AU2001293847A1

AU2001293847A1 - Metabotropic glutamate receptor antagonists

Info

Publication number: AU2001293847A1
Application number: AU2001293847A
Authority: AU
Inventors: Sophie Coupa; Anne Simone Josephine Lesage; Dominique Jean-Pierre Mabire; Alain Philippe Poncelet; Marc Gaston Venet
Original assignee: Janssen Pharmaceutica NV
Current assignee: Janssen Pharmaceutica NV
Priority date: 2000-10-02
Filing date: 2001-09-25
Publication date: 2002-06-27
Anticipated expiration: 2021-09-26

Description

METABOTROPIC GLUTAMATE RECEPTOR ANTAGONISTS

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 mGluRl 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 IE 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 sytem 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 quaternary amine and a stereochemically isomeric form thereof, wherein X represents O; C(R⁶)₂ with R⁶ being hydrogen, aryl or -ealkyl optionally substituted with amino or mono- or S or Ν-R⁷ with R⁷ being amino or hydroxy; R¹ represents -βalkyl; aryl; thienyl; quinolinyl; cycloC₃.₁₂alkyl or

(cycloCs-πalk -ealkyl, 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 ΝR -moiety with R being hydrogen, benzyl or -βalkyloxycarbonyl ; wherein one or more hydrogen atoms in a d-_όalkyl-moiety or in a cycloC₃-₁₂alkyl-moiety optionally may be replaced by

Ci-βalkyl, hydroxyC_t-ealkyl, halo -ealkyl, aminoCι-₆alkyl, hydroxy, Cι-₆alkyloxy, arylC_t-_όalkyloxy, halo, -ealkyloxycarbonyl, aryl, amino, mono- or d -ealky amino, -_όalkyloxycarbonylamino, halo, piperazinyl, pyridinyl, morpholinyl, thienyl or a bivalent radical of formula -O-, -O-CH -O or -

O-CH₂-CH₂-O-; or a radical of formula (a-1)

a-1

wherein Zi is a single covalent bond, O, ΝH or CH₂; Z₂ is a single covalent bond, O, ΝH 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, Ci-βalkyl, Cι-₆alkyloxy or hydroxyCi-βalkyl; 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); b-1 b-2 b-3

R represents hydrogen; halo; cyano; C_halky!; C_!-₆alkyloxy; d-₆alkylthio; d-₆alkylcarbonyl; d-₆alkyloxycarbonyl; d-βalkylcarbonyloxyd-_δalkyl;

C₂-₆alkenyl; hydroxyC₂-₆alkenyl; C₂-₆alkynyl; hydroxyC₂-₆alkynyl; tri(d-₆alkyl)silaneC₂.₆alkynyl; amino; mono- or di(C₁-₆alkyl)amino; mono- or di -_όalkyloxy -ealky amino; mono- or di(C₁.₆alkylthioC₁-₆alkyl)amino; aryl; arylCi-galkyl; arylC₂-₆alkynyl; Cι-₆alkyloxyd-₆alkylaminoCι-₆alkyl; aminocarbonyl optionally substituted with d-ealkyl, d-₆alkyloxyCι-₆alkyl, d-₆alkyloxycarbonylC-_6alkyl or pyridinyld-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 d-ealkyloxyd^alkyl, morpholinyl, thiomorpholinyl, dioxanyl or dithianyl ; a radical -NH-C(=O)R⁹ wherein R⁹ represents d-₆alkyl optionally substituted with cycloC -ι₂alkyl, d-βalkyloxy, C_!-₆alkyloxycarbonyl, aryl, aryloxy, thienyl, pyridinyl, mono- or di(d-₆alkyl)amino, d-6alkylthio, benzylthio, pyridinylthio or pyrimidinylthio; cycloC₃.₁₂alkyl; cyclohexenyl; amino; arylcycloC₃-₁₂alkylamino; mono-or-di(d-₆alkyl)amino; mono- or di(d-₆alkyloxycarbonylCι-₆alkyl)amino; mono- or di(d-₆alkyloxycarbonyl)amino; mono-or di(C₂-6alkenyl)amino; mono- or di(aryld-₆alkyl)amino; mono- or diarylamino; arylC₂.₆alkenyl; furanylC₂-₆alkenyl; piperididinyl; piperazinyl; indolyl; furyl; benzofuryl; tetrahydrofuryl; indenyl; adamantyl; pyridinyl; pyrazinyl; aryl; aryld-₆alkylthio or a radical of formula (a-1) ; a sulfonamid -NH-SO₂-R¹⁰ wherein R¹⁰ represents d-₆alkyl, mono- or poly halod-₆alkyl, arylCi-₆alkyl, arylC₂-₆alkenyl, aryl, quinolinyl, isoxazolyl or di(C₁-₆alkyl)amino; R³ and R⁴ each independently represent hydrogen; halo; hydroxy; cyano; d-₆alkyl; C₁.₆alkyloxy; d-ealkyloxyd-ealkyl; d-₆alkylcarbonyl; d-ealkyloxycarbonyl; C₂-₆alkenyl; hydroxyC₂.₆alkenyl; C₂-₆alkynyl; hydroxyC₂-₆alkynyl; tri(C₁.₆alkyl)silaneC₂.₆alkynyl; amino; mono- or di(C₁.₆alkyl)amino; mono- or d d-ealkyloxyd-ealky amino; mono- or di(C₁-₆alkylthioC₁-6alkyl)amino; aryl; morpholinylCι-₆alkyl or piperidinyld-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-Z -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, d-βalkyl, benzyl or

Cι-₆alkyloxycarbonyl; and wherein each bivalent radical is optionally substituted with d-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; cyclod-^alkyl; piperidinyl; oxo-thienyl; tetrahydrothienyl, aryld-ealkyl; C₁-₆alkyloxyC₁-₆alkyl; d-₆alkyloxycarbonyld-₆alkyl or Ci-₆alkyl optionally substituted with a radical C(=O)NR_xR_y, in which R_x and R_y, each independently are hydrogen, cycloC₃- ₂alkyl, C₂-₆alkynyl or Cι-₆alkyl optionally substituted with cyano, d- alkyloxy, d-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, d-₆alkyl, d-βalkyloxy, phenyloxy, nitro, amino, thio, d-₆alkylthio, halod-₆alkyl, polyhaloCι-₆alkyl, polyhalod-₆alkyloxy, hydroxyd-₆alkyl, d-_όalkyloxyd-βalkyl, aminod-ealkyl, mono-or di(C₁.₆alkyl)amino; mono-or di(C₁-₆alkyl)aminoCι-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 d.₆alkyl; cycloC₃-₆alkyl; phenyl; phenyl substituted with halo, hydroxy, d-₆alkyl, d-₆alkyloxy, halod-₆alkyl, polyhaloCι-₆alkyl, furanyl, thienyl, pyrrolyl, imidazolyl, thiazolyl or oxazolyl; and when the R^!-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 Cι-₆alkyl, d-₆alkyloxy orR¹⁵ and R¹⁶ taken together may form a bivalent radical of formula -CH=CH-CH=CH-.

As used in the foregoing definitions and hereinafter Cι_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; C .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__I2alkyl 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, polyhalod-₆alkyl as a group or part of a group is defined as mono- or polyhalosubsti uted d-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 polyhalod-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-l,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)-l,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 "Al" and "BT'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 Ν-R⁷ with R⁷ being amino or hydroxy;

R¹ represents d-βalkyl, aryl; thienyl; quinolinyl; cycloC₃-₁₂alkyl or

(cyclod-^alky d-_όalkyl, wherein the cycIoC₃-₁₂alkyl moiety optionally may contain a double bond and wherein one carbon atom in the cycloC -₁₂alkyl moiety may be replaced by an oxygen atom or an ΝR⁸-moiety with R⁸ being benzyl or d-₆alkyloxycarbonyl ; wherein one or more hydrogen atoms in a d-ealkyl-moiety or in a cycloC₃-₁₂alkyl-moiety optionally may be replaced by Cι.₆alkyl, halod-₆alkyl, hydroxy, d-βalkyloxy, aryld-₆alkyloxy, halo, aryl, mono- or di(d-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) a-1

wherein Zi 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);

b-1 b-2 b-3

represents hydrogen; halo; cyano; d-₆alkyl; d-₆alkyloxy; Cι-₆alkylthio; d-₆alkylcarbonyl; d-₆alkyloxycarbonyl; C₂-₆aIkenyl; hydroxyC₂-₆alkenyl; C₂-₆alkynyl; hydroxyC₂-₆alkynyl; tri(d-₆alkyl)silaneC₂-₆alkynyl; amino; mono- or di(Cι-6alkyl)amino; mono- or di(d-₆alkyloxyd-₆alkyl)amino; mono- or ditd-_όalkylthiod-_όalky^amino; aryl; aryld-βalkyl; arylC₂-₆alkynyl; d-όalkyloxyCi-_δalkylaminod-ealkyl; aminocarbonyl optionally substituted with d.6alkyloxycarbonylCι-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 d-₆alkyl optionally substituted with cycloC₃-₁₂alkyl, d-₆alkyloxy, d-δalkyloxycarbonyl, aryl, aryloxy, thienyl, pyridinyl, mono- or di(d-6alkyl)amino, d-₆alkylthio, benzylthio, pyridinylthio or pyrimidinylthio; cycloC₃-₁₂alkyl; cyclohexenyl; amino; arylcycloC₃-₁₂alkylamino; mono-or-di(d-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; furanylC₂.₆aIkenyl; 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 d-₆alkyl, mono- or poly halod-βalkyl, arylCι-₆alkyl or aryl; R³ and R⁴ each independently represent hydrogen; d-₆alkyl; d-ealkyloxyd-βalkyl; d-₆alkyloxycarbonyl; or R² and R³ may be taken together to form -R²-R³-, which represents a bivalent radical of formula -(CH₂) -, -(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, d-ealkyl, benzyl or

Cι-₆alkyloxycarbonyl; and wherein each bivalent radical is optionally substituted with d-ealkyl; 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, aryld-₆alkyl; d-₆alkyloxycarbonyld.₆alkyl or Cι-₆alkyl optionally substituted with a radical

C(=O)NR_xR_y, in which R_x and R_y, each independently are hydrogen, cycloC₃-₁₂alkyl, C₂-₆alkynyl or d-₆alkyl optionally substituted with cyano, d.₆alkyloxy or d-βalkyloxycarbonyl; 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, d^alkyloxy, phenyloxy, mono-or cU(d-₆alkyl)amino and cyano; and when the R^!-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 d.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 d-₆alkyl; cycloC₃-₁₂alkyl or (cycloC₃-₁₂alkyl)d-₆alkyl, wherein one or more hydrogen atoms in a d-₆alkyl-moiety or in a cycloC -₁₂alkyl-moiety optionally may be replaced by d-₆alkyloxy, aryl, halo or thienyl; R² represents hydrogen; halo; d-ealkyl or amino;

R³ and R⁴ each independently represent hydrogen or d-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 Ci-βalkyl; and wherein each bivalent radical is optionally substituted with d-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 R^!-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 (i_A/_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.

OH _n _ι I oxidation γ,

R -CH-Q ^ R¹— ϋ-_Q

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

R¹ — c= ΞN + f— Q _R1 _C_Q

(III) (IV) (l/VB-a)

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

Compounds of formula U_/B-a). wherein the R¹ substituent is linked to the carbonyl moiety via an oxygen atom, said R¹ substituent being represented by O-R^la and said compounds by formula U_/B-a-1), can be prepared by reacting an intermediate of formula (NI) with an intermediate of formula (Nil) in the presence of a suitable acid, such as sulfuric acid. o O

R^1a— OH + HO— C— Q R -1"9³-—. O— C— Q

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

(l-A-1)

(VIII)

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(d-₆alkyl)silane in the presence of Cul, an appropriate base, such as for example N,N-diethylethanamine, 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 Cul, 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 d-βalkyl, said compound being represented by formula (I-A-8) in the presence of a suitable alkylating agent, such as for example Sn(Cι-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)(d- 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 Cι-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 d-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-l 1) 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 d-ealkyloxycarbonylCi-ealkyl, said compound being represented by formula (I-A-12), by reaction with an intermediate of formula H₂Ν-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 R² 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.

(I-A-2) (XIII) (l-A-13)

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-l) 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-dimethylformamide.

Compounds of formula (l-A-11) can be converted into the corresponding Ν-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 d-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.

(l-A-15) (I-B-3)

Compounds of formula (I-B-3) can be converted into a compound of formula (I-B), wherein R⁵ represents d-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.

(I-A-15) Compounds of formula (I-B-3) can also be converted into a compound of formula (I- B), wherein R⁵ is d-6alkyloxycarbonylCι-6alkyl or arylCi-βalkyl, said R⁵ being represented by R^5a 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.

(l-A-15) 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 H₂Ν-C(=S)-ΝΗ₂ 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 d.₆alkylthio, said compound being represented by formula (I-A-16), by reaction with a suitable d-₆alkylhalide, such as for example d-₆alkyliodide, in the presence of a suitable base, such as dipotassium carbonate, and a suitable solvent, such as for example acetone.

Compounds of formula (l_A/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 U_/B-b), by reaction with an intermediate of formula (XNI), 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, alkylhydroperoxides, 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 (XNIII), 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.

Q- AC-H ₊ ⁺ R R—l- WW₅ — -► R 1I-C ?'H^H-Q

(XVII) (^{χ ι}»> (II)

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. oxidation ||

Q— CH₂ — OH ► Q— C— H

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.

II reduction

Q— C— O— C_realkyl ► Q— CH₂— OH

(XX) (^χιx)

Intermediates of formula (XX), wherein Q represents a quinoline moiety optionally substituted in position 3 with Cι-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. OH R C — H + Q— ₆ R¹— CH-Q

⁽xxiii⁾ (xxiv) (II)

Intermediates of formula (XXIII) can be prepared by oxidizing an intermediate of formula (XXN) using the Moffatt Pfitzner or Swem oxidation (dimethylsulfoxide adducts with dehydrating agents e.g. DCC, Ac₂O, SO₃, P O₁₀, COCl₂ or C1-CO-COC1) in an inert solvent such as methylene chloride. o

R— CH₂-OH _-- ^R — C— H

(xxv) (x iii)

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. o

R¹ 1— C H— O— Ci-βalk I ► _R- 1___CH2__0H

(XXVI) <^xxv)

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. fj C_r6alkyl— OH jj

R^: — C— OH ► R² — C— O— Cj-galkyl

(XXVII) (XXVI) Intermediates of formula (XXVII), wherein R¹ represents a radical of formula (a-1) with Zi 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 (XXNHI) 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 (XXNII) 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.

(IV-a)

(IV-b)

Intermediates of formula (IV-a), wherein R 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-dimethylformamide (Vilsmeier- Haack formylation followed by cyclization).

(IV-a-1) (XXIX)

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.

(XXX) (XXXI) (XXIX) 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.

+C ₆alkyl— O^" (XXXII)

(IV-a) (IV-c)

Intermediates of formula (IV-a) can also be converted into an intermediate of formula (rV-d-1) by reaction with a suitable amine of formula (XXXϋl-a), wherein Z₃ and Z₄ each independently represent hydrogen, d-βalkyl, d-βalkyloxyd-_όalkyl, d-ealkylthiod-_όalkyl 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.

(IV-a) (XXXIII-a)

(IV-a) (XXXIII-b)

Intermediates of formula (IV-a), wherein R³ represents CH₂-CH₂-CH₂-C1, said intermediates being represented by formula (IV-a-2), can also be converted into an intermediate of formula (IV), wherein R and R are taken together to form a bivalent radical of formula -O-CH₂-CH₂-CH₂-, said intermediate being represented by formula (rV-e-1), by reaction with a suitable acid, such as hydrochloric acid and the like. Intermediates of formula (IN-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.

(IV-e-2) 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 l, -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 (Vll-a), can be prepared by reaction an intermediate of formula (XXXTV) 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.

(XXXVI)

(XXXV)

(VIII)

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 mGluRl.

The mGluRl antagonistic activity of the present compounds can be demonstrated in the Signal transduction on cloned rat mGluRl 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 mGluRl 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 sytem. 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 NJV^*-dimethylformamide, "DIPE" is defined as diisopropylether, "DMSO" is defined as dimethylsulfoxide, "BHT" is defined as 2,6- bis(l,l-dimethylethyl)-4-methylphenol, and "THF" is defined as tetrahydrofuran. Preparation of the intermediates Example Al

Preparation of (interm. 1)

A mixture of 4-(l-methylethoxy)benzoic acid (0.083 mol) and Rh/Al₂O₃ 5% (lOg) in THF (220ml) 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: 16g 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 (250ml) was stirred at room temperature. ZnCl₂ (0.0367 mol) and (CH₂O)_n (lOg) were added. FeCl₃.6H₂O (0.5 mol) was added portionwise and the temperature rised till 60-65°C. Propanal (30ml) 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. lg of 2-ethyl-3-methyl-6-quinolinecarboxylic acid (interm. 2).

Example A3

Preparation of (interm. 3)

Pentanoyl chloride (0.2784 mol) was added at 5°C to a mixture of 4- bromobenzenamine (0.232 mol) and N,N-diethylethanamine (0.2784 mol) in CH₂C1₂ (400ml). The mixture was stirred at room temperature overnight, poured out into water and extracted with CH₂CI₂. The organic layer was separated, washed with a concentrated ΝH-tOH solution and water, dried (MgSO₄), filtered and the solvent was evaporated. The residue (60g) was crystallized from diethylether. The precipitate was filtered off and dried. The residue (35g, 63%) was taken up in CH₂C1₂. The organic layer was separated, washed with a 10% K₂CO₃ solution, washed with water, dried (MgSO₄), filtered and the solvent was evaporated. Yield: 30g of intermediate (3) (54%). Example A4

Preparation of (interm. 4)

A mixture of 6-bromo-2(lH)-quinolinone (0.089 mol) in POCl₃ (55ml) was stirred at

60°C overnight, then at 100°C for 3 hours and the solvent was evaporated. The residue was taken up in CΗ₂CI₂, poured out into ice water, basified with NH₄OH cone, filtered over celite and extracted with CH₂C1₂. The organic layer was separated, dried

(MgSO₄), filtered and the solvent was evaporated. Yield: 14.5g of intermediate (4)

(67%).

Example A5

a) Preparation of (interm. 5)

DMF (37ml) was added dropwise at 10°C under N₂ flow to POCl₃ (108ml). 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: 44.2g of intermediate (5) (50%).

b) Preparation of (interm. 6)

A mixture of intermediate (5) (0.162 mol) in methanol (600ml), and a solution of methanol sodium salt in methanol at 35% (154ml) 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 CH₂CI₂. K.2CO₃ 10% was added and the mixture was extracted with CH₂CI₂. The organic layer was separated, washed with water, dried (MgSO ), filtered and the solvent was evaporated. Yield: 31.9g of intermediate (6) (74%).

Example A6

Preparation of (interm. 7) l,l'-Carbonylbis-lH-imidazole (0.074 mol) was added portionwise to a mixture of 4-methoxycyclohexanecarboxylic acid (0.063 mol) in CΗ₂CI₂ (200ml). 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 CH₂CI₂. The organic layer was separated, washed several times with H₂O, dried (MgSO ), filtered and the solvent was evaporated. Yield: 12.6g of interm. 7. Example A7 a) A mixture of 6-fluoro-4-oxo-4H-l-benzopyran-2-carboxylic acid (0.30mol) in acetic acid (400ml) was hydrogenated with Pd/C (3g) as a catalyst. After uptake of Η₂ (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-l- benzopyran-2-carboxylic acid (interm. 8) (15.0%). b) A mixture of intermediate (8) (0.255 mol) in ethanol (400ml) and Η₂SO (5ml) was stirred and refluxed for 8 hours. The solvent was evaporated till dryness. The residue was dissolved in CH₂C1₂. The organic layer was separated, washed with K₂CO₃ 10%, dried (MgSO₄), filtered and the solvent was evaporated. Yield: 45g of ethyl 6-fluoro-3,4-dihydro-2H-l-benzopyran-2-carboxylate (interm. 9) (79%). c) Reaction under N₂. A mixture of sodium bis(2-methoxyethoxy)aluminumhydride, 70 wt % solution in methylbenzene 3.4M (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 : CΗC1₃). The desired fraction was collected and the eluent was evaporated. Yield: 34 g of 6-fluoro-3,4-dihydro-2H-l-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 CΗ₂CI2 (350 ml) was added sulfinylbis [methane] (30 ml) during 10 minutes. After stirring 10 minutes, a mixture of interm. 10 in CH₂CI₂ (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 CH2CI₂. The organic layer was wased with water, HCl (1M), water, ΝaHCO₃ (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 : CHC1₃). The desired fraction was collected and the eluent was evaporated. Yield: 21.6 g of 6-fluoro-3,4-dihydro-2H-l-benzopyran-2-carboxaldehyde (interm. 11)

e) Preparation of (interm. 12) nButyllithium 1.6M (0.056 mol) was added slowly at -70°C to a solution of intermediate (5) (0.046 mol) in TΗF (100ml). The mixture was stirred at -70°C for 30 minutes. A suspension of interm. 11 (0.056 mol) in TΗF (100ml) was added slowly. The mixture was stirred at -70°C for 1 hour, then brought to room temperature, poured out into Η₂O and extracted with EtOAc. The organic layer was separated, dried

(MgSO₄), filtered and the solvent was evaporated. The residue (21g) was purified by column chromatography over silica gel (eluent: cyclohexane/EtOAc 80/10; 15~35μm). The pure fractions were collected and the solvent was evaporated. Yield: 9.5g of interm. 12 (55%). Example A8

a) Preparation of

(interm. 14)

A mixture of intermediate (5) (0.1127 mol), 2-methoxyethanamine (0.2254 mol) and K₂CO₃ (0.2254 mol) in DMF (500ml) was stirred at 120°C for 15 hours and then cooled. The solvent was evaporated. The residue was taken up in CH₂C1₂ and H2O. The organic layer was separated, dried (MgSO ), filtered and the solvent was evaporated till dryness. The residue (33.53g) 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: 5.7g of interm. 14 (38%) and interm. 13 (34%).

b) Preparation of (interm. 15)

A mixture of intermediate (5) (0.0751 mol), thiomorpholine (0.0891 mol) and K-₂CO₃ (0.15 mol) in DMF (200ml) was stirred at 120°C for 12 hours. The solvent was evaporated till dryness. The residue was taken up in CH₂C1₂ and H₂O. The organic layer was separated, dried (MgSO ), filtered and the solvent was evaporated. The residue (26g) was purified by column chromatography over silica gel (eluent: cyclohexane/EtOAc 80/20; 20-45 μm). Two fractions were collected and their solvents were evaporated. The two fractions were combined. Yield: 9.4g 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 H₂SO₄70% (230ml) and the mixture was stirred and refluxed. 2-propene-l,l-diol, 2-methyl-, diacetate (0.216 mol) was added dropwise and the mixture was refluxed for 4 hours. Ethanol (200ml) was added and the mixture was stirred at 80°C for 48 hours. The mixture was evaporated, the residue was poured into ice water/NEUOH and extracted with CH₂CI₂. 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 : 21g of ethyl 3-methyl-6-quinolinecarboxylate (interm. 16) (45%). b) Interm. 16 (0.098 mol) in THF (270ml) was added at 0°C to a solution of LiAlEU (0.098 mol) in THF under N₂. When the addition was complete, water (10ml) was added. The precipitate was filtered off and washed with CH₂C1₂. The organic layer was dried (MgSO₄), filtered off and evaporated. The product was used without further purification. Yield : 16.71g of 3-methyl-6-quinolinemethanol (interm. 17). c) MnO (0.237 mol) was added to a solution of interm. 17 (0.096 mol) in CH₂C1₂ (200ml) 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 (20g) for 12 hours. MnO₂ (lOg) 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 : 11.71g of 3-methyl-6-quinolinecarboxaldehyde (71%) (interm. 18). d) A solution of bromocyclohexyl (0.14 mol) in 1,1' -oxybisethane (50ml) and Mg turnings (50ml) was added at 10°C to a mixture of THF (0.14 mol) in 1,1'- oxybisethane (10ml). A solution of interm. 18 (0.07 mol) in Mg turnings (100ml) was added carefully at 5°C, the mixture was poured into ice water and extracted with EtOAc. Yield : 11.34g of (±)-α-cyclohexyl-3-methyl-6-quinolinemethanol (63%) (interm. 19). Example AIO

Preparation of (interm. 20)

A mixture of compound (5) (0.001507 mol), tributyl(l-ethoxyethenyl)stannane (0.00226 mol) and Pd(PPh₃)₄ (0.000151 mol) in 1,4-dioxane (5ml) 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: 1.4g of interm. 20.

Example All

Preparation of (interm. 21)

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

(interm. 22) (interm. 23)

A mixture of 5-bromo-lH-indole-2,3-dione (0.221 mol) in NaOH 3N (500 mlO was stirred at 80°C for 30 minutes, brought to room temperature and 2-pentanone (0.221 mol) was added. The mixture was stirred 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

(interm. 24) (interm. 25) 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 1.6M (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, dired (MgSO ), 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 (interm. 26)

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 (100ml).

The mixture was stirred and refluxed for 8 hours and evaporated to dryness. The residue was taken up in CH₂CI₂, 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: 2.5g of interm. 26 (18%).

(interm. 27)

CDI (0.012 mol) was added at room temperature to a solution of interm. 26 (0.011 mol) in CH₂C1₂ (30ml). The mixture was stirred 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 CH₂CI2. 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: 0.95g of interm. 27 (31 ) (mp.:148°C).

Example A14

Preparation of (interm. 28)

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 CH2C12. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. Yielding: 4,6 g of interm. 28 (54%).

Example Al 5

a. Preparation of (interm. 29)

A solution of KOH (0.326 mol) in H₂O (150ml) was added slowly at 5°C to a solution of 1,3-cyclohexanedione (0.268 mol) in H₂O (150ml). The temperature must not reach

12 °C. KI (2g) then 2-bromo-l-(4-nitrophenyl)ethanone (0.294 mol) were added portionwise. The mixture was stirred at room temperature for 48 hours. The precipitate was fitered, washed with H₂O then with diethyl ether and dried. Yielding: 63g (85%).

A part of this fraction (lg) was crystallized from EtOH. The precipitate was filtered off and dried. Yielding: .: 100°C).

b. Preparation of (interm. 30)

A mixture of interm. 29 (0.145 mol) in H₂SO₄ (40ml) was stirred at room temperature for 1 hour, poured out into ice, basified with NH₄OH and extracted with CH₂C1₂- 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: 31g (58%). A part of this fraction (lg) was crystallized from EtOH. The precipitate was filtered off and dried. Yielding: 0.7g of interm. 30 (58%) (mρ.:200°C). c. Preparation of (interm. 31)

A mixture of interm. 30 (0.039 mol), Raney Ni (lOg) in EtOH (100ml) was hydrogenated at room temperature under a 3 bar pressure for 1 hour. The mixture was filtered over celite and washed with CH₂CI₂. The organic layer was separated, dried

(MgSO₄), filtered, and the solvent was evaporated. The residue (9.5g) was crystallized from diethyl ether. The precipitate was filtered off and dried. Yielding: 4.6g (52%). The filtrate was evaporated. The residue (2.7g) was purified by column chromatography over silica gel (eluent: CH₂θ₂/CH₃OH; 99/1; 15-40μm). Two fractions were collected and the solvent was evaporated. Yielding: 1.6g FI and 1.2g F2. F2 was crystallized from EtOH. The precipitate was filtered off and dried. Yielding: 0.24g of interm. 31

(interm. 32)

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 (50ml). 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 CH₂CI₂. The mixture was basified with K₂CO₃ 10% and extracted with CH₂CI₂. 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: 2.5g of interm. 32 (40%).

Example A16

Preparation of (interm. 33)

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

Preparation of (compound 306)

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. l-(4-aminophenyl)-2-phenylethanone (0.024 mol) was added portionwise. The mixture was stirred at 90°C for 3 hours and dissolved in CH₂C1₂. Ice water was added. The mixture was basified with NHjOH and extracted with CH₂C1₂. 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 (compound 2)

KMnO₄ (lOg) 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 (1ml) and CH₂C1₂ (100ml). The mixture was stirred at room temperature for 8 hours, filtered over celite, washed with CH₂C1₂ and dried. The residue (6g, 100%) was crystallized from diethyl ether/petroleum ether. The precipitate was filtered off and dried. Yield: 2g of compound (2) (33%); mp. 82°C.

Example B3

a) Preparation of (compound 3) nBuLi 1.6M (0.07 mol) was added slowly at -70°C to a solution of intermediate (5) (0.058 mol) in THF (150ml). The mixture was stirred at -70°C for 30 minutes. A solution of 2,3-dihydro-lH-Indene-2-carbonitrile (0.07 mol) in TΗF (100ml) 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 (22g) was purified by column chromatography over silica gel (eluent: CH₂Cl₂/ cyclohexane

80/20 to 100; 15-35μm). 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: 0.1 lg of compound (3). The filtrate was concentrated. Yiel

b) Preparation of cis (compound 4) trans (compound 5) nBuLi 1.6M (0.022 mol) was added slowly at -70°C to a solution of intermediate (5)

(0.018 mol) in THF (50ml). 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 (40ml) 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 (MgSO ), filtered and the solvent was evaporated. The residue (6.5g) was purified by column chromatography over silica gel (eluent: toluene/EtOAc 90/10; 15- 40jtιM). Two fractions (FI and F2) were collected and the solvent was evaporated.

FI (2.4g) was crystallized from diethyl ether. The precipitate was filtered off and dried.

Yield: 1.8g of compound (4) (29%); mp. 123 °C. F2 (0.9g) was crystallized from diethyl ether. The precipitate was filtered off and dried. Yield: 0.2g of compound (5)

and

CIS ^TRANS (compound 7) (compound 8) nBuLi 1.6M 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 ws 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 (MgSO ), filtered and the solvent was evaporated. The residue (31g) was purified by column chromatography over silica gel (eluent: cyclohexane EtOAc 85/15; 20-45 μ ). 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 (compound 503)

A solution of chloromethylbenzeen (0.0069 mol) in diethyl ether (8ml) 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 (8ml) 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 (MgSO ), filtered, and the solvent was evaporated. The residue (lg) was purified by column chromatography over kromasil (eluent: CH₂C1₂ 100 to CH₂Cl₂/CH₃OH 99/1; 15-40μm). The pure fractions were collected and the solvent was evaporated. The residue (0.5g, 56%) was crystallized from diethyl ether. The precipitate was filtered off and dried. Yielding: 0.14g of compound 503 (15%).

Example B4: examples of endgroup modifications

(compound 156) trans

A mixture of ( compound 8) trans (prepared according to example B3.c) (0.018 mol) in HCl 3N (60ml) and THF (60ml) was stirred at 60°C overnight. The mixture was basified with a K.₂CO₃ 10% solution and extracted with CH₂C1₂. The organic layer was separated, dried (MgSO₄), filtered and the solvent was evaporated. Yield: 4.6g of compound (156) (82%).

b) Preparation of (compound 9) cis A mixture of ( compound 7)

CIS

(prepared according to example B3.c) (0.0122 mol) in HCl 3N (40ml) and THF (40ml) was stirred and refluxed overnight, poured out into water, basified with K-₂CO₃ 10% and extracted with CH₂CI₂. The organic layer was separated, dried (MgSO ), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: cyclohexane/EtOAc 40/60; 15-40μm). The pure fractions were collected and the solvent was evaporated. Yield: 2g of compound (9) (52%); mp. 226°C.

c) Preparation of cis (compound 10) and (trans) (compound 11)

A mixture of compound (4) (0.0015 mol), 2-methoxyethanamine (0.003 mol) and K₂CO₃ (0.003 mol) in DMF (5ml) 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 (lg) was purified by column chromatography over silica gel (eluent: cyclohexane/EtOAc 60/40; 15-40/zm). Two fractions were collected and the solvent was evaporated. Both fractions were crystallized separately from pentane. The precipitate was filtered off and dried. Yield: 0.05g of compound (10) (9%; mp. 115°C) and 0.057g of compound (11) (10%; mp.

cis (compound 12) and (trans) (compound 13)

A mixture of compound (4) (0.0015 mol) in 2-(methylthio)ethanamine (2ml) was stirred at 120°C for 8 hours. K2CO₃ 10% was added. The mixture was extracted with CH2CI2. The organic layer was separated, dried (MgSO₄), filtered and the solvent was evaporated. The residue (2.2g) was purified by column chromatography over silica gel (eluent: cyclohexane/EtOAc 70/30; 15-40μm). 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: 0.08g of compound (12) (14%); mp. 120°C. The second fraction was crystallized from diethyl ether. The precipitate was filtered off and dried. Yield: 0.18g of compound (13)

cis (compound 14)

A mixture of compound (4) (0.001507 mol), ethynyltrimethylsilane (0.003013 mol), Cul (0.000151 mol) and Pd(PPh₃)₄ (0.000151 mol) in N-N-diethylethanamine (5ml) 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 (1.3g) 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 (0.3g) was crystallized from pentane. The precipitate was filtered off and dried. Yield: 0.1 lg of compound (14) (18%); mp. 114°C.

f) Preparation of (compound 15)

CIS

A mixture of compound (14) (0.013 mol) and KF (0.038 mol) in acetic acid (50ml) 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 (4.4g) was purified by column chromatography over silica gel (eluent: cyclohexane/EtOAc 70/30; 15-40μm). One fraction was collected and the solvent was evaporated. This fraction (3g, 73%) was crystallized from diethyl ether. The precipitate was filtered off and dried. Yield: 2.45g of compound (15

g) Preparation trans (compound 17)

A mixture of

cis (compound 14) and trans (compound 16) prepared according to example B.7.a) (0.0056 mol) in KOH [1M, H₂O] (10ml) and methanol (30ml) 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 (2.2g) was purified by column chromatography over silica gel (eluent: cyclohexane/EtOAc 85/15 to 70/30; 15-40μm).

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: 0.2g of compound (15) (11%); mp. 133°C.

The second fraction was crystallized from diethyl ether. The precipitate was filtered off and dried. Yield: 0.3g °C.

h) Preparation of (compound 18)

cis

A mixture of compound (4) (0.001205 mol), 2-propyn-l-ol (0.002411 mol), Pd(PPh₃)₄

(0.000121 mol) and Cul (0.000121 mol) in N-N-diethylethanamine (5ml) 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 (MgSO ), filtered and the solvent was evaporated. The residue (0.7g) was purified by column chromatography over silica gel (eluent: CH₂Q₂/CΗ3OH 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: O.lg

i) Preparation of cis (compound 19) and (trans) (compound 20) A mixture of compound (4) (0.006027 mol) and KF (0.024108 mol) in DMSO (20ml) 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 ΝaCl, dried (MgSO ), filtered and the solvent was evaporated. The residue (1.7g) 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: 0.21g of compound (19) (11%); mp. 92°C.

The second fraction was crystallized from petroleum ether. The precipitate was filtered off and dried. Yield: 114°C.

j) Preparation of (compound 21)

CIS

A mixture of compound (4) (0.003013 mol), acetyl chloride (0.003315 mol) and sodium iodide (0.006027 mol) in CH₃CN (10ml) was stirred and refluxed for 1 hour.

K₂CO₃ 10% was added. The mixture was extracted with CH₂CI₂. The organic layer was separated, dried (MgSO₄), filtered and the solvent was evaporated. The residue

(lg) 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: 0.12g of compound (21); mp. 110°C.

k) Preparation (compound 22)

CIS

A mixture of compound (21) (0.000898 mol), trimethylsilanecarbonitrile (0.001347 mol) and Pd(PPh₃)₄ (0.00009 mol) in N^V-diethylethanamine (5ml) was stirred at 100°C for 2 hours. Water was added. The mixture was extracted with EtOAc. The organic layer was separated, dried (MgSO ). filtered and the solvent was evaporated. The residue (0.4g) 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 (0.18g, 62%) was crystallized from petroleum ether. The precipitate was filtered off and dried. Yield : 0.13g of compound (22)

cis (compound 23) (trans) (compound 24) cis (compound 25) (trans) (compound 26)

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 (40ml) 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 (MgSO ), filtered and the solvent was evaporated. The residue (6g) was purified by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH 100/0 to 98/2; 15-35μm). Four fractions (F1-F4) were collected and the solvent was evaporated. Yield: 0.13g (cis) FI; 0.02g F2 (cis, compound 25); 0.055g F3 (trans, 3%) and O.llg F4 (trans; compound 26). FI was crystallized from petroleum ether. The precipitate was filtered off and dried. Yield: 0.03g of compound (23) (1%); mp. 91°C.

F3 was crystallized from petroleum ether. The precipitate was filtered off and dried.

Yield: 0.035g of comp

m) Preparation of (compound 25)

CIS

A mixture of compound (4) (0.009 mol) and Zn (0.027 mol) in acetic acid (30ml) was stirred at 60°C for 4 hours, filtered over celite, washed with CH₂C1₂, evaporated till dryness, solubilized in CH₂C1₂ and washed with K2CO₃ 10%. The organic layer was separated, dried (MgSO₄), filtered and the solvent was evaporated. The residue (4g) was purified by column chromatography over silica gel (eluent: cyclohexane/EtOAc

75/25; 15-40μm). One fraction was collected and the solvent was evaporated. This fraction (lg 37%) was crystallized from petroleum ether. The precipitate was filtered off and dried. Yield: c

n) Preparation of (compound 27) cis A mixture of compound (4) (0.001502 mol), Sn(CH₃)₄ (0.003004 mol) andPd(PPh₃) (0.00015 mol) in methylbenzene (5ml) 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 (0.7g) was purified by column chromatography over silica gel (eluent: cyclohexane/EtOAc

85/15; 15-40 μm). Two fractions (FI and F2) were collected and their solvents were evaporated. Yield: 0.27g (F 1, starting material) and 0.14g (F2). F2 was crystallized from pentane and petroleum ether. The precipitate was filtered off and dried. Yield: 0.08g of compound (27) (17%); mp. 110°C.

o) Preparation of (compound 28)

CIS

A mixture of compound (4) (0.001507 mol), tributylethenylstannane (0.002260 mol) and Pd(PPh₃)₄ (0.000151 mol) in dioxane (5ml) 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 (0.65g) 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: 0.07g of compound (28)

(compound 29)

trans A mixture of compound (5) (0.001507 mol), triphenyl(phenylmethyl)stannane

(0.002260 mol) and Pd(PPh₃)₄ (0.000151 mol) in dioxane (5ml) 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 (1.4g) was purified by column chromatography over silica gel (eluent: GHbCh/EtOAc 96/4; 15-40 μm). The pure fractions were collected and the solvent was evaporated. The residue (0.38g) was crystallized from petroleum ether. The precipitate was filtered off and dried. Yield: 0. . 112°C.

q) Preparation of (compound 30)

CIS A mixture of compound (4) (0.001507 mol), tributyl-2-thienylstannane (0.00226 mol) and Pd(PPh₃) (0.0001507 mol) in dioxane (5ml) was stirred at 80°C for 8 hours. K₂CO₃ 10% was added. The mixture was extracted with EtOAc. The organic layer was separated, dried (MgSO ), filtered and the solvent was evaporated. The residue (1.7g) 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 (0.65g) was crystallized from diethyl ether. The precipitate was filtered off and dried. Yield: 0.35g of compound (30) (61%); mp. 142°C.

r) Preparation of (compound 31)

CIS

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 (0.8g) was purified by column chromatography over silica gel (eluent: cyclohexane EtOAc

80/20; 15-40μm). The pure fractions were collected and the solvent was evaporated.

The residue (0.4g, 70%) was crystallized from petroleum ether. The precipitate was filtered off and dried. Yield: 0.39g of compound (31) (68%); p. 113°C.

cis

A mixture of compound (4) (0.003 mol), glycine methyl ester monohydrochloride

(0.0066 mol) and Pd(PPh)₄ (0.0003 mol) in Et₃N (2ml) and toluene (10ml) was stirred at 100°C under 5 bar pressure of CO for 8 hours, filtered over celite, washed with

CH₂CI₂ and evaporated. The residue (2g) was purified by column chromatography over silica gel (eluent: cyclohexane/EtOAc 80/20; 75-35μm). One fraction was collected and the solvent was evaporated. This fraction (lg 80%) was crystallized from diethyl ether.

The precipitate was filtered off and dried. Yielding:

t) Preparation of cis (compound 33) (trans) (compound 34) A mixture of compound (4) (0.003 mol) and hydrazinecarboxaldehyde (0.0045 mol) in

1-butanol (15ml) was stirred and refluxed overnight, poured out into water and extracted with CH₂CI₂. The organic layer was separated, dried (MgSO₄), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: C^CyCT^OH/NHtOH 95/5/0.1; 15-40 μm). Two fractions (FI and

F2) were collected and their solvents were evaporated. Yield: 0.3g FI and 0.3g F2.

FI was crystallized from CH₃CN and diethyl ether. The precipitate was filtered off and dried. Yield: 0.102g of compound (33); mp. 224°C.

F2 was crystallized from CH₃CN and diethyl ether. The precipitate was filtered off and dried. Yield: 0.2g of c

u) Preparation of (compound 35)

CIS

A mixture of compound 4 (0.015 mol) and NaN₃ (0.045 mol) in DMF (50ml) was stirred at 140°C for 2 hours. K₂CO₃ 10% was added and the mixture was extracted with EtOAc. The organic layer was separated, dried (MgSO₄), filtered and the solvent was evaporated. The residue (6g) was purified by column chromatography over silica gel (eluent: cyclohexane/EtOAc 60/40; 15-40μm). 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: 1.26g of compound (35) (24%); mp. 160°C.

v) Preparation of

CIS TRANS

(compound 36) (compound 37)

A mixture of compound (4) (0.009 mol) and thiourea (0.0099 mol) in ethyl alcohol (30ml) was stirred and refluxed for 12 hours and a solution of KOH (0.0149 mol) in H2O (5ml) was added slowly. The mixture was stirred and refluxed for 1 hour, poured out into water and extracted with CH2CI₂. 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; 15-40μm). The pure fractions were collected and the solvent was evaporated. Yielding: l.lg of FI (37%) and 0.4g of F2 (13%). FI 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

CIS TRANS

(compound 38) (compound 39)

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 (15ml). The mixture was stirred at room temperature for 8 hours. Water was added and the mixture was extracted with CH₂CI₂. The organic layer was separated, dried (MgSO₄), filtered and the solvent was evaporated. The residue (1.2g) was purified by column chromatography over silica gel (eluent: cyclohexane EtOAc 85/15; 15-40μm). The pure fractions were collected and the solvent was evaporated. Yielding: 0.6g FI (57%), and 0.18g F2 (17%). FI was crystallized from diethyl ether. The precipitate was filtered off and dried. Yielding: 0.28g compound (38) (27%). F2 was crystallized from diethyl ether. The precipitate was filtered off and dried. Yielding: 0.065g of compound

(compound 40) cis

A mixture of compound (41) prepared according to example B3b (0.0014 mol) in HCl 3N (5ml) and THF (5ml) was stirred and refluxed for a weekend, then poured out into H2O, basified with K₂CO₃ and extracted with CH₂C1₂. The organic layer was separated, dried (MgSO ), filtered and the solvent was evaporated. Yielding: 0.5g of F. This fraction F was crystallized from 2-propanone. The precipitate was filtered off and dried. Yielding: 0.35g of compound

(compound 188) 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/CH2CI2 ;and extracted with CH2CI₂. The organic layer was separated, dried (MgSO ), 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 (11.27g) was purified by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH NH₄OH 96/4/0.1; 15-35μm). The pure fractions were collected and the solvent was evaporated. Yielding: 4.2 g of compound

(compound 248)

A mixture of compound (188) (0.00032 mol), benzoic acid (1.5 equiv., 0.00048 mol), l-ethyl-3-(3'-dimethylaminoproρyl)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 (2ml) 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%).

(compound 6)

trans A mixture of interm. 20 (0.001507 mol) in HCl 3N (10ml) and THF (10ml) was stirred at room temperature for 8 hours, basified with K₂CO₃ 10% and extracted with CH₂C1₂. The organic layer was separated, dried (MgSO ), filtered and the solvent was evaporated. The residue (1.2g) 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 (0.4g) was crystallized from petroleum ether. The precipitate was filtered off and dried. Yield: 0.3g of compound (6) (58%); mp. 108°C. ab) Preparation of (compound 419)

A mixture of compound 213 (prepared according to B4) (0.00305 mol) and CH₃ONa (30% in CH₃OH) (0.00916 mol) in CH₃OH (25ml) 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 (l.lg) was purified by column chromatography over silica gel (eluent: cyclohexane EtOAc; 40/60; 15-40μm). Two fractions were collected and the solvent was evaporated. Yielding: 0.3g FI and 0.5g F2 (50%) F2 was crystallized from diethyl ether/petroleum ether. The precipitate was filtered off and dried. Yielding: 0.26g FI was crystallized from pentane. The precipitate was filtered off and dried. Yielding: 0.19g. This fraction was purified by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH; 98/2; 15-40μm). The pure fractions were collected and the solvent was evaporated. Yielding: 0.1 lg. 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: 0.09g. (9%) This fraction was crystallized from diethyl ether. The precipitate was filtered off and dried. Yielding: 0.08g of compound 419 (8%).

Example B5

Preparation of cis (compound 42) (trans) (compound 43)

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 (30ml) under N₂ flow. The mixture was stirred at room temperature overnight, poured out into H₂O and extracted with CH₂CI₂. 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; 15-40μm). Two fractions were collected and the solvent was evaporated. Yield: 0.35g of compound (42) (30%; mp. 125°C) and 0.35g of compound (43) (30%; mp. 116°C). Example B6

a) Preparation of

cis (compound 44) (trans) (compound 45)

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 (MgSO ), 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: 0.1 lg FI; 0.13g F2; 0.75g F3 and 0.8g 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

cis (compound 46) (trans) (compound 47)

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 (40ml). 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: 0.15g FI, O.lg F2, 0.6g F3 (23%) and 0.8g F4.

F3 was crystallized from diethyl ether. The precipitate was filtered off and dried. Yield: 0.13g 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 CH₂CI₂ (200ml) and the mixture was stirred at room temperature for 12 hours. The mixture was washed with K₂CO₃ 10%. The organic layer was dried (MgSO₄), filtered off and evaporated. The residue was recrystallized from (C₂H₅)₂O. Yield : 8.2g of cyclohexyl (3-methyl-6-quinolinyl)methanone,l -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 (400ml) and CH₂C1₂ (400ml) and the mixture was stirred at room temperature for 1 hour. The mixture was extracted with CH2CI2. The organic layer was dried (MgSO ), filtered off and evaporated. The residue was recrystallized from (dHs^O. Yield : 6.64g of 6-(cyclohexylcarbonyl)-3-methyl~ 2(lH)-quinolinone (compound 50) (85%); mp. 256.1°C. Example B8

a) Preparation of

[l (A),4α] (compound 51) [lα (B),4 ] (compound 52)

A mixture of compound (7) (0.0229 mol), hydroxylamine (0.0252 mol) and N,N-diethylethanamine (0.0252 mol) in ethanol (100ml) was stirred and refluxed for 6 hours, poured out into water and extracted with CH2CI₂. The organic layer was separated, dried (MgSO ), filtered and the solvent was evaporated. The residue was crystallized from CH₃CΝ. The precipitate was filtered off and dried. The residue was purified by column chromatography over silica gel (eluent: CT^C^/EtOAc 80/20; 15- 40μm). Two fractions were collected and the solvent was evaporated. Yielding: 2.8g of compound (44) (36%; mp. 133°C) and 3g of compound (45) (38%; mp. 142°C).

b) Preparation of (compound 53)

[lα(Z),4α] Hydrazine (0.41 mol) was added at room temperature to a solution of compound (7) (0.015 mol) in ethanol (75ml). The mixture was stirred and refluxed for 1 night, poured out into water and extracted with CH₂CI₂. The organic layer was separated, dried (MgSO₄), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: 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: 0.8g of compound (53) (15%); mp. 110°C.

Example B9

Preparation of (compound 520)

Procedure for compounds 400, 401, 402, 403, 404 and 405. A mixture of interm. 21 (prepared according to All) (0.000269 mol), amantadine hydrochloride (0.000404 mol; 1.5 eq.), ^-(ethylcarbonimidoy -^N-dimethyl-l^-propanediamine hydrochloride (0.000404 mol; 1.5 equiv.), 1 -hydroxy- lH-benzotriazole (0.000404 mol; 1.5 equiv.) and Et₃Ν (0.000269 mol) in CΗ₂C1₃ (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 B 10

Preparation of (compound 233)

A mixture of intermediate 27 (0.0026 mol) and intermediate 26 (0.0026 mol) in EtOH (380 ml) and H₂SO₄ cone. (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; 15-35μm). The pure fractions were collected and the solvent was evaporated. Yielding: 0.85 g of FI, 1.1 g F2 and 11.5 g of F3. FI and F2 were crystallized separately from petroleum ether. The precipitate was filtered off and dried. Yielding: 0.34 g of compound 233. Example B 11

Preparation of (compound 511)

A mixture of compound 22 (prepared according to B4) (0.004 mol) in HCl (3N) (20ml) and THF (20ml) was stirred and refluxed for 8 hours, poured out on ice, basified with NH OH and extracted with CH₂C1₂. The organic layer was separated, dried (MgSO₄), filtered, and the solvent was evaporated. The residue (1.2g) was purified by column chromatography over silica gel (eluent: 93/7/0.5; 15-40μm). Two fractions were collected and the solvent was evaporated. Yielding: 0.5g FI (41%) and 0.4g of F2. FI was crystallized from petroleum ether. The precipitate was filtered off and dried. Yielding: 0.17g of compound 511 (14%). Example B 12

Preparation of (compound 514)

A mixture of compound 524 (prepared according to B9a) (0.0018 mol) and KOH 85% (0.0094 mol) in EtOH (15ml) was stirred and refluxed for 24 hours, poured out into H₂O and extracted with CH₂C1₂. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH-OyCyclohexane 80/20; 15-40μm). Two fractions were collected and the solvent was evaporated. Yielding: 0.35g FI (64%) and 0.17g (SM) FI was crystallized from diethyl ether. The precipitate was filtered off and dried. Yielding: 0.33g of compound 514 (60%) (mp.:185°C).

Example B 13

Preparation of (compound 515)

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 (25ml) and Na₂CO₃ [2] (25ml) was stirred and refluxed for 8 hours and extracted with EtOAc. The aqueous layer was basified with NH4OH and extracted with CH2CI2. The organic layer was separated, dried (MgSO₄), filtered, and the solvent was evaporated. The residue (3.6g) was purified by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH 99/1 ; 15-40μm). The pure fractions were collected and the solvent was evaporated. Yielding: 1.8g (33%). This fraction was crystallized from 2-propanone/diethyl ether. The precipitate was filtered off and dried. Yielding: 0.39g of compound 515 (7%) (mp.:134°C). Example B 14

Preparation of (compound 526)

Triethylsilane (0.0012 mol) was added slowly at room temperature to a solution of interm. 32 (0.004 mol) in CF3COOH (5ml) and AcOH (10ml). NaBHt (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 CH₂CI₂. The organic layer was separated, dried (MgSO ), filtered, and the solvent was evaporated. The residue (1.2g) was purified by column chromatography over silica gel (eluent: CH₂CI₂/CH₃OH 99/1; 15-40μm). Two fractions were collected and the solvent was evaporated. Yielding: 0.5g FI (43%) and 0.4g F2. FI was dissolved in iPrOH. HCl/iPrOH (1 eq) were added. The precipitate was filtered off and dried; Yielding: 0.32g of compound 526 (mp.: 248°C).

Example B 15

Preparation of (compound 471)

A mixture of interm. 33 (0.082 mol) and 3-chloro-2-ethyl-2-butenal (0.098 mol) in- AcOH (200ml) was stirred and refluxed for 8 hours. The solvent was evaporated till dryness. The residue was dissolved in CH₂CI₂ 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: CH Cl /EtOAc 95/5 to 92/8; 15-35μm). Two fractions were collected and the solvent was evaporated. Yielding: 0.7g of FI and 5.3g F2. FI was crystallized from 2-propanone/diethyl ether. The precipitate was filtered off and dried. Yielding: 0.25g 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 2

Table 4

02/28837

-82-

Table 7

Table 8:

C. Pharmacological example

Signal transduction at the cloned rat mGluRl receptor in CHO cells

CHO cells expressing the mGluRl 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 Plate 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 secondes) for each concentration of tested compound. pICso values are the -log values of the concentration of the tested compounds resulting in 50% inhibition of the glutamate- induced intracellular Ca rise.

The compounds according to the present invention exhibited a pICso value of at least 5. The compounds that are included in the Tables 1-8 exhibited a pIC₅o value of at least 6.

A particular group of compounds exhibited a pICso value between 7 and 8. It concerns the compounds listed in Table 9.

Table 9:

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

Table 10 :

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 X 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 and a stereochemically isomeric form thereof, wherein

X represents O; C(R⁶)₂ with R⁶ being hydrogen, aryl or C^alkyl optionally substituted with amino or mono- or d^ -_όalky amino; S or Ν-R⁷ with R⁷ being amino or hydroxy;

R¹ represents -_όalkyl; aryl; thienyl; quinolinyl; cycloCs-^alkyl or

(cyclo -^alky -ealkyl, wherein the cycloCs-^alkyl moiety optionally may contain a double bond and wherein one carbon atom in the cycloCs-πalkyl moiety may be replaced by an oxygen atom or an ΝR⁸-moiety with R⁸ being hydrogen, benzyl or Cι-₆alkyloxycarbonyl ; wherein one or more hydrogen atoms in a -galkyl-moiety or in a cycloCs-πalkyl-moiety optionally may be replaced by

Ci-ealkyl, hydroxy -_δalkyl, haloCi-βalkyl, amino -_όalkyl, hydroxy, -_όalkyloxy, aryl -όalkyloxy, halo, C_.-₆alkyloxycarbonyl, aryl, amino, mono- or di(Cι-₆alkyl)amino, Cι-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)

a-1

wherein Zi 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, -βalkyl, -βalkyloxy or hydroxyCi-βalkyl; 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);

b-1 b-2 b-3

R² represents hydrogen; halo; cyano; Cι-₆alkyl; -βalkyloxy; -ealkylthio; d-ealkylcarbonyl; Cι-₆alkyloxycarbonyl; Ci-βalkylcarbonyloxy -βalkyl;

C₂-₆alkenyl; hydroxyC₂.₆alkenyl; C₂-₆alkynyl; hydroxyC₂-₆alkynyl; tri(Cι_ ₆alkyl)silaneC₂-₆alkynyl; amino; mono- or d^ -eal y amino; mono- or mono- or d -oalkylthioCi-ealky amino; aryl; arylCι-₆alkyl; arylC₂-₆alkynyl; Ci-₆alkyloxyCi-6alkylaminoCi-₆alkyl; aminocarbonyl optionally substituted with Ci-βalkyl, -ealkyloxyC_ϊ-_θal yl, or pyridinyl -ealkyl; a heterocycle selected from thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, isothiazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, piperidinyl and piperazinyl, optionally N-substituted with Ci-βalkyloxy -ealkyl, morpholinyl, thiomorpholinyl, dioxanyl or dithianyl ; a radical -NH-C(=O)R⁹ wherein R⁹ represents

Ci-ealkyl optionally substituted with cycloC₃-₁₂alkyl. -_όalkyloxy, -galkyloxycarbonyl, aryl, aryloxy, thienyl, pyridinyl, mono- or d C^al y^amino, C_t-_δalkylthio, benzylthio, pyridinylthio or pyrimidinylthio; cycloC₃-ι₂alkyl; cyclohexenyl; amino; arylcycloC₃-nalkylamino; di(C₁-₆alkyloxycarbonylC₁-₆alkyl)amino; mono- or (-^(Ci-ealkyloxycarbony^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; arylCi-ealkylthio or a radical of formula (a-1) ; a sulfonamid -NH-SO₂-R¹⁰ wherein R represents Cι-₆alkyl, mono- or poly haloCι-₆alkyl, arylCi-βalkyl, arylC₂-₆alkenyl, aryl, quinolinyl, isoxazolyl or di(C₁.₆alkyl)amino; R³ and R⁴ each independently represent hydrogen; halo; hydroxy; cyano; C₁-₆alkyl; Q-βalkyloxy; -ealkyloxy -ealkyl; C..₆alkylcarbonyl; d-ealkyloxycarbonyl; C₂.₆alkenyl; hydroxyC₂-₆alkenyl; C₂-₆alkynyl; hydroxyC₂.6alkynyl; tri(C₁-₆alkyl)silaneC₂-₆alkynyl; amino; mono- or <ft(Cι-6alkyl)amino; mono- or mono- or di(C₁-₆alkylthioC₁-₆alkyl)amino; aryl; morpholinylQ-ealkyl or piperidinylQ-όalkyl ; 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-Z -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, Chalky!, benzyl or Q-ealkyloxycarbonyl; and wherein each bivalent radical is optionally substituted with C_halky!, 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-i₂alkyl; piperidinyl; oxo-thienyl; tetrahydrothienyl, arylQ-ealkyl; d-_όalkyloxyQ-ealkyl; Q-βalkyloxycarbonylCi-ealkyl or C^alkyl optionally substituted with a radical C(=O)NR_xR_y, in which R_x and R_y, each independently are hydrogen, cycloCs-^alk l, C2-₆alkynyl or Q-ealkyl optionally substituted with cyano, Q-ealkyloxy, C_.-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, Q-ealkyl, C^alkyloxy, phenyloxy, nitro, amino, thio, Cι-₆alkylthio, haloCι-₆alkyl, polyhaloCi-βalkyl, poIyhaloQ-ealkyloxy, hydroxyCi-βalkyl, Q-όalkyloxyQ-galkyl, aminoCi-ealkyl, mono-or d Q- ₆alkyl)amino; mono-or di(Cι-₆alkyl)aminoC₁.₆alkyl, cyano, -CO-R¹², -CO-OR¹³, -NR¹³SO₂R¹², -SO₂-NR¹³R¹⁴, -NR¹³C(O)R¹², -C(O)NR¹³R¹⁴, -SOR¹², -SO₂R 12. wherein each R¹², R¹³ and R¹⁴ independently represent C_!-₆alkyl; cycloC₃-₆alkyl; phenyl; phenyl substituted with halo, hydroxy, d-₆alkyl, Ci-₆alkyloxy, haloCι-₆alkyl, polyhalod-όalkyl, furanyl, thienyl, pyrrolyl, imidazolyl, thiazolyl or oxazolyl;

and when the R^J-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 d-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, characterized in that,

X represents O; C(R⁶)₂ with R⁶ being hydrogen or aryl ; or N-R⁷ with R⁷ being amino or hydroxy; R¹ represents d-₆alkyl, aryl; thienyl; quinolinyl; cyclod-^alkyl or

(cyclod-πalky d-ealkyl, 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 NR -moiety with R being benzyl or d-₆alkyloxycarbonyl ; wherein one or more hydrogen atoms in a d.₆alkyl-moiety or in a cycloC₃-i₂alkyl-moiety optionally may be replaced by d-₆alkyl, halod-₆alkyl, hydroxy, d-ealkyloxy, aryld-₆alkyloxy, halo, aryl, mono- or di(d.₆alkyl)amino, d-ealkyloxycarbonylamino, halo, piperazinyl, pyridinyl, morpholinyl, thienyl or a bivalent radical of formula -O- or -O-CH₂-CH₂-O-; or a radical of formula (a-1)

a-1

wherein . 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); b-1 b-2 b-3

R² represents hydrogen; halo; cyano; d-₆alkyl; d-βalkyloxy; d-βalkylthio; d-₆alkylcarbonyl; d-₆alkyloxycarbonyl; C₂-₆alkenyl; hydroxyd-βalkenyl; C₂-₆alkynyl; hydroxyC₂.6alkynyl; tri(C₁_6alkyl)silaneC2-₆alkynyl; amino; mono- or di(d-₆alkyl)amino; mono- or di(C₁.₆alkyloxyC₁-₆alkyl)amino; mono- or di(C₁-₆alkylthioCι-₆alkyl)amino; aryl; aryld-₆alkyl; arylC₂-₆alkynyl;

C i-β lkyloxyC ι -₆alkylaminoC ι -₆alkyl ; aminocarbonyl optionally substituted with d^alkyloxycarbonyld-_όalkyl ; 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 C_!-₆alkyl optionally substituted with cyclod-πalkyl, d-βalkyloxy, d-ealkyloxycarbonyl, aryl, aryloxy, thienyl, pyridinyl, mono- or di(C₁-₆alkyl)amino, C ^alkylthio, benzylthio, pyridinylthio or pyrimidinylthio; cycloC3-i2alkyl; cyclohexenyl; amino; arylcycloC₃.₁₂alkylamino; mono-or-di(C₁-₆alkyl)amino; mono- or di(C₁-₆alkyloxycarbonylC₁-6alkyl)amino; mono- or di(d-ealkyloxycarbonyl)amino; mono-or di(C₂-₆alkenyl)amino; mono- or di(arylCi-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 d-βalkyl, mono- or poly halod-βalkyl, aryld.₆alkyl or aryl; R³ and R⁴ each independently represent hydrogen; d-₆alkyl; d-ealkyloxyd-ealkyl; d-₆alkyloxycarbonyl; or R² and 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, d-₆alkyl, benzyl or d-ealkyloxycarbonyl; and wherein each bivalent radical is optionally substituted with d-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, aryld-βalkyl;

C_ϊ-ealkyloxycarbonylCi-ealkyl or d-₆alkyl optionally substituted with a radical C(=O)NR_xRy, in which R_x and R_y, each independently are hydrogen, cyclod-πalkyl, d-βalkynyl or d-₆alkyl optionally substituted with cyano, d-₆alkyloxy or d-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, d-βalkyloxy, 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 R and R represents d-ealkyl or R and R taken together may form a bivalent radical of formula -CH=CH-CH=CH-.

3. A compound according to claim 1, characterized in that, X represents O;

R¹ represents Cι-₆alkyl; cycloC₃-₁₂alkyl or (cyclod-^alky^d-ealkyl, wherein one or more hydrogen atoms in a d-ealkyl-moiety or in a cyclod-^alkyl-moiety optionally may be replaced by d-₆alkyloxy, aryl, halo or thienyl; R² represents hydrogen; halo; d-₆alkyl or amino; R³ and R⁴ each independently represent hydrogen or Cι-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 d-βalkyl; and wherein each bivalent radical is optionally substituted with d-₆alkyl; or R³ and R⁴ may be taken together to form a bivalent radical of formula R⁵ represents hydrogen;

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

4. A compound as claimed in claim 1, characterized in that, the R*-C(=X) moiety is linked to the quinoline or quinolinone moiety in position 6.

5. A compound as claimed in claim 1 for use as a medicine.

6. Use of a compound as defined in claims 1 to 4 in the manufacture of a medicament for treating or preventing glutamate-induced diseases of the central nervous system.

7. Use according to claim 6, characterized in that, the glutamate-induced disease of the central nervous system is 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).

8. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, and as active ingredient a therapeutically effective amount of a compound as defined in claims 1 to 4.

9. A process of preparing a composition as claimed in claim 8, characterized in that, a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of a compound as described in claims 1 to 4.

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

with R¹ as defined in claim 1 and Q representing the quinoline or the quinolinone moiety of a compound of formula (I-A) or (I-B); or b) reacting an intermediate of formula (HI) with an intermediate of formula (IN) o _β1 « II

FT — C---=Ν + Wf— Q ► R¹ — C— Q with R¹ as defined in claim 1, Q representing the quinoline or the quinolinone moiety of a compound of formula (I-A) or (I-B) and W_t being a suitable leaving group; or c) reacting an intermediate of formula (N) with an intermediate of formula (IN)

with R¹ as defined in claim 1, Q representing the quinoline or the quinolinone moiety of a compound of formula (I-A) or (I-B) and Wi being a suitable leaving group; or d) reacting an intermediate of formula (VI) with an intermediate of formula (NH) in the presence of a suitable acid

O O

R 1a

-OH + HO— C— Q R¹⁹ — O— C— Q with R^la being defined as R¹ according to claim 1 provided that R¹ is linked to the carbonyl moiety via a oxygen atom and Q representing the quinoline or the quinolinone moiety of a compound of formula (I-A) or (I-B); or e) reacting an intermediate of formula (N-QT) in the presence of a suitable acid

(l-A-1)

(VIM) with R¹ , X, R³ and R⁴ defined as in claim 1 ;

and, if desired, converting compounds of formula (I-A) or (I-B) into each other following art-known transformations; and further, if desired, converting the compounds of formula (I-A) or (I-B), into a therapeutically active non-toxic acid addition salt by treatment with an acid, or conversely, converting the acid addition salt form into the free base by treatment with alkali; and, if desired, preparing stereochemically isomeric forms, quaternary amines or N-oxide forms thereof.