound (44) (36%; mp. 133° C.) and 3 g of compound (45) (38%; mp. 142° C.).
b) Preparation of




Hydrazine (0.41 mol) was added at room temperature to a solution of compound (7) (0.015 mol) in ethanol (75 ml). The mixture was stirred and refluxed for 1 night, poured out into water and extracted with CH2Cl2. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 98/2/0.1). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from diethyl ether. The precipitate was filtered off and dried. Yielding: 0.8 g of compound (53) (15%); mp. 110° C.
EXAMPLE B9
Preparation of




Procedure for compounds 400, 401, 402, 403, 404 and 405. A mixture of interm. 21 (prepared according to A11) (0.000269 mol), amantadine hydrochloride (0.000404 mol; 1.5 eq.), N′-(ethylcarbonimidoyl)-N,N-dimethyl-1,3-propanediamine hydrochloride (0.000404 mol; 1.5 equiv.), 1-hydroxy-1H-benzotriazole (0.000404 mol; 1.5 equiv.) and Et3N (0.000269 mol) in CH2Cl3 (2 ml) was stirred at room temperature for 12 hours. The solvent was evaporated. The residue was purified by HPLC. The product fractions were collected and the solvent was evaporated. Yield: 0.063 g of compound 520 (46.37%).
EXAMPLE B10
Preparation of




A mixture of intermediate 27 (0.0026 mol) and intermediate 26 (0.0026 mol) in EtOH (380 ml) and H2SO4 conc. (19 ml) was stirred and refluxed for 15 hours, the cooled to room temperature, poured out into ice water, basified with K2CO3 and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue (17.9 g) was purified by column chromatography over silica gel (eluent: cyclohexane/EtOAc; 80/20; 15-35 μm). The pure fractions were collected and the solvent was evaporated. Yielding: 0.85 g of F1, 1.1 g F2 and 11.5 g of F3. F1 and F2 were crystallized separately from petroleum ether. The precipitate was filtered off and dried. Yielding: 0.34 g of compound 233.
EXAMPLE B11
Preparation of




A mixture of compound 22 (prepared according to B4) (0.004 mol) in HCl (3N) (20 ml) and THF (20 ml) was stirred and refluxed for 8 hours, poured out on ice, basified with NH4OH and extracted with CH2Cl2. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue (1.2 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH; 93/7/0.5; 15-40 μm). Two fractions were collected and the solvent was evaporated. Yielding: 0.5 g F1 (41%) and 0.4 g of F2. F1 was crystallized from petroleum ether. The precipitate was filtered off and dried. Yielding: 0.17 g of compound 511 (14%).
EXAMPLE B12
Preparation of




A mixture of compound 524 (prepared according to B9a) (0.0018 mol) and KOH 85% (0.0094 mol) in EtOH (15 ml) was stirred and refluxed for 24 hours, poured out into H2O and extracted with CH2Cl2. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/Cyclohexane 80/20; 15-40 μm). Two fractions were collected and the solvent was evaporated. Yielding: 0.35 g F1 (64%) and 0.17 g (SM) F1 was crystallized from diethyl ether. The precipitate was filtered off and dried. Yielding: 0.33 g of compound 514 (60%) (mp.:185° C.).
EXAMPLE B13
Preparation of




A mixture of interm. 28 (0.019 mol), 2-benzofuranylboronic acid (0.028 mol), Pd(PPh3)4 (0.001 mol) and BHT (a few quantity) in dioxane (25 ml) and Na2CO3 [2] (25 ml) was stirred and refluxed for 8 hours and extracted with EtOAc. The aqueous layer was basified with NH4OH and extracted with CH2Cl2. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue (3.6 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 99/1; 15-40 μm). The pure fractions were collected and the solvent was evaporated. Yielding: 1.8 g (33%). This fraction was crystallized from 2-propanone/diethyl ether. The precipitate was filtered off and dried. Yielding: 0.39 g of compound 515 (7%) (mp.:134° C.).
EXAMPLE B14
Preparation of




Triethylsilane (0.0012 mol) was added slowly at room temperature to a solution of interm. 32 (0.004 mol) in CF3COOH (5 ml) and AcOH (10 ml). NaBH4 (0.0012 mol) was added portionwise under N2 flow. The mixture was stirred at room temperature for 8 hours, poured out on ice, basified with K2CO3 and extracted with CH2Cl2. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue (1.2 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 99/1; 15-40 μm). Two fractions were collected and the solvent was evaporated. Yielding: 0.5 g F1 (43%) and 0.4 g F2. F1 was dissolved in iPrOH. HCl/iPrOH (1 eq) were added. The precipitate was filtered off and dried; Yielding: 0.32 g of compound 526 (mp.: 248° C.).
EXAMPLE B15
Preparation of




A mixture of interm. 33 (0.082 mol) and 3-chloro-2-ethyl-2-butenal (0.098 mol) in AcOH (200 ml) was stirred and refluxed for 8 hours. The solvent was evaporated till dryness. The residue was dissolved in CH2Cl2 and washed with K2CO3 10%. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue (27 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/EtOAc 95/5 to 92/8; 15-35 μm). Two fractions were collected and the solvent was evaporated. Yielding: 0.7 g of F1 and 5.3 g F2. F1 was crystallized from 2-propanone/diethyl ether. The precipitate was filtered off and dried. Yielding: 0.25 g of compound 471 (2%) (mp.: 140° C.).
Tables 1 to 8 list the compounds of formula (I-A) and (I-B) which were prepared according to one of the above examples.







TABLE 1













 













Co.
Ex.




physical


no.
no.
R2
R3
R4
R1
data
















54
B2
Cl
ethyl
H




—


 


3
B3a
Cl
ethyl
H




mp. 145° C.


 


55
B3b
Cl
ethyl
H




mp. 131° C.


 


56
B3b
Cl
ethyl
H




mp. 104° C.


 


57
B3b
Cl
ethyl
H
phenylethyl
mp. 100° C.


 


58
B3b
Cl
ethyl
H




mp. 126° C.


 


59
B3b
Cl
ethyl
H




mp. 150° C.


 


60
B3b
Cl
ethyl
H




mp. 138° C.


 


61
B3b
OCH3
ethyl
H




—


 


62
B3b
OCH3
ethyl
H




mp. 130° C.


 


63
B3b
OCH3
ethyl
H




mp. 116° C.


 


64
B3b
Cl
ethyl
H
—(CH2)2—O—CH3
mp. 82° C.


65
B3b
OCH3
ethyl
H
1-methylcyclohexyl
mp. 82° C.


66
B3b
OCH3
ethyl
H
3-methoxycyclohexyl
trans;








mp. 94° C.


67
B3b
OCH3
ethyl
H
3-methoxycyclohexyl
cis;








mp. 108° C.


68
B3b
OCH3
ethyl
H
4-(methylethoxy-
(A),







cyclohexyl
mp. 820° C.


69
B3b
OCH3
ethyl
H
4-[C(CH3)3]cyclohexyl
cis;








mp. 92° C.


70
B3b
OCH3
ethyl
H
4-[C(CH3)3]cyclohexyl
trans;








mp. 108° C.


71
B3b
OCH3
ethyl
H
4-methylcyclohexyl
(B),








mp. 92° C.


72
B3b
OCH3
ethyl
H
4-methylcyclohexyl
(A),








mp. 80° C.


2
B2
Cl
ethyl
H
CH2—CH(CH3)2
mp. 82° C.


73
B3b
Cl
ethyl
H
—CH2—O—C2H5
mp. 82° C.


48
B2
H
methyl
H
cyclohexl
—


 


74
B4
I
ethyl
H




—


 


75
B4
I
ethyl
H




mp. 124° C.


 


76
B4
I
ethyl
H




mp. 138° C.


 


77
B4
I
ethyl
H




mp. 120° C.


 


78
B4
CN
ethyl
H




mp. 128° C.


 


79
B4
CN
ethyl
H




mp. 136° C.


 


80
B4
CN
ethyl
H




mp. 120° C.


 


81
B4
CN
ethyl
H




mp. 139° C.


 


82
B4
methyl
ethyl
H




mp. 106° C.


 


83
B4
methyl
ethyl
H




mp. 149° C.


 


84
B4
methyl
ethyl
H




mp. 118° C.


 


85
B4
methyl
ethyl
H




mp. 180° C.


 


86
B4
methyl
ethyl
H
phenylethyl
mp. 53° C.


 


87
B4
methyl
ethyl
H




mp. 87° C.


 


88
B4
methyl
ethyl
H
—CH2—CH(CH3)2
mp. 68° C.


 


89
B4
methyl
ethyl
H




mp. 120° C.


 


31
B4
3-thiazolyl
ethyl
H
4-methoxycyclohexyl
cis; 113° C.


90
B3b
OCH3
H
H
4-methoxycyclohexyl
trans,








mp. 126° C.


91
B3b
OCH3
H
H
4-methoxycyclohexyl
cis,








mp. 100° C.


92
B3b
OCH3
H
CH3
4-methoxycyclohexyl
cis;








mp. 120° C.


93
B3b
OCH3
H
CH3
4-methoxycyclohexyl
trans;








mp. 111° C.


94
B3b
OCH3
methyl
H
4-methoxycyclohexyl
cis,








mp. 96° C.


95
B3b
OCH3
phenyl
H
4-methoxycyclohexyl
cis; HCl








(1:1),








mp. 138° C.


96
B3b
OCH3
propyl
H
4-methoxycyclohexyl
trans; 








mp. 118° C.


97
B3b
OCH3
propyl
H
4-methoxycyclohexyl
cis;








mp. 108° C.


98
B3b
OCH3
methyl
H
4-methoxycyclohexyl
cis;








mp. 104° C.


99
B4
N(CH3)2
ethyl
H




(B); mp. 102° C.


 


100
B3b
Cl
ethyl
H




mp. 114° C.


 


101
B4
methyl
ethyl
H
4-butoxycyclohexyl
cis;








mp. 86° C.


 


102
B3b
Cl
ethyl
H




mp. 78° C.


 


103
B3b
Cl
ethyl
H




mp. 91° C.


 


104
B4
N(CH3)2
ethyl
H




mp. 103° C.


 


105
B4
N(CH3)2
ethyl
H




mp. 170° C.


 


106
B3b
Cl
ethyl
H




mp. 137° C.


 


107
B3b
Cl
ethyl
H




mp. 137° C.


 


108
B4
methyl
ethyl
ethyl
4-methoxycyclohexyl
cis;








mp. 91° C.


109
B4
methyl
ethyl
H
4-ethoxycyclohexyl
trans;








mp. 150° C.


 


110
B4
methyl
ethyl
H




mp. 90° C.


 


111
B4
methyl
ethyl
H




mp. 94° C.


 


112
B4
methyl
ethyl
H




mp. 176° C.


 


113
B4
methyl
ethyl
H




mp. 106° C.


 


114
B4
propyl
H
H
4-methoxycyclohexyl
cis;








mp. 74° C.


115
B4
methyl
ethyl
H
4-ethoxycyclohexyl
cis;








mp. 108° C.


 


116
B4
methyl
ethyl
H




mp. 110° C.


 


117
B3b
Cl
ethyl
H




mp. 124° C.


 


118
B3b
Cl
ethyl
H




mp. 107° C.


 


119
B3b
Cl
ethyl
H




mp. 129° C.


 


120
B4
methyl
ethyl
H




mp. 106° C.


 


41
B3b
Cl
ethyl
H




trans; mp. 157° C.


 


182
B3b
methyl
ethyl
H




cis; mp. 170° C.


 


183
B3b
methyl
ethyl
H




trans; mp. 144° C.


 


184
B3b
methyl
ethyl
H




mp. 138° C.


 


185
B3b
Cl
ethyl
H




mp. 120° C.


 


186
B3b
Cl
ethyl
H






 


187
B3b
methyl
ethyl
H




mp. 162° C.


 


216
B4
C≡N
ethyl
H




mp.: 160° C.


 


217
B4
methyl
ethyl
H




.ethanedioate (1:1); mp.: 143° C.


 


218
B4
I
ethyl
H




mp.: 102° C.


 


219
B4
C≡N
ethyl
H




mp.: 115° C.


 


220
B4
Cl
ethyl
H




(A); mp.: 107° C.


 


221
B4
Cl
ethyl
H




(B); mp.: 113° C.


 


222
B4
I
ethyl
H




mp.: 206° C.


 


223
B4
Cl
ethyl
H




(trans); mp.;117° C.


 


224
B4
methyl
ethyl
H




(A); mp. 103° C.


 


225
B2
Cl
ethyl
H




mp.: 94° C.


 


226
B3b
Cl
ethyl
H




(trans); mp.: 157° C.


 


227
B3c
methoxy




H




mp.: 204° C.


 


228
B4
Cl
ethyl
H




(A); mp.: 136° C.


 


229
B3b
n-propyl
H
H




(trans);.HCl (1:1); mp.:150° C.


 


230
B3b
Cl
ethyl
H




mp.: 116° C.


 


231
B3b
Cl
ethyl
H




mp.: 120° C.


 


232
B3b
Cl
ethyl
H




mp.: 112° C.


 


233
B10
i-propyl
H
C(═O)O—C2H5




(cis); mp.: 91° C.


 


234
B4
methyl
ethyl
H




mp.: 122° C.


 


235
B4
methyl
ethyl
H




mp.: 106° C.


 


236
B4
methyl
ethyl
H




mp.: 104° C.


 


237
B4
methyl
ethyl
H




mp.: 90° C.


 


238
B4
methyl
H
H




(cis); mp.: 80° C.


 


239
B3b
Cl
ethyl
H




(trans); mp.: 126° C.


 


240
B3b
Cl
ethyl
H




(cis); mp.: 128° C.


 


241
B4
methyl
ethyl
H




(A); mp.: 90° C. 


 


242
B4
methyl
ethyl
H




(B); mp.: 110° C.


 


243
B3b
Cl
ethyl
H




mp.: 134° C.


 


244
B3b
Cl
ethyl
H




mp.: 127° C.


 


245
B4
NHC(═O)NH2
ethyl
H




(cis); mp.: 176° C.


 


246
B4
methyl
ethyl
H




(B)


 


247
B3b
Cl
ethyl
H




mp.: 92° C.


 


248
B4
methyl
ethyl
H




(A); mp.: 80° C.


 


249
B3b
Cl
ethyl
H




(B); mp.: 138° C.


 


250
B4
methyl
ethyl
H




(trans); mp.: 118° C.


 


251
B4
methyl
ethyl
H




(B);.HCl (1:1)


 


252
B3b
Cl
ethyl
H




(A)


 


253
B3b
Cl
ethyl
H




(B)


 


254
B3b
methyl
ethyl
H




mp.: 74° C.


 


255
B4
methyl
ethyl
H




(cis); mp.: 68° C.


 


256
B4
methyl
ethyl
H




mp.: 210° C.


 


257
B4
methyl
ethyl
H




mp.. 113° C.


 


258
B4
methyl
ethyl
H




mp.: 92° C.


 


259
B3b
methyl
ethyl
H




mp.: 115° C.


 


260
B3b
methyl
ethyl
H




mp.: 60° C.


 


261
B3b
Cl
ethyl
H




(A); mp.: 86° C.


 


262
B3b
Cl
ethyl
H




(B); mp.: 101° C.


 


263
B3b
methyl
ethyl
H




mp.: 130° C.


 


264
B3b
Cl
ethyl
H




(A); mp.: 124° C.


 


265
B3b
Cl
ethyl
H




(B); mp.: 126° C.


 


266
B4
N(CH3)2
ethyl
H




(trans), mp.: 102° C.


 


267
B4
N(CH3)2
ethyl
H




(cis);.HCl (1:1); mp.: 170° C.


 


268
B4
methyl
ethyl
H




(A);.HCl (1:1); mp.: 206° C.


 


269
B4
methyl
ethyl
H




mp.: 104° C.


 


270
B3b
methyl
ethyl
H




mp.: 117° C.


 


271
B4
NCH2H5OCH3
ethyl
H




—


 


272
B4
methyl
ethyl
H




—


 


273
B4
NH2
ethyl
H




—


 


274
B3b
Cl
ethyl
H




—


 


275
B3b
Cl
ethyl
H




mp.: 99° C.


 


276
B3b
Cl
ethyl
H




mp.: 95° C.


 


277
B4
methyl
ethyl
H




mp.: 105° C.


 


278
B3b
Cl
ethyl
H




mp.: 141° C.


 


279
B4
Cl
ethyl
H




mp.: 168° C.


 


280
B4
Cl
ethyl
H




—


 


281
B4
Cl
ethyl
H




mp.: 140° C.


 


282
B4
Cl
ethyl
H




mp.: 169° C.


 


283
B4
methyl
ethyl
H




mp.: 96° C.


 


284
B3b
Cl
CH2N(CH3)2
H




mp.: 115° C.


 


285
B4
methyl
ethyl
H




mp.: 133° C.


 


286
B4
methyl
CH2OCH3
H




(trans); mp.: 106° C.


 


287
B4
methyl
CH2N(CH3)2
H




(cis); mp.: 110° C.


 


288
B3b
Cl
n-propyl
H




mp.: 110° C.


 


289
B4
NH2
ethyl
H




mp.: 218° C.


 


290
B4
methyl
n-propyl
H




mp.: 90° C.


 


291
B3b
Cl
n-propyl
H




(cis); mp.: 128° C.


 


292
B3b
Cl
n-propyl
H




(trans); mp.: 104° C.


 


293
B3b
Cl
ethyl
H




mp.:106° C.


 


294
B4
methyl
n-propyl
H




(cis); mp.: 94° C.


 


295
B4
methyl
CH2N(CH3)2
H




mp.: 83° C.


 


296
B3b
Cl
ethyl
H




mp.: 99° C.


 


297
B3b
Cl
ethyl
H




mp.: 110° C.


 


298
B4
methyl
ethyl
H




mp.: 93° C.


 


299
B4
methyl
ethyl
H




mp.: 105° C.


 


300
B4
methyl
ethyl
H




mp.: 114° C.


 


301
B3b
methyl
ethyl
H




mp.: 143° C.


 


302
B4
methoxy
ethyl
H




mp.: 93° C.


 


303
B4
methyl
ethyl
H




mp.: 82° C.


 


304
B4
n-butyl
ethyl
H




—


 


305
B3b
Cl
n-propyl
H




mp.: 125° C.


 


306
B1
methyl
C(═O)OC2H5
H




mp.: 136° C.


 


307
B4
methyl
n-propyl
H




mp.: 81° C.


 


308
B4
methoxy
n-propyl
H




mp.: 80° C.


 


309
B4
I
n-propyl
H




mp.: 120° C.


 


310
B3d
methyl
ethyl
H




.HCl(1:1); mp.: 129° C.


 


311
B3b
Cl
H
H




mp.: 160° C.


 


312
B3b
Cl
H
H




(trans); mp.: 145° C.


 


313
B3b
Cl
H
H




mp.: 103° C.


 


314
B4
n-propyl
n-propyl
H




.HCl (1:1); mp.: 150° C.


 


315
B4
n-propyl
ethyl
H




.HCl (1:1)


 


316
B4
n-propyl
H
H




.HCl (1:1); mp.: 140° C.


 


317
B3b
Cl
H
H




mp.: 168° C.


 


318
B4
methyl
n-propyl
H




.HCl (1:1); mp.: 200° C.


 


509
B3b
Cl
ethyl
H




—


 


510
B4
methyl
ethyl
H




.H2O (1:1)


 


513
B4
methyl
ethyl
H




—


 


516
B4
Cl
ethyl
H




mp.: 120° C.


 


517
B4
I
ethyl
H
CH2CH(CH3)2
—


 


518
B4
Cl
ethyl
H




—


 


519
B4
Cl
ethyl
H




(A + B)


 


521
B4
I
ethyl
H




—


 


522
B4
methyl
ethyl
H




(A)


 


1
B4
methyl
ethyl
H




(A)


 


525
B4
Cl
ethyl
H






 


527
B4
F
ethyl
H




mp.: 116° C.
















TABLE 2













 











Co.
Ex.





no.
no.
R2
X
physical data














5
B3b
Cl
O
trans; mp. 120° C.


121
B3b
1-piperidinyl
O
cis; HCl (1:1)


122
B3b
1-piperidinyl
O
trans; HCl (1:1);






mp. 128° C.


123
B3b
4-thiomorpholinyl
O
cis; mp. 105° C.


124
B3b
4-thiomorpholinyl
O
trans; mp. 115° C.


125
B3b
4-morpholinyl
O
trans; mp. 118° C.


126
B3b
4-morpholinyl
O
cis; mp. 118° C.


127
B3b
—N(CH3)2
O
trans; mp. 96° C.


128
B3b
—N(CH3)2
O
cis; mp. 114° C.


4
B3b
Cl
O
cis; mp. 123° C.


8
B3c
OCH3
O
trans, mp. 68° C.


7
B3c
OCH3
O
cis, mp. 116° C.


6
B4
acetyl
O
trans; mp. 108° C.


129
B4
acetyl
O
cis; mp. 106° C.


11
B4
NH—(CH2)2—OCH3
O
trans; mp. 107° C.


10
B4
NH—(CH2)2—OCH3
O
cis; mp. 115° C.


12
B4
NH—(CH2)2—SCH3
O
cis; mp. 120° C.


13
B4
NH—(CH2)2—SCH3
O
trans; mp. 125° C.


14
B4
—C≡C—Si(CH3)3
O
cis; mp. 114° C.


16
B4
—C≡C—Si(CH3)3
O
trans; mp. 108° C.


15
B4
—C≡CH
O
cis; mp. 132-133° C.


17
B4
—C≡CH
O
trans; mp. 128° C.


18
B4
—C≡C—CH2OH
O
cis; mp. 113° C.


130
B4
—C≡C—CH2OH
O
trans; mp. 108° C.


19
B4
F
O
cis; mp. 92-99° C.


20
B4
F
O
trans; mp. 114° C.


21
B4
I
O
cis; mp. 110° C.


22
B4
CN
O
cis; mp. 137-138° C.


26
B4
H
O
trans


23
B4
—C(═O)—OCH3
O
cis; mp. 91° C.


24
B4
—C(═O)—OCH3
O
trans; mp. 99° C.


25
B4
H
O
cis; mp. 88° C.


27
B4
methyl
O
cis; mp. 110-112° C.


131
B4
methyl
O
trans; mp. 25° C.


28
B4
ethenyl
O
cis; mp. 108° C.


132
B4
ethenyl
O
trans; mp. 103° C.


29
B4
phenyl
O
trans; mp. 112° C.


30
B4
2-thienyl
O
cis; 142° C.


133
B4
2-thiazolyl
O
cis; 108° C.


134
B4
2-furanyl
O
cis; mp. 105° C.


51
B8a
OCH3
N—OH
[1α(A), 4α];






mp. 133° C.


52
B8a
OCH3
N—OH
[1α(B), 4α];






mp. 142° C.


53
B8b
OCH3
NNH2
[1α(Z), 4α];






mp. 110° C.


135
B4
NH2
O
cis; mp. 203° C.


136
B4
NH2
O
trans; mp. 202° C.


137
B4
—C(═O)—OCH(CH3)2
O
cis; mp. 105° C.


138
B4
—C(═O)—OCH(CH3)2
O
trans; mp. 88° C.


38
B4
SCH3
O
cis; mp. 124° C.


39
B4
SCH3
O
trans; mp. 116° C.


 


32
B4




O
cis; mp. 130° C.


 


139
B4
ethyl
O
cis; mp.180° C.


188
B4
NH2
O
cis + trans


 


189
B4




O
cis; mp. 154° C.


 


190
B4




O
trans; mp. 156° C.


 


191
B4




O
cis; mp. >260° C.


 


192
B4




O
.H2O (1:1); trans; mp. 248° C.


 


193
B4




O
cis; mp. 224° C.


 


194
B4




O
trans; mp. 234° C.


 


195
B4




O
cis; mp. 108° C.


 


196
B4




O
trans; mp. 127° C.


 


197
B4




O
cis; mp. 150° C.


 


198
B4




O
trans; mp. 90° C.


 


199
B4




O
LC/MS [M + H]+; 475.4


 


200
B4




O
LC/MS [M + H]+; 464.3


 


201
B4




O
LC/MS [M + H]+; 523.3


 


202
B4




O
LC/MS [M + H]+; 465.3


 


203
B4




O
LC/MS [M + H]+; 475.4


 


204
B4




O
LC/MS [M + H]+; 465.3


 


205
B4




O
—


 


319
B4




O
(cis); .ethanedioate (1:1); mp.: 160° C.


 


320
B4




O
(cis); mp.: 150° C.


 


321
B4
methoxy
CH2
(cis); .HCl (1:1);






mp.:118° C.


322
B4
n-butyl
O
(cis); .HCl (1:1);






mp.:158° C.


 


323
B4




O
—


 


324
B4




O
—


 


325
B4




O
—


 


326
B4




O
—


 


327
B4




O
—


 


328
B4




O
—


 


329
B4




O
—


 


330
B4




O
—


 


331
B4




O
—


 


332
B4




O
—


 


333
B4




O
—


 


334
B4




O
—


 


335
B4




O
—


 


336
B4




O
—


 


337
B4




O
—


 


338
B4




O
—


 


339
B4




O
—


 


340
B4




O
—


 


341
B4




O
—


 


342
B4




O
—


 


343
B4




O
—


 


344
B4




O
—


 


345
B4




O
—


 


346
B4




O
—


 


347
B4




O
—


 


348
B4
CH2OC(═O)CH3
O
(cis); mp.: 74° C.


 


349
B4




O
—


 


350
B4




O
—


 


351
B4




O
—


 


352
B4




O
—


 


353
B4




O
(A); .HCl (1:2) .H2O (1:1); mp.: 166° C.


 


354
B4




O
(cis)


 


355
B4




O
—


 


356
B4




O
—


 


357
B4




O
—


 


358
B4




O
—


 


359
B4




O
—


 


360
B4




O
—


 


361
B4




O
—


 


362
B4




O
—


 


363
B4




O
—


 


364
B4




O
—


 


365
B4




O
—


 


366
B4




O
—


 


367
B4




O
—


 


368
B4




O
—


 


369
B4




O
—


 


370
B4




O
—


 


371
B4




O
—


 


372
B4




O
—


 


373
B4




O
—


 


374
B4




O
—


 


375
B4




O
—


 


376
B4




O
—


 


377
B4




O
—


 


378
B4




O
—


 


379
B4




O
—


 


380
B4




O
—


 


381
B4




O
—


 


382
B4




O
—


 


383
B4




O
(cia); mp.: 148° C.


 


384
B4




O
(trans); mp.: 141° C.


 


385
B4




O
mp.: 130° C.


 


386
B4




O
(cia); mp.: 140° C.


 


387
B4




O
(trans); mp.: 155° C.
















TABLE 3













 











Co.
Ex.





no.
no.
Y.
R1
physical data














140
B4
O




mp. 220° C.


 


141
B4
O




mp. 213° C.


 


142
B4
O




mp. 148° C.


 


143
B4
O
1-methylcyclohexyl
mp. 195-210° C.


144
B4
O
3-methoxycyclohexyl
cis; mp. 156° C.


145
B4
O
3-methoxycyclohexyl
trans;






mp. 156-163° C.


146
B4
O
4-(dimethylethyl)cyclohexyl
mp. 230° C.


147
B4
O
4-(methylethoxy)cyclohexyl
mp. 186° C.


148
B4
O
4-methylcyclohexy
trans; mp. 214° C.


36
B4
S
4-methoxycyclohexyl
cis; mp. 224° C.


37
B4
S
4-methoxycyclohexyl
trans; mp. 220° C.


 


149
B4
O




mp. 188° C.


 


40
B4
O




mp. 192° C.


 


150
B4
O




cis; mp. 226° C.


 


151
B4
O




trans; mp. 226° C.


 


152
B4
O




mp. 213° C.


 


153
B4
O




mp. 200° C.


 


154
B4
O




mp. 210° C.


 


155
B4
O
4,4-dimethylcyclohexyl
mp. 242° C.


388
B4
O
CH2CH(CH3)2
mp. 189° C.


 


389
B4
O




mp. 228° C.


 


390
B4
O




mp. 197° C.


 


391
B4
O




mp. 145° C.


 


392
B4
O




mp. 192° C.


 


393
B4
O




(B); mp.: 224° C.


 


394
B4
O




(A); mp.: 201° C.


 


395
B4
O




(A); mp.: 207° C.


 


396
B4
O




mp.: 212° C.


 


397
B4
O




(B); mp.: 238° C.


 


398
B4
O




mp.: 234° C.


 


399
B4
O




(cis); mp.:192° C.
















TABLE 4













 













Co.
Ex.







no.
no.
R3
R4
R5
R
physical data
















156
B4
ethyl
H
H
OCH3
trans; mp. 252° C.


157
B4
H
H
H
OCH3
(cis + trans); mp. 244° C.


158
B4
H
methyl
H
OCH3
cis; mp. >260° C.


159
B4
methyl
H
H
OCH3
cis; mp. 254° C.


160
B4
methyl
H
H
OCH3
trans; mp.>260° C.


161
B4
propyl
H
H
OCH3
mp. 208° C.


162
B4
propyl
H
H
OCH3
trans; mp. 232° C.


9
B4
ethyl
H
H
OCH3
cis; mp. 224-226° C.


43
B5
ethyl
H
CH3
OCH3
trans; mp. 116° C.


42
B5
ethyl
H
CH3
OCH3
cis; mp. 125° C.


44
B6
ethyl
H
CH2—COOC2H5
OCH3
cis; mp. 152° C.


45
B4
ethyl
H
CH2—COOC2H5
OCH3
trans; mp. 147° C.


46
B4
ethyl
H
benzyl
OCH3
cis; mp.137° C.


47
B4
ethyl
H
benzyl
OCH3
trans; mp. 130° C.


50
B7
methyl
H
H
H
mp. 256.1° C.


163
B4
ethyl
ethyl
H
OCH3
cis; mp. 221° C.


164
B4
ethyl
ethyl
H
OCH3
cis; mp. 221° C.


165
B4
ethyl
ethyl
H
OCH3
trans; mp.215° C.


 


166
B4
ethyl
H




OCH3
LC/MS [M + H]+; 429.4


 


167
B4
ethyl
H




OCH3
LC/MS [M + H]+; 451.3


 


168
B4
H
H
H
OCH3
cis; mp. 106° C.


 


169
B4
ethyl
H




OCH3
LC/MS [M + H]+; 409.3


 


400
B9
ethyl
H




OCH3
—


 


401
B9
ethyl
H




OCH3
—


 


402
B9
ethyl
H




OCH3
—


 


403
B9
ethyl
H




OCH3
—


 


404
B9
ethyl
H




OCH3
—


 


405
B9
ethyl
H




OCH3
—


 


406
B4
ethyl
H




OCH3
—


 


407
B4
ethyl
H




OCH3
—


 


408
B4
ethyl
H




OCH3
—


 


409
B3b




H
H
OCH3
mp.: 168° C.


 


410
B4
CH2OCH3
H
H
OCH3
mp.: 194° C.


 


508
B4
ethyl
H




OCH3
—


 


520
B9
ethyl
H




OCH3
—
















TABLE 5













 












Co.
Ex.






no.
no.
R4
R1
X
physical data















33
B4
H
methoxycyclohexyl
CH
cis; mp. 224° C.


34
B4
H
metboxycyclohexyl
CH
trans; mp. 185° C.


35
B4
H
methoxycyclohexyl
N
cis; mp. 160–172° C.


170
B4
H
methoxycyclohexyl
N
trans; mp. 146° C.


 


171
B4
H




N
(B); mp. 165° C.


 


172
B4
H
methylcyclohexyl
N
cis + trans; mp. 143° C.


173
B4
ethyl
methoxycyclohexyl
N
cis; mp.: 126° C.


 


411
B4
H




N
mp.: 109° C.


 


412
B4
H




N
mp.: 180° C.


 


413
B4
H




N
(A)


 


414
B4
H




N
mp.: 156° C.
















TABLE 6













 











Co.
Ex.





no.
no.
R
L
physcial data














49
B7
H




—


 


174
B3b
OCH3




cis; mp. 115° C.


 


175
B3b
OCH3




trans; mp. 141° C.


 


176
B3b
OCH3




cis; mp. 149° C.


 


177
B3b
OCH3




mp. 126° C.


 


178
B3b
OCH3




trans; mp. 160° C.


 


179
B3b
OCH3




cis; mp. 119° C.


 


180
B3b
OCH3




trans; mp. 124° C.


 


181
B3b
OCH3




trans; mp. 92° C.


 


206
B3b
OCH3




cis; m.p. 144° C.


 


207
B3b
OCH3




trans; m.p. 125° C.


 


208
B3b
OCH3




cis; m.p. 127° C.


 


209
B3b
OCH3




cis; m.p. 101° C.


 


210
B3b
OCH3




cis; m.p. 104° C.


 


211
B3b
OCH3




trans; m.p. 134° C.


 


212
B4
OCH3




cis; m.p. 141° C.


 


213
B4
OCH3




trans; m.p. 215° C.


 


214
B4
OCH3




cis; m.p. 139° C.


 


215
B3b
OCH3




trans


 


415
B3b
OCH3




(cis); mp.: 136° C.


 


416
B3b
OCH3




(cis)


 


417
B4
OCH3




(cis); mp.: 149° C.


 


418
B3b
OCH3




(trans); mp.: 132° C.


 


419
B4
OCH3




(cis); mp.: 217° C.


 


420
B3b
OCH3




(cis); .HCl(1:1); mp.: 200° C.


 


421
B4
OH




(cis); mp.: 215° C.


 


422
B4
OH




(trans); mp.: 178° C.


 


423
B3b
OCH3




mp.: 160° C.


 


424
B3b
OCH3




(cis); mp.: 106° C.


 


425
B3b
OCH3




(trans); mp.: 120° C.


 


426
B3b
OCH3




(cis); mp.: 121° C.


 


427
B3b
H




mp.: 156° C.


 


428
B3b
OCH3




(cis); mp.: 156° C.


 


429
B3b
OCH3




(trans); mp.: 197° C.


 


430
B3b
CH3




(B)


 


431
B3b
CH3




(A)
















TABLE 7













 











Co.
Ex.





no.
no.
R1
L
physcial data





432
B4








mp.: 128° C.


 


433
B4








mp.: 175° C.


 


434
B4








mp.: 170° C.


 


435
B4








mp.: 103° C.


 


436
B4








mp.: 151° C.


 


437
B4








(trans); mp.: 110° C.


 


438
B4








mp.: 150° C.


 


439
B4








mp.: 150° C.


 


440
B4








(cis)


 


441
B4








mp.: 166° C.


 


442
B4








mp.: 173° C.


 


443
B4








mp.: 208° C.


 


444
B4








mp.: 149° C.


 


445
B4








mp.: 133° C.


 


446
B3b








mp.: 150° C.


 


447
B3b








mp.: 165° C.


 


448
B3b








mp.: 147° C.


 


449
B3b








mp.: 154° C.


 


450
B3b








mp.: 157° C.


 


451
B4








mp.: 190° C.


 


452
B4








mp.: 187° C.


 


453
B3b








mp.: 200° C.


 


454
B3b








mp.: 160° C.


 


455
B3b








mp.: 139° C.


 


456
B3b








(A); mp.: 174° C.


 


457
B3b








(B); mp.: 160° C.


 


458
B3b








mp.: 184° C.


 


459
B4








—


 


460
B4








mp.: 134° C.


 


461
B4








(B); mp.: 156° C.


 


462
B4








mp.: 153° C.


 


463
B3b








mp.: 161° C.


 


464
B4








mp.: 135° C.


 


465
B4








mp.: 131° C.


 


466
B3b








.HCl(1:1); mp.: 206° C.


 


467
B3d








mp.: 142° C.


 


468
B4








.hydrate(1:1); mp.: 104° C.


 


469
B3b
dimethylethyl




mp.: 104° C.


 


470
B3b








mp.: 161° C.


 


472
B3b








mp.: 144° C.


 


473
B4








mp.: 143° C.


 


474
B4








mp.: 196° C.


 


475
B4








mp.: 162° C.


 


476
B4








mp.: 171° C.


 


477
B4








mp.: 155° C.


 


478
B2
trimethylmethyl




mp.: 124° C.


 


479
B4








(A); mp.: 146° C.


 


480
B4








(B); mp.: 162° C.


 


481
B4








(A); mp.: 129° C.


 


482
B4








mp.: 115° C.


 


483
B2








mp.: 187° C.


 


484
B2








mp.: 162° C.


 


485
B4








(A); mp.: 130° C.


 


486
B4








(A); mp.: 124° C.


 


487
B4








(B); mp.: 128° C.


 


488
B4








mp.: 85° C.


 


489
B2








mp.: 150° C.


 


490
B4








(A); mp.: 117° C.


 


491
B2








mp.: 220° C.


 


492
B4








mp.: 136° C.


 


493
B2








mp.: 131° C.


 


494
B4








(A); mp.: 125° C.


 


495
B4








mp.: 135° C.


 


496
B4








mp.: 139° C.


 


497
B4








mp.: 127° C.


 


498
B4








mp.: 195° C.


 


499
B2








mp.: 201° C.


 


500
B3b








mp.: 143° C.


 


501
B3b








mp.: 137° C.


 


502
B2








mp.: 210° C.


 


503
B3d








mp.: 134° C.


 


504
B2








mp.: 163° C.


 


505
B4








mp.: 142° C.


 


506
B2








mp.: 139° C.


 


507
B4








mp.: 171° C.


 


512
B3b








—


 


523
B3b








—



















TABLE 8





Co.
Ex.




no.
no.
Structure
physical data







511
B11




—


 


514
B12




—


 


515
B13




—


 


524
B9a




mp.: 185° C.


 


471
B15




(E)


 


526
B14




.HCl(1:1)









C. Pharmacological Example

Signal Transduction at the Cloned Rat mGluR1 Receptor in CHO Cells

CHO cells expressing the mGluR1 receptor were plated in precoated black 96-well plates. The next day, the effect of the present compounds on glutamate-activated intracellular Ca2+ increase was evaluated in a fluorescent based assay. The cells were loaded with Fluo-3 AM, plates were incubated for 1 hour at room temperature in the dark, cells were washed and the present compounds were added onto the cells for 20 minutes. After this incubation time, the glutamate-induced Ca2+ rise was recorded for each well in function of time using the Fluorescent Image Plated Reader (FLIPR, Molecular Devices Inc.). Relative fluorescence units were recorded and average data graphs of quadruple wells were obtained. Concentration-response curves were constructed based on peak fluorescence (maximum signal between 1 and 90 seconds) for each concentration of tested compound. pIC50 values are the —log values of the concentration of tested compounds resulting in 50% inhibition of the glutamated-induced intracellular Ca2+ rise.
The compounds according to the present invention exhibited a pIC50 value of at least 5.
The compounds that are included in the Tables 1-8 exhibited a pIC50 value of at least 6.
A particular group of compounds exhibited a pIC50 value between 7 and 8. It concerns the compounds listed in Table 9.










TABLE 9







Com. nr.
pIC50



















463
7.98



441
7.95



334
7.95



22
7.94



421
7.94



15
7.93



440
7.93



139
7.93



178
7.92



338
7.91



87
7.90



462
7.90



394
7.90



423
7.89



21
7.87



220
7.87



479
7.86



483
7.86



485
7.84



9
7.84



110
7.84



248
7.84



341
7.83



163
7.81



433
7.79



238
7.79



224
7.78



437
7.78



498
7.78



449
7.77



242
7.76



346
7.74



182
7.73



486
7.73



447
7.72



7
7.72



175
7.71



475
7.71



480
7.71



213
7.70



239
7.70



241
7.67



461
7.65



115
7.64



445
7.63



281
7.63



487
7.63



299
7.63



431
7.61



98
7.57



464
7.57



446
7.56



251
7.55



484
7.54



494
7.53



128
7.52



344
7.52



161
7.49



298
7.48



454
7.45



456
7.45



277
7.44



91
7.43



356
7.42



229
7.41



333
7.41



326
7.41



369
7.40



430
7.39



435
7.38



35
7.36



228
7.36



429
7.36



117
7.35



291
7.35



313
7.35



280
7.34



460
7.34



482
7.34



343
7.33



425
7.32



473
7.32



287
7.31



448
7.31



243
7.29



323
7.28



159
7.28



289
7.27



184
7.26



436
7.26



89
7.25



108
7.25



373
7.25



255
7.23



527
7.23



303
7.22



296
7.22



221
7.21



193
7.21



14
7.20



131
7.19



438
7.19



148
7.18



496
7.18



236
7.17



332
7.17



481
7.16



191
7.16



457
7.14



20
7.14



145
7.13



268
7.13



512
7.13



474
7.13



10
7.11



307
7.11



426
7.11



466
7.10



97
7.08



83
7.08



434
7.08



300
7.08



199
7.07



290
7.06



112
7.05



348
7.05



286
7.03



442
7.03



422
7.02



283
7.02



318
7.02



36
7.00



396
7.00










A particular group of compounds exhibited a pIC50 value of at least 8. It concern the compounds listed in Table 10.









TABLE 10





Comp.




nr.
Structure
pIC50

















416




8.587


 


27




8.527


 


174




8.49


 


506




8.48


 


25




8.45


 


4




8.4


 


19




8.38


 


429




8.38


 


424




8.355


 


176




8.33


 


210




8.315


 


114




8.28


 


488




8.27


 


504




8.27


 


477




8.25


 


432




8.237


 


214




8.233


 


465




8.145


 


135




8.14


 


420




8.135


 


292




8.13


 


427




8.115


 


208




8.095


 


419




8.065


 


455




8.055


 


418




8.045


 


497




8.025


 


439




8.023


 


237




8.01


 


499




8









Cold Allodynia Test in Rats with a Bennett Ligation

Surgery:
Male SD rats, weighing 240-280 g at the time of surgery were used.
For surgery, the animals were anaesthetised with Thalamonal (1 ml; subcutane) and sodium pentobarbital (40 mg/kg; intraperitoneal (IP)). The common sciatic nerve of the left hindpaw was exposed at the level of the middle of the thigh by blunt dissection through the biceps femoris. Proximal to the sciatic's trifurcation, about 7 mm of nerve was freed and four loose ligatures with 4.0 chromic gut were placed around the sciatic nerve. Great care was taken to tie the ligatures such that the diameter of the nerve was barely constricted. After surgery, the animals received 1.25 mg/kg naloxone IP.
Cold Plate Testing:
Cold plate testing was performed on a metal plate of 30×30 cm with transparent acrylic walls around it. The cold plate was cooled to 0.0 (±0.5)° C. using a Julabo F25 cooler. For testing, the animal was placed on the cold plate and the duration of lifting of both the left and the right hindpaw was measured during 5 minutes. The difference in lifting time between the ligated and non-ligated paw was calculated.
Testing Procedure:
At least one week after the operation, animals were placed on the cold plate test and a pre-drug measurement was taken. Animals having a difference in lifting time >25 secondes between the ligated and the non-ligated paw were selected for drug testing. These selected animals were injected IP with a compound of the present invention and were retested after 60 minutes (post drug test). The results obtained during the post drug test were expressed as a percentage of those of the predrug test.
The data were analysed in terms of all or none criterion (based on the results of control animals) with the limits being:

    Inhibition: (post-drug/pre-drug)*100<40%
    Antagonism: (post-drug/pre-drug)*100<25%


Compound (27) showed antagonism at a dose of 2.5 mg/kg bodyweight.

## Claims

1. A compound of formula



an N-oxide form, a pharmaceutically acceptable addition salt, a quaternary amine or a stereochemically isomeric form thereof, wherein
X represents O; C(R6)2 with R6 being hydrogen, aryl or C1-6alkyl optionally substituted with amino or mono- or di(C1-6alkyl)amino; S or N—R7 with R7 being amino or hydroxy;
R1 represents C1-6alkyl; thienyl; quinolinyl; cycloC3-12alkyl or cycloC3-12alkylC1-6alkyl, wherein the cycloC3-12alkyl moiety optionally may contain a double bond and wherein one carbon atom in the cycloC3-12alkyl moiety may be replaced by an oxygen atom or an NR8-moiety with R8 being hydrogen, benzyl or C1-6alkyloxycarbonyl; wherein one or more hydrogen atoms in a C1-6alkyl-moiety or in a cycloC3-12alkyl-moiety optionally may be replaced by C1-6alkyl, hydroxyC1-6alkyl, haloC1-6alkyl, aminoC1-6alkyl, hydroxy, C1-6alkyloxy, arylC1-6alkyloxy, C1-6alkyloxycarbonyl, aryl, amino, mono- or di(C1-6alkyl)amino, C1-6alkyloxycarbonylamino, piperazinyl, pyridinyl, morpholinyl, thienyl or a bivalent radical of formula —O—, —O—CH2—O or —O—CH2—CH2—O—; or a radical of formula (a-1)





wherein
Z1 is a single covalent bond, O, NH or CH2;
Z2 is a single covalent bond, O, NH or CH2;
n is an integer of 0, 1, 2 or 3;
and wherein each hydrogen atom in the phenyl ring independently may optionally be replaced by halo, hydroxy, C1-6alkyl, C1-6alkyloxy or hydroxyC1-6alkyl;


or X and R1 may be taken together with the carbon atom to which X and R1 are attached to form a radical of formula (b-1), (b-2) or (b-3);




R3 represents hydrogen; halo; hydroxy; cyano; C1-6alkyl; C1-6alkyloxy; C1-6alkyloxyC1-6alkyl; C1-6alkylcarbonyl; C1-6alkyloxycarbonyl; C2-6alkenyl; hydroxyC2-6alkenyl; C2-6alkynyl; hydroxyC2-6alkynyl; tri(C1-6alkyl)silaneC2-6alkynyl; amino; mono- or di(C1-6alkyl)amino; mono- or di(C1-6alkyloxyC1-6alkyl)amino; mono- or di(C1-6alkylthioC1-6alkyl)amino; aryl; morpholinylC1-6alkyl or piperidinylC1-6alkyl;
R4 represents hydrogen; halo; hydroxy; cyano; C1-6alkyl; C1-6alkyloxy; C1-6alkyloxyC1-6alkyl; C1-6alkylcarbonyl; C1-6alkyloxycarbonyl; C2-6alkenyl; hydroxyC2-6alkenyl; C2-6alkynyl; hydroxyC2-6alkynyl; tri(C1-6alkyl)silaneC2-6alkynyl; amino; mono- or di(C1-6alkyl)amino; mono- or di(C1-6alkyloxyC1-6alkyl)amino; mono- or di(C1-6alkylthioC1-6alkyl)amino; morpholinylC1-6alkyl or piperidinylC1-6alkyl; or
R3 and R4 may be taken together to form a bivalent radical of formula —CH═CH—CH═CH— or —CH2—CH2—CH2—CH2—;
R5 represents hydrogen; cycloC3-12alkyl; piperidinyl; oxo-thienyl; tetrahydrothienyl, arylC1-6alkyl; C1-6alkyloxyC1-6alkyl; C1-6alkyloxycarbonylC1-6alkyl or C1-6alkyl optionally substituted with a radical C(═O)NRxRy in which Rx and Ry, each independently are hydrogen, cycloC3-12alkyl, C2-6alkynyl or C1-6alkyl optionally substituted with cyano, C1-6alkyloxy, C1-6alkyloxycarbonyl, furanyl, pyrrolidinyl, benzylthio, pyridinyl, pyrrolyl or thienyl;
Y represents O or S;
or Y and R5 may be taken together to form ═Y—R5— which represents a radical of formula


—CH═N—N═  (c-1);



—N═N—N═  (c-2); or



—N—CH═CH—  (c-3);


aryl represents phenyl or naphthyl optionally substituted with one or more substituents selected from halo, hydroxy, C1-6alkyl, C1-6alkyloxy, phenyloxy, nitro, amino, thio, C1-6alkylthio, haloC1-6alkyl, polyhaloC1-6alkyl, polyhaloC1-6alkyloxy, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl, aminoC1-6alkyl, mono- or di(C1-6alkyl)amino; mono- or di(C1-6alkyl)aminoC1-6alkyl, cyano, —CO—R12, —CO—OR13, —NR13SO2R12, —SO2—NR13R14, —NR13C(O)R12, —C(O)NR13R14, —SOR12, —SO2R12; wherein each R12, R13 and R14 independently represent C1-6alkyl; cycloC3-6alkyl; phenyl; phenyl substituted with halo, hydroxy, C1-6alkyl, C1-6alkyloxy, haloC1-6alkyl, polyhaloC1-6alkyl, furanyl, thienyl, pyrrolyl, imidazolyl, thiazolyl or oxazolyl;
and when the R1—C(═X) moiety is linked to another position than the 7 or 8 position, then said 7 and 8 position may be substituted with R15 and R16 wherein either one or both of R15 and R16 represents C1-6alkyl, C1-6alkyloxy or R15 and R16 taken together may form a bivalent radical of formula —CH═CH—CH═CH.

2. A compound according to claim 1, wherein
X represents O; C(R6)2 with R6 being hydrogen or aryl; or N—R7 with R7 being amino or hydroxy;
R1 represents C1-6alkyl, thienyl; quinolinyl; cycloC3-12alkyl or (cycloC3-12alkyl)C1-6alkyl, wherein the cycloC3-12alkyl moiety optionally may contain a double bond and wherein one carbon atom in the cycloC3-12alkyl moiety may be replaced by an oxygen atom or an NR8-moiety with R8 being benzyl or C1-6alkyloxycarbonyl; wherein one or more hydrogen atoms in a C1-6alkyl-moiety or in a cycloC3-12alkyl-moiety optionally may be replaced by C1-6alkyl, haloC1-6alkyl, hydroxy, C1-6alkyloxy, arylC1-6alkyloxy, aryl, mono- or di(C1-6alkyl)amino, C1-6alkyloxycarbonylamino, piperazinyl, pyridinyl, morpholinyl, thienyl or a bivalent radical of formula —O— or —O—CH2—CH2—O—;
or a radical of formula (a-1)





wherein
Z1 is a single covalent bond, O or CH2;
Z2 is a single covalent bond, O or CH2;
n is an integer of 0, 1, or 2;
and wherein each hydrogen atom in the phenyl ring independently may optionally be replaced by halo or hydroxy;


or X and R1 may be taken together with the carbon atom to which X and R1 are attached to form a radical of formula (b-1), (b-2) or (b-3);




R3 and R4 each independently represent hydrogen; C1-6alkyl; C1-6alkyloxyC1-6alkyl; C1-6alkyloxycarbonyl; or
R3 and R4 may be taken together to form a bivalent radical of formula —CH═CH—CH═CH— or —CH2—CH2—CH2—CH2—;
R5 represents hydrogen; piperidinyl; oxo-thienyl; tetrahydrothienyl, arylC1-6alkyl; C1-6alkyloxycarbonylC1-6alkyl or C1-6alkyl optionally substituted with a radical C(═O)NRxRy, in which Rx and Ry, each independently are hydrogen, cycloC3-12alkyl, C2-6alkynyl or C1-6alkyl optionally substituted with cyano, C1-6alkyloxy or C1-6alkyloxycarbonyl;
Y represents O or S;
or Y and R5 may be taken together to form ═Y—R5— which represents a radical of formula


—CH═N—N═  (c-1); or



—N═N—N═  (c-2);


aryl represents phenyl or naphthyl optionally substituted with one or more substituents selected from halo, C1-6alkyloxy, phenyloxy, mono-or di(C1-6alkyl)amino and cyano;
and when the R1—C(═X) moiety is linked to another position than the 7 or 8 position, then said 7 and 8 position may be substituted with R15 and R16 wherein either one or both of R15 and R16 represents C1-6alkyl or R15 and R16 taken together may form a bivalent radical of formula —CH═CH—CH═CH—.

3. A compound according to claim 1, wherein
X represents O;
R1 represents C1-6alkyl; cycloC3-12alkyl or (cycloC3-12alkyl)C1-6alkyl, wherein one or more hydrogen atoms in a C1-6alkyl-moiety or in a cycloC3-12alkyl-moiety optionally may be replaced by C1-6alkyloxy, aryl, or thienyl;
R3 and R4 each independently represent hydrogen or C1-6alkyl; or
R3 and R4 may be taken together to form a bivalent radical of formula —CH2—CH2—CH2—CH2—;

R5 represents hydrogen;
Y represents O; and
aryl represents phenyl optionally substituted with halo.

4. A compound as claimed in claim 1, having the formula:

5. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, and as active ingredient a therapeutically effective amount of a compound as defined in claim 1.

6. A process of preparing a composition as claimed in claim 5, comprising combining a pharmaceutically acceptable carrier with a therapeutically effective amount of said compound.

7. A process of preparing a compound of formula (I-B) as claimed in claim 1, comprising
a) oxidizing an intermediate of formula (II) in the presence of a suitable oxidizing agent




with Q representing the quinolinone or quinoline-2-thione moiety of a compound of formula (I-B); or
b) reacting an intermediate of formula (III) with an intermediate of formula (IV)




with Q representing the quinolinone or quinoline-2-thione moiety of a compound of formula (I-B) and W1 being a suitable leaving group; or
c) reacting an intermediate of formula (V) with an intermediate of formula (IV)




with Q representing the quinolinone or quinoline-2-thione moiety of a compound of formula (I-B) and W1 being a suitable leaving group; or
d) reacting an intermediate of formula (VI) with an intermediate of formula (VII) in the presence of a suitable acid




with R1a being defined as R1 provided that R1 is linked to the carbonyl moiety via a oxygen atom and Q representing the quinolinone or quinoline-2-thione moiety of a compound of formula (I-B); or
e) reacting an intermediate of formula (VIII) in the presence of a suitable acid





and, optionally, interconverting a first compound of formula (I-B) to yield a second compound of formula (I-B); and further, optionally, converting the compounds of formula (I-B) into a therapeutically active non-toxic acid addition salt by treatment with an acid, or converting the acid addition salt form into the free base by treatment with alkali; and, optionally, preparing stereachemically isomeric forms, quaternary amines or N-oxide forms thereof.

8. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, and as active ingredient a therapeutically effective amount of a compound of formula



an N-oxide form, a pharmaceutically acceptable addition salt, a quaternary amine or a stereochemically isomeric form thereof, wherein
X represents O; C(R6)2 with R6 being hydrogen, aryl or C1-6alkyl optionally substituted with amino or mono- or di(C1-6alkyl)amino; S or N—R7 with R7 being amino or hydroxy;
R1 represents C1-6alkyl; thienyl; quinolinyl; cycloC3-12alkyl or (cycloC3-12alkyl)C1-6alkyl, wherein the cycloC3-12alkyl moiety optionally may contain a double bond and wherein one carbon atom in the cycloC3-12alkyl moiety may be replaced by an oxygen atom or an NR8-moiety with R8 being hydrogen, benzyl or C1-6alkyloxycarbonyl; wherein one or more hydrogen atoms in a C1-6alkyl-moiety or in a cycloC3-12alkyl-moiety optionally may be replaced by C1-6alkyl, hydroxyC1-6alkyl, haloC1-6alkyl, aminoC1-6alkyl, hydroxy, C1-6alkyloxy, arylC1-6alkyloxy, C1-6alkyloxycarbonyl, aryl, amino, mono- or di(C1-6alkyl)amino, C1-6alkyloxycarbonylamino, piperazinyl, pyridinyl, morpholinyl, thienyl or a bivalent radical of formula —O—, —O—CH2—O or —O—CH2—CH2—O—;
or a radical of formula (a-1)





wherein
Z1 is a single covalent bond, O, NH or CH2;
Z2 is a single covalent bond, O, NH or CH2;
n is an integer of 0, 1, 2 or 3;
and wherein each hydrogen atom in the phenyl ring independently may optionally be replaced by halo, hydroxy, C1-6alkyl, C1-6alkyloxy or hydroxyC1-6alkyl;


or X and R1 may be taken together with the carbon atom to which X and R1 are attached to form a radical of formula (b-1), (b-2) or (b-3);




R2 represents hydrogen; halo; cyano; C1-6alkyl; C1-6alkyloxy; C1-6alkylthio; C1-6alkylcarbonyl; C1-6alkyloxycarbonyl; C1-6alkylcarbonyloxyC1-6alkyl; C2-6alkenyl; hydroxyC2-6alkenyl; C2-6alkynyl; hydroxyC2-6alkynyl; tri(C1-6alkyl)silaneC2-6alkynyl; amino; mono- or di(C1-6alkyl)amino; mono- or di(C1-6alkyloxyC1-6alkyl)amino; mono- or di(C1-6alkylthioC1-6alkyl)amino; aryl; arylC1-6alkyl; arylC2-6alkynyl; C1-6alkyloxyC1-6alkylaminoC1-6alkyl; aminocarbonyl optionally substituted with C1-6alkyl, C1-6alkyloxyC1-6alkyl, C1-6alkyloxycarbonylC1-6alkyl or pyridinylC1-6alkyl; a heterocycle selected from thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, isothiazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, piperidinyl and piperazinyl, optionally N-substituted with C1-6alkyloxyC1-6alkyl, morpholinyl, thiomorpholinyl, dioxanyl or dithianyl; a radical —NH—C(═O)R9 wherein R9 represents
C1-6alkyl optionally substituted with cycloC3-12alkyl, C1-6alkyloxy, C1-6alkyloxycarbonyl, aryl, aryloxy, thienyl, pyridinyl, mono- or di(C1-6alkyl)amino, C1-6alkylthio, benzylthio, pyridinylthio or pyrimidinylthio; cycloC3-12alkyl; cyclohexenyl; amino; arylcycloC3-12alkylamino; mono-or-di(C1-6alkyl)amino; mono- or di(C1-6alkyloxycarbonylC1-6alkyl)amino; mono- or di(C1-6alkyloxycarbonyl)amino; mono-or di(C2-6alkenyl)amino; mono- or di(arylC1-6alkyl)amino; mono- or diarylamino; arylC2-6alkenyl; furanylC2-6alkenyl; piperididinyl; piperazinyl; indolyl; furyl; benzofuryl; tetrahydrofuryl; indenyl; adamantyl; pyridinyl; pyrazinyl; aryl; arylC1-6alkylthio or a radical of formula (a-1);

a sulfonamid —NH—SO2—R10 wherein R10 represents C1-6alkyl, mono- or polyhaloC1-6alkyl, arylC1-6alkyl, arylC2-6alkenyl, aryl, quinolinyl, isoxazolyl or di(C1-6alkyl)amino;
R3 represents hydrogen; halo; hydroxy; cyano; C1-6alkyl; C1-6alkyloxy; C1-6alkyloxyC1-6alkyl; C1-6alkylcarbonyl; C1-6alkyloxycarbonyl; C2-6alkenyl; hydroxyC2-6alkenyl; C2-6alkynyl; hydroxyC2-6alkynyl; tri(C1-6alkyl)silaneC2-6alkynyl; amino; mono- or di(C1-6alkyl)amino; mono- or di(C1-6alkyloxyC1-6alkyl)amino; mono- or di(C1-6alkylthioC1-6alkyl)amino; aryl; morpholinylC1-6alkyl or piperidinylC1-6alkyl;
R4 represents C1-6alkyloxy or amino; or
R2 and R3 may be taken together to form —R2—R3—, which represents a bivalent radical of formula —(CH2)3—, —(CH2)4—, —(CH2)5—, —(CH2)6—, —CH═CH—CH═CH—, -Z4-CH═CH—, —CH═CH-Z4-, -Z4-CH2—CH2—CH2—, —CH2-Z4-CH2—CH2—, —CH2—CH2-Z4-CH2—, —CH2—CH2—CH2-Z4-, -Z4-CH2—CH2—, —CH2-Z4-CH2— or —CH2—CH2-Z4-, with Z4 being O, S, SO2 or NR11 wherein R11 is hydrogen, C1-6alkyl, benzyl or C1-6alkyloxycarbonyl; and wherein each bivalent radical is optionally substituted with C1-6alkyl;
or R3 and R4 may be taken together to form a bivalent radical of formula —CH═CH—CH═CH— or —CH2—CH2—CH2—CH2—;
aryl represents phenyl or naphthyl optionally substituted with one or more substituents selected from halo, hydroxy, C1-6alkyl, C1-6alkyloxy, phenyloxy, nitro, amino, thio, C1-6alkylthio, haloC1-6alkyl, polyhaloC1-6alkyl, polyhaloC1-6alkyloxy, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl, aminoC1-6alkyl, mono-or di(C1-6alkyl)amino; mono-or di(C1-6alkyl)aminoC1-6alkyl, cyano, —CO—R12, —CO—OR13, —NR13SO2R12, —SO2—NR13R14, —NR13C(O)R12, —C(O)NR13R14, —SOR12, —SO2R12; wherein each R12, R13 and R14 independently represent C1-6alkyl; cycloC3-6alkyl; phenyl; phenyl substituted with halo, hydroxy, C1-6alkyl, C1-6alkyloxy, haloC1-6alkyl, polyhaloC1-6alkyl, furanyl, thienyl, pyrrolyl, imidazolyl, thiazolyl or oxazolyl;
and when the R1—C(═X) moiety is linked to another position than the 7 or 8 position, then said 7 and 8 position may be substituted with R15 and R16 wherein either one or both of R15 and R16 represents C1-6alkyl, C1-6alkyloxy or R15 and R16 taken together may form a bivalent radical of formula —CH═CH—CH═CH—.

9. A process of preparing a composition as claimed in claim 8, comprising combining a pharmaceutically acceptable carrier with a therapeutically effective amount of said compound.