HK1141009B - Sulfonyl-quinoline derivatives - Google Patents

Description

Sulfonyl-quinoline derivatives

Technical Field

The present invention relates to novel mGluR1 and mGluR5 receptor subtype-preferring ligands of formula (I) and/or salts and/or hydrates and/or solvates thereof, to processes for their preparation and intermediates used in their preparation, to pharmaceutical compositions containing these compounds and to their use in the treatment and/or prevention of disorders requiring the modulation of mGluR1 and mGluR5 receptors.

Background

The major excitatory neurotransmitter in the mammalian Central Nervous System (CNS) is the glutamate molecule, which binds to neurons, thereby activating cell surface receptors. These receptors can be divided into 2 broad classes, namely ionotropic and metabotropic glutamate receptors, based on the structural characteristics of the receptor proteins, the manner in which the receptors transduce signals into the cell, and the pharmacological properties.

Metabotropic glutamate receptors (mglurs) are G protein-coupled receptors that, upon binding to glutamate, activate a number of intracellular second messenger systems. Activation of mglurs in intact mammalian neurons elicits one or more of the following responses: activation of phospholipase C; an increase in Phosphoinositide (PI) hydrolysis; intracellular calcium release; activation of phospholipase D; activation or inhibition of adenosine cyclase; an increase or decrease in cyclic adenosine monophosphate (cAMP) formation; activation of guanylate cyclase; an increase in cyclic guanosine monophosphate (cGMP) formation; activation of phospholipase a 2; an increase in arachidonic acid release; and increases or decreases in the activity of voltage-and ligand-gated ion channels (trends pharmacol. sci., 1993, 14, 13; neurochem. int., 1994, 24, 439; Neuropharmacology, 1995, 34, 1; prog. neurobiol., 1999, 59, 55).

By molecular cloning, 8 different mGluR subtypes have been identified, termed mGluR1 through mGluR8(Neuron, 1994, 13, 1031; Neuropharmacology, 1995, 34, 1; J.Med.Chem., 1995, 38, 1417). Further receptor diversity is generated by the expression of alternatively spliced forms of certain mGluR subtypes (PNAS, 1992, 89, 10331; BBRC, 1994, 199, 1136; j. neurosci., 1995, 15, 3970).

Metabotropic glutamate receptor subtypes can be subdivided into 3 groups, i.e., group I, group II, and group III mglurs, based on amino acid sequence homology, the second messenger system used by the receptors, and their pharmacological characteristics. Group I mglurs include mGluR1, mGluR5 and alternatively splice variants thereof.

Attempts to elucidate the physiological role of group I mglurs suggest that activation of these receptors causes neuronal excitation. There is evidence that this excitation is due to direct activation of postsynaptic mGluRs, but activation of presynaptic mGluRs has also been implicated as occurring, leading to increased neurotransmitter release (Trends Pharmacol. Sci., 1992, 15, 92; neurochem. int., 1994, 24, 439; neuropharmacolgy, 1995, 34, 1; Trends Pharmacol. Sci., 1994, 15, 33).

Metabotropic glutamate receptors have been implicated in many normal processes in the mammalian CNS. Activation of mGluRs has been shown to be required for induction of hippocampal long-term potentiation and cerebellar long-term inhibition (Nature, 1993, 363, 347; Nature, 1994, 368, 740; Cell, 1994, 79, 365; Cell, 1994, 79, 377). The role of mGluR activation in nociception and analgesia has also been demonstrated (Neuroreport, 1993, 4, 879; Brain Res., 1999, 871, 223).

Group I metabotropic glutamate receptors and more specifically mGluR5 have been proposed to play a role in a number of pathophysiological processes and disorders affecting the CNS. They include stroke, head injury, hypoxic and ischemic injury, hypoglycemia, epilepsy, neurodegenerative disorders such as Alzheimer's disease, acute and chronic Pain, substance abuse and withdrawal, obesity and gastroesophageal reflux disease (GERD) and irritable bowel syndrome (Trends Pharmacol. Sci., 1993, 14, 13; Life Sci., 1994, 54, 135; Ann. Rev. Neurosci., 1994, 17, 31; Neuropharmacolgy, 1995, 34, 1; J.Med.Chem., 1995, 38, 1417; Trends Pharmacol. Sci., 2001, 22, 331; Curr. Opin. Pharmacol., 2002, 2, 43; Pain, 2002, 98, 1, Curr Top Chem., 2005; 5 (9): 897). Many of these pathological conditions are thought to be due to excessive glutamate-induced excitation of CNS neurons. Since group I mglurs appear to increase glutamate-mediated neuronal excitation through postsynaptic mechanisms and enhanced presynaptic glutamate release, their activation may contribute to pathological conditions. Therefore, selective antagonists of group I mGluR receptors may be therapeutically beneficial, especially as neuroprotective agents, analgesics, or anticonvulsants.

WO 2006120573 relates to a method of inhibiting the proliferation of cancer cells in a mammal comprising administering to said mammal a therapeutically effective amount of a heterocyclic mono-N-oxide of an N-oxide of a compound of formula (I) of the present invention.

General methods for preparing quinolines are described in this application, which can be found in WO 2005070890, j.med.chem, 2003, 46, 49 and j.med.chem., 2005, 48, 1107. In the cited publication, 4-amino-3-cyano-quinoline derivatives are prepared by condensing anilines with 2-cyano-3-ethoxy-acrylic acid ethyl ester and subsequently ring-closing the obtained intermediate. Thermal cyclization gives 3-cyano-4-hydroxy-quinoline derivatives, which are converted with phosphoryl chloride (V) into 3-cyano-4-chloro-quinoline derivatives. Cyclization with phosphorus oxyhalide (V) directly produces 3-cyano-4-halo-quinoline derivatives. From these intermediates, the 3-arylsulfonyl-4-aryl-quinoline derivatives of the formula (I) according to the invention cannot be prepared or are characterized by the physical properties of WO 2006120573 or the cited publications.

WO 200558834 provides the use of novel quinoline derivatives in the treatment of Liver X Receptor (LXR) -mediated diseases, in particular multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease and atherosclerosis, which inhibit Th-1 type lymphokine production, leading to increased HDL levels and cholesterol metabolism. The general formula of WO 2005058834 covers some of the compounds of formula (I) according to the invention, but 3-benzenesulfonyl-4-phenyl-8-trifluoromethyl-quinoline is prepared only by reacting the appropriate aniline derivative (described in scheme 9 of WO 200558834) with 1, 2-bis (benzenesulfonyl) -ethene. The formula of the present invention does not cover the compound and demonstrates that the compound is inactive at the mGluR1 and mGluR5 receptors.

WO 200530129 relates to compounds useful as potassium channel inhibitors. Such compounds are useful as Kv1.5 antagonists for the treatment and prevention of cardiac arrhythmias, etc., and as Kv1.3 inhibitors for the treatment of immunosuppression, autoimmune diseases, etc. The general formula of WO 200530129 covers some of the compounds of formula (I) according to the invention, but does not allow the preparation or characterization of the physical properties of the 3-arylsulfonyl-4-aryl-quinoline derivatives of formula (I) according to the invention, but only the preparation or characterization of the physical properties of the 2-substituted-6-methoxy-quinoline-3-carbonitrile derivatives.

The compounds mentioned in the above publications are neither disclosed nor suggested to have activity at the mGluR1 and mGluR5 receptors.

Disclosure of Invention

The present invention relates to novel mGluR1 and mGluR5 receptor subtype-preferential ligands of formula (I):

wherein

Ar₁Represents optionally substituted phenyl or heteroaryl;

Ar₂represents a substituted phenyl group or an optionally substituted heteroaryl group;

R₁，R₂，R₃and R₄Independently represent a substituent selected from hydrogen, halogen, cyano, alkyl, alkoxy, hydroxy, trifluoromethyl, amino, alkylamino, dialkylamino, aminomethyl, alkylaminomethyl, dialkylaminomethyl,

and/or salts and/or hydrates and/or solvates thereof, to processes and intermediates for their production, to pharmaceutical compositions comprising them and to their use in the treatment and/or prevention of pathological conditions such as neurological disorders, psychiatric disorders, acute and chronic pain and neuromuscular dysfunctions of the lower urinary tract.

Detailed Description

The present invention relates to novel mGluR1 and mGluR5 receptor subtype-preferential ligands of formula (I):

wherein

Ar₁Represents optionally substituted phenyl or heteroaryl;

Ar₂represents a substituted phenyl group or an optionally substituted heteroaryl group;

R₁，R₂，R₃and R₄Independently represent a substituent selected from hydrogen, halogen, cyano, alkyl, alkoxy, hydroxy, trifluoromethyl, amino, alkylamino, dialkylamino, aminomethyl, alkylaminomethyl, dialkylaminomethyl,

and/or a salt thereof and/or a hydrate thereof and/or a solvate thereof.

When Ar is₁When representing phenyl, the phenyl may be optionally substituted by one or more substituents selected from hydrogen, halogen, cyano, alkyl, alkoxy, trifluoromethyl, dialkylamino. When Ar is₂When representing phenyl, the phenyl is substituted by one or more substituents selected from halogen, cyano, alkyl, alkoxy, trifluoromethyl, dialkylamino.

When Ar is₁And/or Ar₂When it represents a heteroaryl group, the heteroaryl groupMay be an aromatic 5-6 membered heterocyclic ring containing 1-2 heteroatoms selected from 0, N or S, e.g. pyridyl, thiazolyl, oxazolyl. Heteroaryl groups may be optionally substituted with one or more substituents selected from hydrogen, alkyl, alkoxy, halogen.

When R is₁And/or R₂And/or R₃And/or R₄When alkyl is represented, the alkyl group contains 1 to 4 carbon atoms having a straight or branched chain.

When R is₁And/or R₂And/or R₃And/or R₄When alkoxy, alkylamino, dialkylamino, alkylaminomethyl, dialkylaminomethyl are indicated, the alkyl part in the group contains 1-4 carbon atoms with a direct or branched chain.

The term "halogen" includes fluorine, chlorine, bromine and iodine atoms.

The term "halogen" in this specification may be fluorine, chlorine, bromine or iodine.

The compounds of formula (I) contain basic functional groups and can thus form salts with acids. The invention also relates to salts of the compounds of formula (I) with acids, especially with pharmaceutically acceptable acids. The meaning of the compounds of formula (I) is the free base or salt, even if not indicated separately.

Both organic and inorganic acids may be used in the formation of acid addition salts. Suitable inorganic acids may be, for example, hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid. Representative of monovalent organic acids may be, for example, formic acid, acetic acid, propionic acid and the various butyric, valeric and capric acids. Representative of divalent organic acids may be, for example, oxalic acid, malonic acid, maleic acid, fumaric acid, and succinic acid. Other organic acids may also be used, such as hydroxy acids, e.g. citric acid, tartaric acid, or aromatic carboxylic acids, e.g. benzoic acid or salicylic acid, as well as aliphatic and aromatic sulfonic acids, e.g. methanesulfonic acid, naphthalenesulfonic acid and p-toluenesulfonic acid. The group of particularly valuable acid addition salts are those in which the acid component itself is physiologically acceptable and has no therapeutic effect in the applied dose or it has no adverse effect on the effect of the active ingredient. These acid addition salts are pharmaceutically acceptable acid addition salts. Acid addition salts which are not pharmaceutically acceptable acid addition salts are also encompassed by the present invention since they can facilitate the purification and isolation of the desired compound under the circumstances in which it is intended.

Solvates and/or hydrates of the compounds of formula (I) are also included within the scope of the present invention.

Preferred compounds of the invention are the following compounds of formula (I), wherein

Ar₁Represents phenyl or heteroaryl, optionally substituted by one or more substituents selected from hydrogen, fluoro, chloro, cyano, methyl, methoxy;

Ar₂represents phenyl substituted by one or more substituents selected from fluoro, chloro, cyano, methyl, methoxy; or

Heteroaryl, optionally substituted with one or more substituents selected from hydrogen, fluoro, chloro, cyano, methyl, methoxy;

R₁，R₂，R₃and R₄Independently represent a substituent selected from hydrogen, fluorine, chlorine, cyano, methyl, methoxy, hydroxy, trifluoromethyl, amino, methylamino, dimethylamino, aminomethyl, methylaminomethyl, dimethylaminomethyl,

and/or a salt thereof and/or a hydrate thereof and/or a solvate thereof.

Particularly preferred compounds of the invention are the following compounds of formula (I), wherein

Ar₁Represents phenyl, pyridyl, thienyl or oxazolyl, optionally substituted by one or more substituents selected from hydrogen, fluoro, chloro, cyano, methyl, methoxy;

Ar₂represents phenyl substituted by one or more substituents selected from fluoro, chloro, cyano, methyl, methoxy; or

Pyridyl, thienyl or oxazolyl, optionally substituted with one or more substituents selected from hydrogen, fluoro, chloro, cyano, methyl, methoxy;

R₁，R₂，R₃and R₄Independently represent a substituent selected from hydrogen, fluorine, chlorine, cyano, methyl, methoxy, hydroxy, trifluoromethyl, amino, methylamino, dimethylamino, aminomethyl, methylaminomethyl, dimethylaminomethyl,

and/or a salt thereof and/or a hydrate thereof and/or a solvate thereof.

Particularly important compounds of the formula (I) according to the invention are the following:

4- (4-chloro-phenyl) -3- (4-methyl-benzenesulfonyl) -quinoline,

7-chloro-3- (4-chloro-benzenesulfonyl) -4- (4-fluoro-phenyl) -quinoline,

8-chloro-4- (3-chloro-phenyl) -3- (3, 4-dichloro-benzenesulfonyl) -quinoline,

7-fluoro-3- (4-fluoro-benzenesulfonyl) -4- (3-fluoro-phenyl) -quinoline,

4- (4-chloro-phenyl) -7-fluoro-3- (4-methoxy-benzenesulfonyl) -quinoline,

7-fluoro-3- (4-methoxy-benzenesulfonyl) -4- (4-methoxy-phenyl) -quinoline,

7-fluoro-3- (3-fluoro-benzenesulfonyl) -4- (3-fluoro-phenyl) -quinoline,

7-fluoro-3- (3-fluoro-benzenesulfonyl) -4- (4-fluoro-phenyl) -quinoline,

4- (3-chloro-phenyl) -3- (3, 4-dimethyl-benzenesulfonyl) -7-fluoro-quinoline,

3- (3, 4-dimethyl-benzenesulfonyl) -7-fluoro-4- (3-fluoro-phenyl) -quinoline,

3- (3, 4-dimethyl-benzenesulfonyl) -7-fluoro-4- (3-methoxy-phenyl) -quinoline,

4- (3-chloro-phenyl) -8-fluoro-3- (4-fluoro-benzenesulfonyl) -quinoline,

4- (4-chloro-phenyl) -8-fluoro-3- (4-fluoro-benzenesulfonyl) -quinoline,

8-fluoro-3- (4-fluoro-benzenesulfonyl) -4- (3-fluoro-phenyl) -quinoline,

8-fluoro-3- (4-fluoro-benzenesulfonyl) -4- (3-methoxy-phenyl) -quinoline,

4- (4-chloro-phenyl) -6-fluoro-3- (4-methoxy-benzenesulfonyl) -quinoline,

4- (4-chloro-phenyl) -3- (3, 4-dimethyl-benzenesulfonyl) -6-fluoro-quinoline,

4- (4-chloro-phenyl) -3- (3, 5-difluoro-benzenesulfonyl) -7-fluoro-quinoline,

3- (3, 5-difluoro-benzenesulfonyl) -7-fluoro-4- (4-fluoro-phenyl) -quinoline,

4- (4-chloro-phenyl) -3- (3-cyano-benzenesulfonyl) -7-fluoro-quinoline,

3- (3-cyano-benzenesulfonyl) -7-fluoro-4- (3-fluoro-phenyl) -quinoline,

3- (3-cyano-benzenesulfonyl) -7-fluoro-4- (4-fluoro-phenyl) -quinoline,

7-fluoro-3- (4-fluoro-benzenesulfonyl) -4- (4-fluoro-phenyl) -quinoline,

4- (4-chloro-phenyl) -7-fluoro-3- (3-fluoro-benzenesulfonyl) -quinoline,

4- (3-chloro-phenyl) -7-fluoro-3- (3-methoxy-benzenesulfonyl) -quinoline,

7-fluoro-4- (4-fluoro-phenyl) -3- (3-methoxy-benzenesulfonyl) -quinoline,

4- (4-chloro-phenyl) -3- (3, 4-dimethyl-benzenesulfonyl) -7-fluoro-quinoline,

3- (3, 4-dimethyl-benzenesulfonyl) -7-fluoro-4- (4-fluoro-phenyl) -quinoline,

4- (3-chloro-phenyl) -3- (3-chloro-4-methoxy-benzenesulfonyl) -7-fluoro-quinoline,

3- (3-chloro-4-methoxy-benzenesulfonyl) -7-fluoro-4- (3-fluoro-phenyl) -quinoline,

3- (3-chloro-4-methoxy-benzenesulfonyl) -7-fluoro-4- (4-fluoro-phenyl) -quinoline,

3- (3, 5-dichloro-benzenesulfonyl) -8-fluoro-4- (4-fluoro-phenyl) -quinoline,

3- (3, 5-difluoro-benzenesulfonyl) -8-fluoro-4- (3-fluoro-phenyl) -quinoline,

8-fluoro-3- (4-fluoro-benzenesulfonyl) -4- (4-methoxy-phenyl) -quinoline,

4- (3-chloro-phenyl) -8-fluoro-3- (4-methoxy-benzenesulfonyl) -quinoline,

4- (4-chloro-phenyl) -8-fluoro-3- (4-methoxy-benzenesulfonyl) -quinoline,

8-fluoro-4- (4-fluoro-phenyl) -3- (4-methoxy-benzenesulfonyl) -quinoline,

8-fluoro-3- (4-methoxy-benzenesulfonyl) -4- (4-methoxy-phenyl) -quinoline,

8-fluoro-3- (4-methoxy-benzenesulfonyl) -4- (3-methoxy-phenyl) -quinoline,

4- (3-chloro-phenyl) -8-fluoro-3- (3-fluoro-benzenesulfonyl) -quinoline,

4- (4-chloro-phenyl) -8-fluoro-3- (3-fluoro-benzenesulfonyl) -quinoline,

8-fluoro-3- (3-fluoro-benzenesulfonyl) -4- (3-fluoro-phenyl) -quinoline,

8-fluoro-3- (3-fluoro-benzenesulfonyl) -4- (4-methoxy-phenyl) -quinoline,

8-fluoro-3- (3-fluoro-benzenesulfonyl) -4- (3-methoxy-phenyl) -quinoline,

8-fluoro-3- (3-fluoro-benzenesulfonyl) -4- (4-fluoro-phenyl) -quinoline,

3- (3-cyano-benzenesulfonyl) -6-fluoro-4- (3-fluoro-phenyl) -quinoline,

3- (3-cyano-benzenesulfonyl) -6-fluoro-4- (3-methoxy-phenyl) -quinoline,

3- (3-cyano-benzenesulfonyl) -6-fluoro-4- (4-fluoro-phenyl) -quinoline,

4- (3-chloro-phenyl) -6-fluoro-3- (3-methoxy-benzenesulfonyl) -quinoline,

6-fluoro-4- (4-fluoro-phenyl) -3- (3-methoxy-benzenesulfonyl) -quinoline,

3- (3-chloro-4-methoxy-benzenesulfonyl) -6-fluoro-4- (4-methoxy-phenyl) -quinoline,

3- (3-chloro-4-methoxy-benzenesulfonyl) -6-fluoro-4- (3-methoxy-phenyl) -quinoline,

4- (4-chloro-phenyl) -7-fluoro-3- (4-fluoro-benzenesulfonyl) -quinoline,

3- (3, 4-dimethyl-benzenesulfonyl) -7-fluoro-4- (4-methoxy-phenyl) -quinoline,

3- (3-chloro-4-methoxy-benzenesulfonyl) -4- (4-chloro-phenyl) -6-fluoro-quinoline,

3- (3-chloro-4-methoxy-benzenesulfonyl) -6-fluoro-4- (3-fluoro-phenyl) -quinoline,

3- (3, 5-dichloro-benzenesulfonyl) -7-fluoro-4- (4-methoxy-phenyl) -quinoline,

3- (3, 5-dichloro-benzenesulfonyl) -7-fluoro-4- (3-methoxy-phenyl) -quinoline,

3- (3, 5-difluoro-benzenesulfonyl) -7-fluoro-4- (4-fluoro-phenyl) -quinoline,

4- (3-chloro-phenyl) -7-fluoro-3- (3-fluoro-4-methyl-benzenesulfonyl) -quinoline,

7-fluoro-3- (3-fluoro-4-methyl-benzenesulfonyl) -4- (3-fluoro-phenyl) -quinoline,

7-fluoro-3- (3-fluoro-4-methyl-benzenesulfonyl) -4- (4-fluoro-phenyl) -quinoline,

3- (3, 5-difluoro-benzenesulfonyl) -7-fluoro-4- (3-fluoro-phenyl) -quinoline,

3- (3, 5-difluoro-benzenesulfonyl) -7-fluoro-4- (4-methoxy-phenyl) -quinoline,

3- (3, 5-difluoro-benzenesulfonyl) -7-fluoro-4- (3-methoxy-phenyl) -quinoline,

4- (3-chloro-phenyl) -3- (3-cyano-benzenesulfonyl) -7-fluoro-quinoline,

3- (3-cyano-benzenesulfonyl) -7-fluoro-4- (4-methoxy-phenyl) -quinoline,

3- (3-cyano-benzenesulfonyl) -7-fluoro-4- (3-methoxy-phenyl) -quinoline,

3- (3-chloro-4-methyl-benzenesulfonyl) -7-fluoro-4- (3-fluoro-phenyl) -quinoline,

3- (3, 4-difluoro-benzenesulfonyl) -7-fluoro-4- (3-fluoro-phenyl) -quinoline,

3- (3, 4-difluoro-benzenesulfonyl) -7-fluoro-4- (4-methoxy-phenyl) -quinoline,

3- (3, 4-difluoro-benzenesulfonyl) -7-fluoro-4- (3-methoxy-phenyl) -quinoline,

3- (3, 4-difluoro-benzenesulfonyl) -7-fluoro-4- (4-fluoro-phenyl) -quinoline,

3- (3-chloro-4-fluoro-benzenesulfonyl) -4- (4-chloro-phenyl) -7-fluoro-quinoline,

3- (3-chloro-4-fluoro-benzenesulfonyl) -7-fluoro-4- (3-fluoro-phenyl) -quinoline,

3- (3-chloro-4-fluoro-benzenesulfonyl) -7-fluoro-4- (4-methoxy-phenyl) -quinoline,

3- (3-chloro-4-fluoro-benzenesulfonyl) -7-fluoro-4- (4-fluoro-phenyl) -quinoline,

3- (3, 5-dichloro-benzenesulfonyl) -8-fluoro-4- (3-fluoro-phenyl) -quinoline,

3- (3, 5-dichloro-benzenesulfonyl) -8-fluoro-4- (4-methoxy-phenyl) -quinoline,

3- (3, 5-dichloro-benzenesulfonyl) -8-fluoro-4- (3-methoxy-phenyl) -quinoline,

4- (3-chloro-phenyl) -8-fluoro-3- (3-fluoro-4-methyl-benzenesulfonyl) -quinoline,

4- (4-chloro-phenyl) -8-fluoro-3- (3-fluoro-4-methyl-benzenesulfonyl) -quinoline,

8-fluoro-3- (3-fluoro-4-methyl-benzenesulfonyl) -4- (3-fluoro-phenyl) -quinoline,

8-fluoro-3- (3-fluoro-4-methyl-benzenesulfonyl) -4- (4-methoxy-phenyl) -quinoline,

8-fluoro-3- (3-fluoro-4-methyl-benzenesulfonyl) -4- (3-methoxy-phenyl) -quinoline,

8-fluoro-3- (3-fluoro-4-methyl-benzenesulfonyl) -4- (4-fluoro-phenyl) -quinoline,

4- (3-chloro-phenyl) -3- (3, 5-difluoro-benzenesulfonyl) -8-fluoro-quinoline,

4- (4-chloro-phenyl) -3- (3, 5-difluoro-benzenesulfonyl) -8-fluoro-quinoline,

3- (3, 5-difluoro-benzenesulfonyl) -8-fluoro-4- (4-methoxy-phenyl) -quinoline,

3- (3, 5-difluoro-benzenesulfonyl) -8-fluoro-4- (3-methoxy-phenyl) -quinoline,

3- (3, 5-difluoro-benzenesulfonyl) -8-fluoro-4- (4-fluoro-phenyl) -quinoline,

4- (4-chloro-phenyl) -3- (3, 4-difluoro-benzenesulfonyl) -8-fluoro-quinoline,

3- (3, 4-difluoro-benzenesulfonyl) -8-fluoro-4- (3-fluoro-phenyl) -quinoline,

3- (3, 4-difluoro-benzenesulfonyl) -8-fluoro-4- (4-methoxy-phenyl) -quinoline,

3- (3, 4-difluoro-benzenesulfonyl) -8-fluoro-4- (4-fluoro-phenyl) -quinoline,

3- (3, 5-dichloro-benzenesulfonyl) -6-fluoro-4- (3-fluoro-phenyl) -quinoline,

3- (3, 5-dichloro-benzenesulfonyl) -6-fluoro-4- (4-methoxy-phenyl) -quinoline,

3- (3, 5-dichloro-benzenesulfonyl) -6-fluoro-4- (3-methoxy-phenyl) -quinoline,

4- (3-chloro-phenyl) -6-fluoro-3- (3-fluoro-4-methyl-benzenesulfonyl) -quinoline,

6-fluoro-3- (3-fluoro-4-methyl-benzenesulfonyl) -4- (3-fluoro-phenyl) -quinoline,

6-fluoro-3- (3-fluoro-4-methyl-benzenesulfonyl) -4- (4-methoxy-phenyl) -quinoline,

6-fluoro-3- (3-fluoro-4-methyl-benzenesulfonyl) -4- (3-methoxy-phenyl) -quinoline,

6-fluoro-3- (3-fluoro-4-methyl-benzenesulfonyl) -4- (4-fluoro-phenyl) -quinoline,

4- (3-chloro-phenyl) -3- (3-cyano-benzenesulfonyl) -6-fluoro-quinoline,

4- (4-chloro-phenyl) -3- (3-cyano-benzenesulfonyl) -6-fluoro-quinoline,

3- (3-cyano-benzenesulfonyl) -6-fluoro-4- (4-methoxy-phenyl) -quinoline,

3- (3-chloro-4-methyl-benzenesulfonyl) -4- (3-chloro-phenyl) -6-fluoro-quinoline,

3- (3-chloro-4-methyl-benzenesulfonyl) -4- (4-chloro-phenyl) -6-fluoro-quinoline,

3- (3-chloro-4-methyl-benzenesulfonyl) -6-fluoro-4- (3-fluoro-phenyl) -quinoline,

3- (3-chloro-4-methyl-benzenesulfonyl) -6-fluoro-4- (3-methoxy-phenyl) -quinoline,

3- (3-chloro-4-methyl-benzenesulfonyl) -6-fluoro-4- (4-fluoro-phenyl) -quinoline,

4- (4-chloro-phenyl) -6-fluoro-3- (3-methoxy-benzenesulfonyl) -quinoline,

6-fluoro-3- (3-methoxy-benzenesulfonyl) -4- (3-methoxy-phenyl) -quinoline,

3- (3, 4-dimethyl-benzenesulfonyl) -6-fluoro-4- (3-fluoro-phenyl) -quinoline,

3- (3, 4-dimethyl-benzenesulfonyl) -6-fluoro-4- (4-methoxy-phenyl) -quinoline,

3- (3, 4-dimethyl-benzenesulfonyl) -6-fluoro-4- (4-fluoro-phenyl) -quinoline,

3- (3, 4-difluoro-benzenesulfonyl) -6-fluoro-4- (3-fluoro-phenyl) -quinoline,

3- (3, 4-difluoro-benzenesulfonyl) -6-fluoro-4- (4-fluoro-phenyl) -quinoline,

3- (3-chloro-4-fluoro-benzenesulfonyl) -4- (4-chloro-phenyl) -6-fluoro-quinoline,

3- (3-chloro-4-fluoro-benzenesulfonyl) -6-fluoro-4- (3-methoxy-phenyl) -quinoline,

3- (3-chloro-4-fluoro-benzenesulfonyl) -6-fluoro-4- (4-fluoro-phenyl) -quinoline,

4- (3-chloro-phenyl) -3- (3, 5-dichloro-benzenesulfonyl) -7-fluoro-quinoline,

4- (4-chloro-phenyl) -3- (3, 5-dichloro-benzenesulfonyl) -7-fluoro-quinoline,

4- (3-chloro-phenyl) -3- (3, 5-dichloro-benzenesulfonyl) -8-fluoro-quinoline,

4- (4-chloro-phenyl) -3- (3, 5-dichloro-benzenesulfonyl) -8-fluoro-quinoline,

4- (3-chloro-phenyl) -3- (3, 5-dichloro-benzenesulfonyl) -6-fluoro-quinoline,

4- (4-chloro-phenyl) -3- (3, 5-dichloro-benzenesulfonyl) -6-fluoro-quinoline,

6-fluoro-3- (4-methoxy-benzenesulfonyl) -4- (4-methoxy-phenyl) -quinoline,

7-chloro-4- (4-chloro-phenyl) -3- (3, 5-difluoro-benzenesulfonyl) -quinoline,

7-chloro-4- (4-chloro-phenyl) -3- (3, 4-difluoro-benzenesulfonyl) -quinoline,

7-chloro-4- (4-chloro-phenyl) -3- (3-cyano-benzenesulfonyl) -quinoline,

7-chloro-3- (3, 5-dichloro-benzenesulfonyl) -4- (4-fluoro-phenyl) -quinoline,

7-chloro-3- (4-fluoro-benzenesulfonyl) -4- (4-fluoro-phenyl) -quinoline,

7-chloro-3- (3-fluoro-benzenesulfonyl) -4- (4-fluoro-phenyl) -quinoline,

7-chloro-3- (3, 4-difluoro-benzenesulfonyl) -4- (4-fluoro-phenyl) -quinoline,

7-chloro-3- (3-chloro-4-fluoro-benzenesulfonyl) -4- (4-fluoro-phenyl) -quinoline,

7-chloro-3- (3-cyano-5-fluoro-benzenesulfonyl) -4- (4-fluoro-phenyl) -quinoline,

6-chloro-3- (3-chloro-4-fluoro-benzenesulfonyl) -4- (4-chloro-phenyl) -7-fluoro-quinoline,

6-chloro-3- (3-chloro-4-fluoro-benzenesulfonyl) -7-fluoro-4- (4-fluoro-phenyl) -quinoline,

3- (3-chloro-4-fluoro-benzenesulfonyl) -7-cyano-4- (2-fluoro-phenyl) -quinoline,

7-chloro-3- (3, 4-difluoro-benzenesulfonyl) -8-fluoro-4- (3-fluoro-phenyl) -quinoline,

7-chloro-3- (3-chloro-4-fluoro-benzenesulfonyl) -4- (4-fluoro-phenyl) -8-fluoro-quinoline,

7-chloro-3- (3-chloro-4-fluoro-benzenesulfonyl) -8-fluoro-4- (3-fluoro-phenyl) -quinoline,

7-chloro-4- (4-chloro-phenyl) -3- (3, 4-difluoro-benzenesulfonyl) -8-fluoro-quinoline,

7-chloro-3- (3-chloro-4-fluoro-benzenesulfonyl) -8-fluoro-4- (4-fluoro-phenyl) -quinoline;

3- (3-cyano-4-fluoro-benzenesulfonyl) -4- (3-fluoro-phenyl) -quinoline,

3- (3-cyano-5-fluoro-benzenesulfonyl) -4- (3-fluoro-phenyl) -quinoline,

3- (3-chloro-4-fluoro-benzenesulfonyl) -4- (4-chloro-phenyl) -8-fluoro-quinoline,

3- (3-chloro-4-fluoro-benzenesulfonyl) -8-fluoro-4- (2-fluoro-phenyl) -quinoline,

3- (3-chloro-4-fluoro-benzenesulfonyl) -8-fluoro-4- (3-fluoro-phenyl) -quinoline,

3- (3-cyano-4-fluoro-benzenesulfonyl) -4- (4-fluoro-phenyl) -quinoline,

3- (3-chloro-4-fluoro-benzenesulfonyl) -8-fluoro-4- (4-fluoro-phenyl) -quinoline,

3- (3-cyano-benzenesulfonyl) -8-fluoro-4- (2-fluoro-phenyl) -quinoline,

3- (3-cyano-benzenesulfonyl) -4- (3-fluoro-phenyl) -quinoline,

3- (3-cyano-benzenesulfonyl) -8-fluoro-4- (3-fluoro-phenyl) -quinoline,

3- (3-cyano-4-fluoro-benzenesulfonyl) -7-fluoro-4- (3-fluoro-phenyl) -quinoline,

4- (3-chloro-phenyl) -3- (3-cyano-4-fluoro-benzenesulfonyl) -quinoline,

3- (3-cyano-5-fluoro-benzenesulfonyl) -7-fluoro-4- (4-fluoro-phenyl) -quinoline,

7-chloro-3- (3-cyano-4-fluoro-benzenesulfonyl) -4- (3-fluoro-phenyl) -quinoline,

3- (3, 5-dichloro-benzenesulfonyl) -4- (3, 4-difluoro-phenyl) -8-fluoro-quinoline,

7-chloro-3- (3-cyano-5-fluoro-benzenesulfonyl) -4- (3-fluoro-phenyl) -quinoline,

3- (3-cyano-benzenesulfonyl) -8-fluoro-4- (4-fluoro-phenyl) -quinoline,

3- (3, 5-dichloro-benzenesulfonyl) -8-fluoro-4- (2-fluoro-phenyl) -quinoline,

3- (3-chloro-4-fluoro-benzenesulfonyl) -7-fluoro-4- (2-fluoro-phenyl) -quinoline,

4- (4-chloro-phenyl) -3- (3-cyano-benzenesulfonyl) -8-fluoro-quinoline,

4- (3-chloro-phenyl) -3- (3-cyano-5-fluoro-benzenesulfonyl) -quinoline,

7-chloro-3- (3-cyano-benzenesulfonyl) -4- (2-fluoro-phenyl) -quinoline,

3- (3-cyano-5-fluoro-benzenesulfonyl) -7-fluoro-4- (3-fluoro-phenyl) -quinoline,

3- (3-chloro-4-fluoro-benzenesulfonyl) -4- (3-chloro-phenyl) -8-fluoro-quinoline,

3- (3-cyano-benzenesulfonyl) -7-fluoro-4- (2-fluoro-phenyl) -quinoline,

3- (3-cyano-5-fluoro-benzenesulfonyl) -4- (3, 4-difluoro-phenyl) -7-fluoro-quinoline,

3- (3-cyano-4-fluoro-benzenesulfonyl) -4- (3, 4-dichloro-phenyl) -quinoline,

7-chloro-3- (3-chloro-4-fluoro-benzenesulfonyl) -4- (2-fluoro-phenyl) -quinoline,

7-chloro-3- (3-cyano-benzenesulfonyl) -4- (3-fluoro-phenyl) -quinoline,

4- (3-chloro-phenyl) -3- (3-cyano-4-fluoro-benzenesulfonyl) -7-fluoro-quinoline,

3- (3, 4-difluoro-benzenesulfonyl) -4- (3, 5-difluoro-phenyl) -8-fluoro-quinoline,

3- (3, 4-difluoro-benzenesulfonyl) -4- (4-fluoro-phenyl) -quinoline,

3- (3, 4-difluoro-benzenesulfonyl) -4- (3, 4-difluoro-phenyl) -8-fluoro-quinoline,

3- (3, 5-dichloro-benzenesulfonyl) -4- (3, 4-difluoro-phenyl) -7-fluoro-quinoline,

3- (3, 4-difluoro-benzenesulfonyl) -4- (3-fluoro-phenyl) -quinoline,

7-chloro-3- (3-cyano-benzenesulfonyl) -4- (4-fluoro-phenyl) -quinoline,

7-chloro-4- (3-chloro-phenyl) -3- (3-cyano-4-fluoro-benzenesulfonyl) -quinoline,

3- (3, 4-difluoro-benzenesulfonyl) -8-fluoro-4- (2-fluoro-phenyl) -quinoline,

4- (3-chloro-phenyl) -3- (3-cyano-5-fluoro-benzenesulfonyl) -7-fluoro-quinoline,

3- (3-cyano-benzenesulfonyl) -4- (3, 5-difluoro-phenyl) -7-fluoro-quinoline,

4- (3-chloro-phenyl) -3- (3-cyano-benzenesulfonyl) -8-fluoro-quinoline,

4- (4-chloro-phenyl) -3- (3, 4-difluoro-benzenesulfonyl) -7-fluoro-quinoline,

7-chloro-3- (3, 4-dichloro-benzenesulfonyl) -4- (3, 4-difluoro-phenyl) -quinoline,

3- (3, 5-dicyano-benzenesulfonyl) -7-fluoro-4- (4-fluoro-phenyl) -quinoline,

7-chloro-3- (3-chloro-5-fluoro-benzenesulfonyl) -4- (3-chloro-phenyl) -quinoline,

3- (3, 4-difluoro-benzenesulfonyl) -4- (3, 4-difluoro-phenyl) -7-fluoro-quinoline,

7-chloro-4- (3-chloro-phenyl) -3- (3, 5-dichloro-benzenesulfonyl) -8-fluoro-quinoline,

7-chloro-4- (3-chloro-phenyl) -3- (3-cyano-benzenesulfonyl) -8-fluoro-quinoline,

7-chloro-4- (3-chloro-phenyl) -3- (3-cyano-benzenesulfonyl) -quinoline,

7-chloro-3- (3, 5-dichloro-benzenesulfonyl) -4- (2-fluoro-phenyl) -quinoline,

3- (3, 5-dicyano-benzenesulfonyl) -4- (3, 4-difluoro-phenyl) -7-fluoro-quinoline,

3- (3, 5-dichloro-benzenesulfonyl) -7-fluoro-4- (2-fluoro-phenyl) -quinoline,

3- (3-chloro-4-fluoro-benzenesulfonyl) -4- (3-chloro-phenyl) -7-fluoro-quinoline,

4- (3-chloro-phenyl) -3- (3, 4-difluoro-benzenesulfonyl) -8-fluoro-quinoline,

4- (3, 4-dichloro-phenyl) -3- (3, 4-difluoro-benzenesulfonyl) -quinoline,

3- (3, 4-difluoro-benzenesulfonyl) -7-fluoro-4- (2-fluoro-phenyl) -quinoline,

7-chloro-3- (3-chloro-4-fluoro-benzenesulfonyl) -4- (3, 5-difluoro-phenyl) -quinoline,

7-chloro-4- (3-chloro-phenyl) -3- (3, 5-dichloro-benzenesulfonyl) -quinoline,

7-amino-3- (3, 4-difluoro-benzenesulfonyl) -4- (3-fluoro-phenyl) -quinoline,

4- (3-chloro-phenyl) -3- (3-cyano-benzenesulfonyl) -quinoline,

3- (3-cyano-5-fluoro-benzenesulfonyl) -4- (3, 4-difluoro-phenyl) -quinoline,

3- (3-cyano-5-fluoro-benzenesulfonyl) -7-fluoro-4- (4-fluoro-phenyl) -quinoline,

4- (4-chloro-phenyl) -3- (3-cyano-5-fluoro-benzenesulfonyl) -7-fluoro-quinoline,

7-chloro-3- (3-chloro-5-fluoro-benzenesulfonyl) -4- (4-chloro-phenyl) -quinoline,

7-chloro-3- (3-chloro-5-fluoro-benzenesulfonyl) -4- (4-fluoro-phenyl) -quinoline,

3- (3-chloro-5-fluoro-benzenesulfonyl) -4- (4-fluoro-phenyl) -quinoline,

3- (3-chloro-5-fluoro-benzenesulfonyl) -4- (4-chloro-phenyl) -quinoline,

3- (3-chloro-4-fluoro-benzenesulfonyl) -4- (4-chloro-phenyl) -quinoline,

3- (3-chloro-4-fluoro-benzenesulfonyl) -4- (4-chloro-phenyl) -7-fluoro-quinoline,

3- (3-chloro-4-fluoro-benzenesulfonyl) -7-fluoro-4- (4-fluoro-phenyl) -quinoline,

7-chloro-3- (3-chloro-4-fluoro-benzenesulfonyl) -4- (4-fluoro-phenyl) -quinoline,

7-chloro-3- (3-chloro-4-fluoro-benzenesulfonyl) -4- (4-chloro-phenyl) -quinoline,

7-amino-3- (3-chloro-5-fluoro-benzenesulfonyl) -4- (4-fluoro-phenyl) -quinoline,

7-amino-3- (3-chloro-5-fluoro-benzenesulfonyl) -4- (3-fluoro-phenyl) -quinoline.

Pharmaceutical preparation

The invention also relates to pharmaceutical compositions containing a compound of formula (I) and/or a physiologically acceptable salt and/or hydrate and/or solvate thereof as active ingredient, and one or more physiologically acceptable carriers.

The compounds of formula (I) and/or their physiologically acceptable salts and/or hydrates and/or solvates may be administered by any conventional means, for example by oral, parenteral (including subcutaneous, intramuscular, and intravenous), buccal, sublingual, nasal, rectal or transdermal administration, to which the pharmaceutical compositions are accordingly adapted.

The compounds of formula (I) and/or their physiologically acceptable salts and/or hydrates and/or solvates which are active when administered orally can be formulated as liquids or solids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.

Liquid formulations of the compounds of formula (I) and/or their physiologically acceptable salts and/or hydrates and/or solvates generally consist of a suspension or solution of the compound of formula (I) and/or its physiologically acceptable salts and/or hydrates and/or solvates in a suitable liquid carrier, for example an aqueous solvent, such as water and ethanol or glycerol, or a non-aqueous solvent, such as polyethylene glycol or oil. The formulations may also contain suspending agents, preservatives, flavoring or coloring agents.

Solid form tablet compositions may be prepared using any suitable pharmaceutical carrier conventionally used to prepare solid formulations. Examples of such carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Alternatively, the tablets may be coated by standard aqueous or non-aqueous techniques.

The solid form capsule composition may be prepared using conventional encapsulation processes. For example, granules containing the active ingredient may be prepared using standard carriers and then filled into hard gelatin capsules; alternatively, dispersions or suspensions may be prepared using any suitable pharmaceutical carrier, for example, aqueous gums, celluloses, silicates or oils, and then filled into soft gelatin capsules.

Typical parenteral compositions consist of a solution or suspension of a compound of formula (I) and/or a physiologically acceptable salt and/or hydrate and/or solvate thereof in a sterile aqueous carrier or a parenterally acceptable oil, for example polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil or sesame oil. Alternatively, the solution may be lyophilized and then reconstituted with a suitable solvent just prior to administration.

Compositions of the invention containing a compound of formula (I) and/or physiologically acceptable salts and/or hydrates and/or solvates thereof for nasal administration may conveniently be formulated as aerosols, drops, gels and powders. The aerosol formulations of the present invention generally comprise a solution or fine suspension of a compound of formula (I) and/or a physiologically acceptable salt and/or hydrate and/or solvate in a physiologically acceptable aqueous or non-aqueous solvent, usually in sterile form in single or multiple doses in a sealed container, which may take the form of a kit or be refilled (with an aerosolization device). Alternatively, the sealed container may be a unitary dispensing device, such as a single dose nasal inhaler or aerosol dispenser, fitted with a metering valve which is disposable once the container contents have been depleted. If the dosage form comprises an aerosol dispenser, it will contain a propellant which may be a compressed gas, for example compressed air, or an organic propellant, for example fluorochlorohydrocarbon. Aerosol formulations may also take the form of pump sprays.

Compositions of the invention comprising a compound of formula (I) and/or physiologically acceptable salts and/or hydrates and/or solvates thereof suitable for buccal or sublingual administration include tablets, lozenges and pastilles, wherein the active ingredient is formulated in a carrier, for example sugar and acacia, tragacanth, or gelatin, glycerol and the like.

Compositions of the invention containing a compound of formula (I) and/or physiologically acceptable salts and/or hydrates and/or solvates thereof for rectal administration are conveniently in the form of suppositories, containing conventional suppository bases such as cocoa butter and other materials commonly used in the art. Suppositories may be conveniently formed as follows: the composition and softened or melted carrier are first mixed, then cooled and shaped in a mold.

The compositions of the present invention containing a compound of formula (I) and/or a physiologically acceptable salt and/or hydrate and/or solvate thereof for transdermal administration include ointments, gels and patches.

The compositions of the invention containing a compound of formula (I) and/or a physiologically acceptable salt and/or hydrate and/or solvate thereof are preferably in unit dosage form, such as tablets, capsules or ampoules.

Each of the dosage units of the invention for oral administration preferably contains 0.1 to 500mg, calculated as the free base, of a compound of the formula (I) and/or a physiologically acceptable salt and/or hydrate and/or solvate thereof.

Each of the dosage units of the invention for parenteral administration preferably contains 0.1 to 500mg, calculated as the free base, of a compound of the formula (I) and/or a physiologically acceptable salt and/or hydrate and/or solvate thereof.

The compounds of formula (I) and/or their physiologically acceptable salts and/or hydrates and/or solvates may generally be administered in a daily dosage regimen. In the treatment of mGluR1 and mGluR5 mediated disorders (e.g., schizophrenia, anxiety, depression, panic, bipolar disorders, and circadian rhythm disorders or chronic and acute pain disorders), dosage levels of from about 0.01mg/kg to about 140mg/kg body weight per day are suitable, or from about 0.5mg to about 7g per patient per day.

The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, formulations for oral administration to humans may conveniently contain from about 0.5mg to about 5g of the active agent, in combination with a suitable and convenient amount of carrier material, which may comprise from about 5 to about 95% of the total composition. Unit dosage forms typically contain from about 1mg to about 1000mg of the active ingredient, typically 25mg, 50mg, 100mg, 200mg, 250 mg, 300mg, 400mg, 500mg, 600mg, 800mg or 1000 mg.

It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.

Medical applications

It has been found that the compounds of formula (I) and/or physiologically acceptable salts and/or hydrates and/or solvates of the invention exhibit biological activity at the mGluR1 and mGluR5 receptors and are expected to be useful in the treatment of mGluR1 and mGluR5 mediated disorders.

It has been found that the compounds according to the invention or salts thereof exhibit a high degree of potency and selectivity for the respective metabotropic glutamate receptor (mGluR) subtype. More specifically, there are compounds of the invention that are potent and selective for the mGluR1 and mGluR5 receptors. Accordingly, it is expected that the compounds of the present invention may be useful for the prevention and/or treatment of disorders associated with excitatory activation of mGluR1 and mGluR5 receptors, and may be useful for inhibiting neuronal damage caused by excitatory activation of mGluR1 and mGluR5 receptors. The compounds may be used to produce inhibitory effects of mGluR1 and mGluR5 in mammals, including humans.

Thus, the compounds of the present invention are expected to be very useful for the prevention and/or treatment of mGluR1 and mGluR5 receptor mediated disorders, such as acute and chronic neurological and psychiatric disorders, chronic and acute pain disorders and neuromuscular dysfunction of the lower urinary tract.

The dosage required for the therapeutic or prophylactic treatment of a particular condition will necessarily vary with the host treated and the route of administration.

The present invention relates to a compound of formula (I) as hereinbefore defined for use in therapy.

The present invention relates to compounds of formula (I) as hereinbefore defined for use in the prevention and/or treatment of mGluR1 and mGluR5 receptor mediated disorders.

The present invention relates to a compound of formula (I) as defined hereinbefore for use in the prevention and/or treatment of neurological disorders.

The present invention relates to compounds of formula (I) as defined hereinbefore for use in the prevention and/or treatment of psychiatric disorders.

The present invention relates to compounds of formula (I) as defined hereinbefore for use in the prevention and/or treatment of chronic and acute pain disorders.

The present invention relates to compounds of formula (I) as defined hereinbefore for use in the prevention and/or treatment of neuromuscular dysfunctions of the lower urinary tract.

The present invention relates to compounds of formula (I) as defined hereinbefore for use in the prevention and/or treatment of migraine, inflammatory pain, neuropathic pain conditions, such as diabetic neuropathy, arthritis and rheumatoid arthritis, amine pain, post-operative pain and pain associated with various conditions, including angina in the kidney or biliary colic, menstruation, migraine and gout.

The present invention relates to compounds of formula (I) as defined hereinbefore for use in the prevention and/or treatment of alzheimer's disease, senile dementia, AIDS-induced dementia, parkinson's disease, amyotrophic lateral sclerosis, huntington's chorea, migraine, epilepsy, schizophrenia, depression, anxiety, acute anxiety, obesity, obsessive compulsive disorders, ophthalmic disorders such as retinopathy, diabetic retinopathy, glaucoma, auditory neurological disorders such as tinnitus, chemotherapy-induced neuropathy, post-herpetic neuralgia and trigeminal neuralgia, tolerance, substance abuse and withdrawal, fragile X, autism, mental retardation, schizophrenia and down syndrome.

The present invention relates to compounds of formula (I) as defined hereinbefore for use in the prevention and/or treatment of stroke, head injury, hypoxic and ischemic injury, hypoglycemia, cardiovascular disease and epilepsy.

The compounds are also very suitable for the treatment of neuromuscular dysfunctions of the lower urinary tract, such as urgency, overactive bladder, urinary frequency, reduced urinary compliance, cystitis, incontinence, enuresis and dysuria.

The compounds are also well suited for the treatment of gastrointestinal disorders such as Transient Lower Esophageal Sphincter Relaxations (TLESR), gastrointestinal reflux disease and irritable bowel syndrome.

The invention also relates to the use of a compound of formula (I) as hereinbefore defined in the manufacture of a medicament for the prevention and/or treatment of mGluR1 and mGluR5 receptor mediated disorders and any of the disorders listed above.

The invention also provides a method of treatment and/or prevention of mGluR1 and mGluR5 receptor mediated disorders and any of the disorders listed above or in a patient suffering from such disorders, which comprises administering to said patient an effective amount of a compound of formula (I) as hereinbefore defined.

In the context of this specification, the term "treatment" includes both treatment and prophylaxis, unless there is a specific indication to the contrary. The terms "therapeutic" and "therapeutically" should be understood accordingly.

In this specification, unless otherwise indicated, the term "antagonist" refers to a compound that, by any means, partially or completely blocks the transduction pathway leading to the ligand producing a response.

The term "disorder" refers to any condition or disease associated with metabotropic glutamate receptor activity, unless otherwise indicated.

Preparation method

The reaction is carried out by conventional methods. Protecting groups are used to protect functional groups, if necessary, as will be apparent to those skilled in the art.

The process according to the invention for preparing compounds of formula (I):

wherein

Ar₁Represents optionally substituted phenyl or heteroaryl;

Ar₂represents a substituted phenyl group or an optionally substituted heteroaryl group;

R₁，R₂，R₃and R₄Independently represent a substituent selected from hydrogen, halogen, cyano, alkyl, alkoxy, hydroxy, trifluoromethyl, amino, alkylamino, dialkylamino, aminomethyl, alkylaminomethyl, dialkylaminomethyl,

reacting a compound of formula (II):

wherein R is₁，R₂，R₃And R₄Reacting with a compound of formula (III) as defined above for a compound of formula (I):

Ar₁-S^-M⁺

(III)

wherein M is selected from alkali metals or alkaline earth metals, Ar₁Obtaining a compound of formula (IV) as defined above for the compound of formula (I):

wherein R is₁，R₂，R₃，R₄And Ar₁(IV) as defined above for the compound of formula (I), thereafter oxidizing the compound of formula (IV) to give the compound of formula (V):

wherein R is₁，R₂，R₃，R₄And Ar₁Thereafter oxidizing the compound of formula (V) to give the compound of formula (VI) as defined above for the compound of formula (I):

wherein R is₁，R₂，R₃，R₄And Ar₁The compound of formula (VI) obtained is thereafter converted into a compound of formula (VII) as defined above for the compound of formula (I):

wherein X is selected from chloro, bromo, benzenesulfonyloxy, 4-fluoro-benzenesulfonyloxy, 4-methyl-benzenesulfonyloxy, methanesulfonyloxy or trifluoromethanesulfonyloxy, and R is₁，R₂，R₃，R₄And Ar₁As defined above for the compound of formula (I), the compound of formula (VII) obtained is thereafter reacted with a boronic acid derivative of formula (VIII) in the presence of a base (e.g. sodium carbonate) and a catalyst (e.g. tetrakis (triphenylphosphine) -palladium (0)) in a solvent:

Ar₂-B(OH)₂

(VIII)

and optionally thereafter forming a salt and/or hydrate and/or solvate of formula (I).

According to scheme 1, compounds of formula (IV) can be obtained by reacting a 3-bromo-quinolin-4-ol derivative of formula (II) with an alkali or alkaline earth metal salt (e.g., sodium salt) of thiophenol of formula (III) (e.g., bioorg.med.chem.lett., 2001, 9, 1141). Advantageously, the reaction can be carried out in the presence of a palladium catalyst and under microwave conditions. The 3-bromo-quinolin-4-ol derivatives of formula (II) are known (e.g., 3-bromo-6-chloro-quinolin-4-ol: J. chem. Soc., 1950, 384; 3-bromo-7-trifluoromethyl-quinolin-4-ol: Synthesis, 1977, 865) or may be synthesized by conventional methods. The alkali metal or alkaline earth metal salts of thiophenols of the formula (III) are commercially available or can be prepared by conventional methods.

The oxidation of the 3-arenethinyl-quinolin-4-ol derivative of formula (IV) may be carried out using hydrogen peroxide in a suitable acid, such as trifluoroacetic acid, to give the sulfoxides of formula (V) and the sulfones of formula (VI), respectively.

Suitable reagents (e.g., POCl) can be used by well-known halogenation methods₃，SOCl₂，PCl₅，POBr₃，PBr₃) Or by converting the 3-arenesulfonyl-quinolin-4-ol derivative of formula (VI) to the compound of formula (VII) by acylation using an appropriate sulfonic acid halide or sulfonic anhydride derivative.

Scheme 1

Another method of preparing an intermediate of formula (VI) comprises reacting a compound of formula (IX):

Ar₁-SO₂Na

(IX)

wherein Ar is₁Reacting with an α -halo-acetate of formula (X) as defined above for the compound of formula (I):

Hlg-CH₂-COOR₅

(X)

wherein Hlg is halogen and R₅Is ethyl or methyl, to give a compound of formula (XI):

Ar₁-SO₂-CH₂-COOR₅

(XI)

wherein Ar is₁As defined above for the compounds of formula (I) and R₅As defined above for the compound of formula (X); reacting a compound of formula (XI) with a trialkyl orthoformate of formula (XII):

CH(OR₆)₃

(XII)

wherein R is₆Is ethyl or methyl, to give a compound of formula (XIII):

wherein Ar is₁As defined above for the compounds of formula (I), R₅As defined above for the compound of formula (X) and R₆As defined above for the compound of formula (XII); reacting a compound of formula (XIII) with an aniline derivative of formula (XIV):

wherein R is₁，R₂，R₃And R₄As defined above for the compound of formula (I), to give the compound of formula (VI).

Wherein R is₁，R₂，R₃And R₄The compound of formula (VI) obtained is thereafter converted into a compound of formula (I) as described above.

According to scheme 2, a compound of formula (IX) is reacted with α -halo-acetates of formula (X) in a suitable solvent (e.g. DMF, water). Compounds of formula (IX) are commercially available or may be prepared from the appropriate benzenesulfonyl chloride derivatives by well-known methods (e.g., org. lett., 2003, 5(21), 3895). The compounds of the formula (XIII) [ J.Org.chem.USSR (Ehgl.Transl., 1980, 16(7), 1275; Zh.Org.Khim., 1980, 16(7), 1485 ]. the compounds of the formula (XIII) are reacted with aniline derivatives of the compounds of the formula (XIV) to give benzenesulfonyl-phenylamino-acrylates [ for example J.Org.chem.USSR (Engl.Transl., 1980, 16(7), 1275; Zh.Org.Khim., 1980, 16(7), 1483-1487], which can be converted in situ into quinoline-4-ol derivatives of the formula (VI) (cf. analogous reaction: J.chem.Soc.Perkin, 1, Trak, 4, 387-1994) ].

Scheme 2

The compounds of formula (IV), the compounds of formula (V), the compounds of formula (VI) and the compounds of formula (VII) and/or their enantiomers and/or racemates and/or diastereoisomers and/or their pharmaceutically acceptable salts with acids or bases are novel.

The compounds of formula (I) contain basic functional groups, whereby the basic functional groups can be converted into their salts with acids and/or can be released from the resulting acid-added salts by treatment with bases.

The compounds of formula (I) may be converted to hydrates and/or solvates.

The compounds of formula (I) may optionally be interconverted with different compounds of formula (I) by conventional synthetic methods.

Biological test method

MGlur1 receptor binding assay

The MGluR1 receptor binding assay was performed according to the modified method of Lavreysen et al (mol. pharm., 2003, 63, 1082). Based on the high homology between the human and rat mGluR1 receptors, the rat cerebellar membrane preparation was used to determine the binding properties of the reference and novel compounds to rat mGluR 1. [3H] R214127(3nM) was used as radioligand and nonspecific binding was determined in the presence of 1. mu.MR 214127.

IC-50 values were determined from the displacement curves by nonlinear regression analysis and converted to K by the equation method of Cheng and Prusoff (biochem. Pharmacol., 1973, 22, 3099)_iThe value is obtained.

MGlur5 receptor binding assay

MGlur5 receptor binding was determined according to Gasparini et al (bioorg. Med. chem. Lett.2000, 12: 407-containing 409) with modifications. Rat cerebral cortical membrane preparations were used to determine the binding properties of the reference and novel compounds to rat mGluR 5. The binding properties of chemical compounds to the human mGluR5a receptor were determined using the a18 cell line (purchased from Euroscreen) expressing hmGluR5 a. [3H] -M-MPEP (2nM) was used as radioligand. Nonspecific binding was determined in the presence of 10. mu. M M-MPEP.

Evaluation of functional Activity

Cell cultures of native rat mGluR5 and mGluR1 receptors

Functional potency at The native rat mGluR5 and mGluR1 receptors was assessed using Primary cerebral neocortical Cell cultures derived from 17-day old Charles River rat embryos and Primary cerebellar Cell cultures derived from 4-day old Wistar rats, respectively (for details on Neural Cell Culture preparation, see Johnson, M.I.; Bunge, R.P. (1992): Primary Cell cultures of peripheral and central nerves and glia. in: Protocols for Neural Cell Culture, eds: Fedoroff, S.; Richardson A., The Humana Press Inc., 51-77). After isolation, cells were plated onto standard 96-well microplates and cultures were maintained at 95% air-5% CO₂Atmosphere, 37 ℃. Brain neocortex and cerebellum cultures were used for in vitro calcium measurements after 5-7 and 3-4 days, respectively.

Cell culture of recombinant human mGluR5a receptor

Chinese Hamster Ovary (CHO) cells stably expressing recombinant human mGluR5a receptor (CHO-mGluR5a, purchased from Euroscreen) were cultured in F12 medium containing 10% FCS, 1% antibiotic antifungal solution, 400. mu.g/ml G418, 250. mu.g/ml Zeocin (an antibiotic), 5. mu.g/ml puromycin. The cells were maintained in a humidified incubator at 37 ℃ in 5% CO₂Passage 3 times per week under 95% air atmosphere. At 2.5-3.5X 10⁴Cells/well, cells were seeded on standard 96-well microplates and receptor expression was induced by addition of 600ng/ml doxycycline the following day. Calcium measurements were taken 16-24 hours after addition of the inducer.

Fluorescence measurement of cytosolic calcium concentration

Cytosolic calcium concentration ([ Ca ] was measured on primary cerebral neocortex and cerebellum cultures, and on CHO-mGluR5a cells stably expressing the human mGluR5a receptor²⁺]_i). Cells were cultured in standard 96-well microplates and, prior to measurement, were loaded with Ca²⁺Sensitive fluorescent dye fluo-4/AM (2. mu.M): neural cell cultures were loaded in their growth medium, CHO-mGluR5a cells loaded with 2mM sodium pyruvate and 30. mu.g/ml glutamate-pyruvate transaminase (in the case of CHO-mGluR5a cells, these additives were also present [ Ca-mGluR 5a cells ]²⁺]_iIn-process measurement) assay buffer (145mM NaCl, 5mM KCl, 2mM MgCl₂，2mM CaCl₂10mM HEPES, 20mM D-glucose, 2mM probenecid, pH 7.4). By mixing with 100. mu.l/well dye solution at 37 deg.C in a humidified incubator with 5% CO₂And incubating the cells for 40-120min under the atmosphere of 95% air to finish loading. To stop the dye loading, cells were washed 2 times with assay buffer. After washing, depending on the experimental setup, different concentrations of test compound (diluted in assay buffer from DMSO or Dimethylformamide (DMF) stock solutions, final DMSO/DMF concentration < 0.1%) or buffer were added to each well. In the case of brain neocortex cultures, the assay buffer also contained TTX (0.5. mu.M to inhibit [ Ca ]²⁺]_iSpontaneous shaking of (2) replacement of probenecid with sulpirtone (0.25mM) in the case of cerebellum cultures.

After incubation at 37 ℃ for 10-20min, baseline and agonist-induced [ Ca ] measurements were performed column by column with a plate reading fluorometer (FlexStation II, Molecular Devices)²⁺]_iAnd (4) changing. From the bottom of the plate, excitation and emission detection was performed. The entire measurement procedure was performed at 37 ℃ and controlled with custom software. By measuring agonist-induced [ Ca ] in the presence of different concentrations of the compound²⁺]_iThe decrease in elevation, the inhibitory potency of the test compound was evaluated. DHPG was used as an agonist for all 3 cultures, at concentrations of 20 and 100 μ M for brain neocortex and cerebellum cultures, respectively. In the case of CHO-mGluR5a cells, the EC 80-values were derived from a dose-response curve determined daily using DHPG at an EC80 concentration. Fluorescence data was expressed as Δ F/F (fluorescence change normalized to baseline).

All treatments to a single plate were measured in multiple wells. Data from all wells of the same treatment were averaged and the average was used for analysis. The inhibitory potency of a compound at a single concentration point is expressed as a percentage of inhibition in response to a control agonist. IC 50-values were determined as the concentration that produced half of the maximum inhibition by the compound using sigmoidal concentration-inhibition curve fitting data (derived from at least 3 independent experiments). Raw fluorescence data were analyzed using Soft Max Pro (Molecular Devices) software and curve fitted with GraphPad Prism.

Results

The compounds of formula (I) of the present invention exhibit affinity for both rat and human mGluR1 and mGluR5 receptors and demonstrate to be functional antagonists that inhibit the functional response elicited by stimulation of the mGluR5 receptor.

The invention is further illustrated by the following non-limiting examples.

All operations were carried out at room temperature, i.e. in the temperature range 18-25 ℃ unless otherwise stated. The course of the reaction is followed by Thin Layer Chromatography (TLC) and the reaction times given are only given as examples. The structures of all intermediates and final products are elucidated by IR, NMR and MS spectra. When yields are given by way of illustration only, NMR data is in the form of delta (δ) values for the primary diagnostic protons, given in parts per million (ppm) relative to Tetramethylsilane (TMS) as an internal standard, using the indicated solvents. Conventional abbreviations are used for signal shape.

Examples

All starting materials are commercially available or can be synthesized by different well-known methods described in the literature.

Example 1

4- (4-chloro-phenyl) -3- (4-methyl-benzenesulfonyl) -quinoline; TABLE I, Compound 1

3- (4-Methylphenylsulfanyl) -quinolin-4-ol

A mixture of 3-bromo-quinolin-4-ol (0.448g, 2 mmol; J.Am.chem.Soc.1946, 68, 1229-1231), 4-methylphenylthiol (0.30g, 2.4mmol), tetrakis- (triphenylphosphine) palladium (0) (0.115g, 0.1mmol), sodium tert-butyrate (0.23g, 2.4mmol) and DMF (2.0ml) was stirred and irradiated in an 8ml microwave vial at 142 ℃ for 3 hours. The solvent was evaporated in vacuo and the residue was purified by gradient silica gel flash chromatography (80g silica gel, eluent a: chloroform, eluent B: chloroform: methanol 95: 5) to give 0.33g of the title compound in 62% yield.

MS(EI)M⁺＝268.2

3- (4-methyl-benzenesulfonyl) -quinolin-4-ol

To a mixture of 3- (4-methyl-benzenesulfanyl) -quinolin-4-ol (0.25g, 0.936mmol) and trifluoroacetic acid (5.0ml) was added dropwise a solution of hydrogen peroxide in trifluoroacetic acid (c ═ 3.0M, 3.7 ml). The solution was stirred at room temperature for 8 hours. To the reaction mixture was added dropwise 6ml of water. The precipitate was filtered off, washed with water and dried in vacuo to give 0.24g of the title compound in 86% yield.

MS(EI)M⁺＝300.1

4-chloro-3- (4-methyl-benzenesulfonyl) -quinoline

A mixture of 3- (4-methyl-benzenesulfonyl) -quinolin-4-ol (0.24g, 0.8mmol) and phosphorus oxychloride (V) (15ml) was refluxed for 5 hours. The phosphorus oxychloride (V) was distilled off and the residue was poured onto ice. The slurry was stirred at 0-5 ℃ for 2h, neutralized with sodium carbonate and extracted with chloroform (50 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and the solvent was removed in vacuo to give 0.23g of the title compound in 90% yield.

MS(EI)M⁺＝318.2

4- (4-chloro-phenyl) -3- (4-methyl-benzenesulfonyl) -quinoline

A mixture of 4-chloro-3- (4-methyl-benzenesulfonyl) -quinolin-4-ol (0.2g, 0.67mmol) and 4-chlorophenylboronic acid (0.16g, 1.0mmol) in 8ml dioxane was stirred with potassium carbonate (0.5g, 3.6mmol) and tetrakis- (triphenylphosphine) palladium (0) (0.04g, 0.035mmol) at 90 ℃ for 20 hours. After cooling, the mixture was concentrated in vacuo. The crude residue was purified by silica gel column chromatography (Kieselgel 60, eluent: chloroform) to give 0.21g of the title compound in 80% yield.

¹H NMR(500MHz，DMSO-d₆)：9.61(s，1H)；8.21(dm，J＝8.6Hz，1H)；7.98(ddd，J＝8.5，6.8，1.4Hz，1H)；7.64(ddd，J＝8.5，6.8，1.2Hz，1H)；7.49-7.44(m，2H)；7.37-7.32(m，2H)；7.30-7.24(m，3H)；7.04-6.98(m，2H)，2.36(s，3H).

MS(EI)M⁺＝393.8

4- (4-chloro-phenyl) -3- (4-methyl-benzenesulfonyl) -quinoline hydrochloride

4- (4-chloro-phenyl) -3- (4-methyl-benzenesulfonyl) -quinoline (40mg, 0.102mmol) was dissolved in ethyl acetate (1.5ml) and to this solution was added dropwise a solution of hydrogen chloride in ethyl acetate (c ═ 1.6M, 0.14ml, 0.224 mmol). The solid was filtered off, washed with ethyl acetate and dried in vacuo to give 35mg of the title compound in 80% yield.

¹H NMR(500MHz，DMSO-d₆)：9.61(s，1H)；8.22(dm，J＝8.6Hz，1H)；7.98(ddd，J＝8.6，6.8，1.4Hz，1H)；7.64(ddd，J＝8.6，6.8，1.2Hz，1H)；7.50-7.43(m，2H)；7.37-7.31(m，2H)；7.31-7.23(m，3H)；7.05-6.98(m，2H)，2.36(s，3H).

MS(EI)M⁺＝393.8

Example 2

(4-chloro-benzenesulfonyl) -acetic acid methyl ester (intermediate)

A mixture of methyl bromoacetate (11.25ml, 116mmol) and sodium 4-chloro-benzenesulfinate (25.2g, 116mmol) in DMF (120ml) was stirred and heated at 80 ℃ for 2 h. The solution was diluted with water (360 ml). With chloroformThe separated oil was extracted (200ml) and washed with water (3X80 ml). The organic phase was evaporated in vacuo to give 22.4g of the title compound in 77.7% yield. MS (EI) M⁺＝249.1。

The following compounds were prepared using the procedure described above: for example

(3-chloro-benzenesulfonyl) -acetic acid methyl ester (MS (EI) M⁺＝249.1)；

(3, 5-dichloro-benzenesulfonyl) -acetic acid methyl ester (MS (EI) M⁺＝283.1)；

(4-methoxy-benzenesulfonyl) -acetic acid methyl ester (MS (EI) M⁺＝245.1)；

(3-chloro-4-fluoro-benzenesulfonyl) -acetic acid methyl ester (MS (EI) M⁺＝267.1)；

(3, 5-difluoro-benzenesulfonyl) -acetic acid methyl ester (MS (EI) M⁺＝251.1)；

(3-fluoro-benzenesulfonyl) -acetic acid methyl ester (MS (EI) M⁺＝233.2)。

Example 3

2- (4-chloro-benzenesulfonyl) -3-ethoxy-acrylic acid methyl ester (intermediate)

A mixture of (4-chloro-benzenesulfonyl) -acetic acid methyl ester (22.4g, 90mmol), triethyl orthoformate (33.2ml, 216mmol) and acetic anhydride (19.1ml, 203mmol) was refluxed for 3h while distilling ethanol, triethyl orthoformate and acetic anhydride and then evaporated to dryness. The crude product (22.7g, 82.8%) was used in the next step without purification. MS (EI) M⁺＝305.1。

The following compounds were prepared using the procedure described above: for example, 2- (3-chloro-benzenesulfonyl) -3-ethoxy-acrylic acid methyl ester (MS (EI) M⁺305.1); 2- (3-chloro-4-fluoro-benzenesulfonyl) -3-ethoxy-acrylic acid methyl ester (MS (EI) M⁺323.1); 2- (3, 5-dichloro-benzenesulfonyl) -3-ethoxy-acrylic acid methyl ester (MS (EI) M)⁺340.1); 2- (4-fluoro-benzenesulfonyl) -3-ethoxy-acrylic acid methyl ester (MS (EI) M⁺289.1); 2- (3-cyano group)-5-fluoro-benzenesulfonyl) -3-ethoxy-acrylic acid methyl ester (MS (EI) M⁺＝314.2)。

Example 4

7-chloro-3- (4-chloro-benzenesulfonyl) -quinolin-4-ol (intermediate)

A mixture of methyl 2- (4-chloro-benzenesulfonyl) -3-ethoxy-acrylate (7.62g, 25mmol) and 3-chloroaniline (3.19g, 25mmol) in diphenyl ether (20ml) was heated at near reflux for 1 h. After cooling, the precipitate was filtered and washed with diethyl ether to give 4.25g of the title compound in 48.0% yield. MS (EI) M⁺＝355.1。

The following compounds were prepared using the procedure described above: for example 8-chloro-3- (4-chloro-benzenesulfonyl) -quinolin-4-ol (MS (EI) M⁺355.1); 6-chloro-3- (4-fluoro-benzenesulfonyl) -quinolin-4-ol (MS (EI) M⁺338.1); 6-cyano-3- (4-fluoro-benzenesulfonyl) -quinolin-4-ol (MS (EI) M⁺329.2); 8-chloro-3- (3, 4-dichloro-benzenesulfonyl) -quinolin-4-ol (MS (EI) M⁺390.1); 7-chloro-3- (3, 5-difluoro-benzenesulfonyl) -quinolin-4-ol (MS (EI) M⁺＝356.1)。

Example 5

3- (4-chloro-benzenesulfonyl) -4, 7-dichloroquinoline (intermediate)

7-chloro-3- (4-chloro-benzenesulfonyl) -4-hydroxyquinoline (4.25g, 12mmol) in phosphorus oxychloride (V) (5.6ml, 60mmol) was refluxed for 3 h. The reaction mixture was poured into water (50ml) and basified with 5M sodium hydroxide solution. After cooling, the precipitate was filtered and washed with water to give 3.8g of the title compound in 85.0% yield. MS (EI) M⁺＝373.2。

The following compounds were prepared using the procedure described above: for example

3- (3-chloro-benzenesulfonyl) -4, 6-dichloroquinoline (MS (EI) M⁺＝373.2)；

3- (4-chloro-benzenesulfonyl) -4, 8-dichloroquinoline (MS (EI) M⁺＝373.2)；

4-chloro-6-cyano-3- (4-fluoro-benzenesulfonyl) -quinoline (MS (EI) M⁺＝347.1)；

4-chloro-3- (4-chloro-benzenesulfonyl) -6-fluoro-quinoline (MS (EI) M⁺＝357.1)。

Example 6

4-bromo-7-chloro-3- (4-chloro-benzenesulfonyl) -quinoline (intermediate)

A mixture of 7-chloro-3- (4-chloro-benzenesulfonyl) -quinolin-4-ol (0.5g, 1.41mmol) and phosphoryl bromide (V) (1.2g, 4.2mmol) in chloroform (30ml) and triethylamine (1ml) was refluxed for 6 hours. The reaction mixture was diluted with water (30ml) and the pH was adjusted to 10 with aqueous sodium hydroxide solution. The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo. The obtained product was purified by crystallization from diethyl ether to yield 0.45g of the title compound in 77% yield. MS (EI) M⁺＝418.1。

The following compounds were prepared using the procedure described above: for example

4-bromo-3- (4-chloro-benzenesulfonyl) -6-fluoro-quinoline (MS (EI) M⁺＝347.1)；

4-bromo-7-chloro-3- (3, 5-difluoro-benzenesulfonyl) -quinoline (MS (EI) M⁺＝420.1)；

4-bromo-7-chloro-3- (4-chloro-benzenesulfonyl) -6-fluoro-quinoline (MS (EI) M⁺＝436.1)；

4-bromo-7-chloro-3- (4-fluoro-benzenesulfonyl) -quinoline (MS (EI) M⁺＝402.1)；

4-bromo-7-chloro-3- (3-fluoro-benzenesulfonyl) -quinoline (MS (EI) M⁺＝402.1)；

4-bromo-7-chloro-3- (3-cyano-benzenesulfonyl) -quinoline (MS (EI) M⁺＝409.2)；

4-bromo-7-chloro-3- (3-cyano-5-fluoro-benzenesulfonyl) -quinoline (MS (EI) M⁺＝427.1)。

Example 7

7-chloro-3- (4-chloro-benzenesulfonyl) -4- (4-fluoro-phenyl) -quinoline

Compound 4 of table I

A mixture of 4-bromo-7-chloro-3- (4-chloro-benzenesulfonyl) -quinoline (0.42g, 1mmol), 4-fluorophenylboronic acid (0.21g, 1.5mmol) and tetrakis- (triphenylphosphine) palladium (0) (0.08g, 0.07mmol) in 30ml of 1, 2-dimethoxyethane and 8ml of 2M aqueous sodium carbonate was stirred at 70 ℃ for 2 hours. After cooling, the mixture was concentrated in vacuo. The crude residue was purified by column chromatography on silica gel (Kieselgel 60, eluent: chloroform) and crystallized from methanol to yield 0.29g of the title compound in 67% yield.

¹H NMR(400MHz，DMSO-d₆)：6.92-6.98m(2H)[H-14，18]；7.06-7.13m (2H)[H-15，17]；7.25-7.32 m(5H)[H-6，22，23，25，26]；7.44dd (1H)[H-7]；9.23 d(1H)[H-9]；9.77s (1H)[H-2]

MS(EI)M⁺＝433.2

The following compounds were prepared using the procedure described above: for example

7-fluoro-3- (4-fluoro-benzenesulfonyl) -4- (3-fluoro-phenyl) -quinoline (Table I Compound 9, MS (EI) M⁺＝400.2)，

4- (3-chloro-phenyl) -3- (3, 4-dimethyl-benzenesulfonyl) -7-fluoro-quinoline (Table I Compound 17, MS (EI) M⁺＝426.2)，

4- (4-chloro-phenyl) -3- (3, 5-difluoro-benzenesulfonyl) -7-fluoro-quinoline (Table I Compound 35, MS (EI) M⁺＝434.2)，

4- (3-chloro-phenyl) -8-fluoro-3- (4-methoxy-benzenesulfonyl) -quinoline (Table I Compound 53, MS (EI) M⁺＝428.2)，

3- (3-cyano-benzenesulfonyl) -6-fluoro-4- (3-methoxy-phenyl) -quinoline (Table I Compound 68, MS (EI) M⁺＝419.3)，

3- (3, 4-difluoro-benzenesulfonyl) -7-fluoro-4- (4-fluoro-phenyl) -quinoline (Table I Compound 101, MS (EI) M⁺＝418.2)，

7-chloro-3- (3, 4-difluoro-benzenesulfonyl) -4- (3-fluoro-phenyl) -quinoline (Table I Compound 170, MS (EI) M⁺＝434.2)，

7-chloro-3- (3-cyano-5-fluoro-benzenesulfonyl) -4- (4-fluoro-phenyl) -quinoline (Table I Compound 186, MS (EI) M⁺＝441.2)。

Examples of compounds of formula (I) and their affinity for the rat mGluR5 and mGluR5 receptors are given in the table below.

Watch (A)

***K_i＜200nM

**200nM＜K_i＜500nM

*500nM＜K_i

Example 8

Preparation of the pharmaceutical composition:

a) and (3) tablet preparation:

mixing 0.01-50% of active ingredient of formula (I), 15-50% lactose, 15-50% potato starch, 5-15% polyvinylpyrrolidone, 1-5% talc, 0.01-3% magnesium stearate, 1-3% colloidal silicon dioxide and 2-7% ultrabranched starch, then granulating by wet process and compressing into tablets.

b) Sugar-coated tablets, film-coated tablets:

tablets prepared as described above are coated with a layer consisting of an enteric-or gastro-soluble film, or a layer consisting of sugar and talc. Sugar-coated tablets were polished with a mixture of beeswax and carnauba wax.

c) And (3) capsule preparation:

0.01-50% of the active ingredient of formula (I), 1-5% of sodium lauryl sulfate, 15-50% of starch, 15-50% of lactose, 1-3% of colloidal silicon dioxide and 0.01-3% of magnesium stearate are thoroughly mixed, the mixture is sieved and filled into hard gelatin capsules.

d) Suspension:

the components: 0.01-15% of active ingredient of formula (I), 0.1-2% of sodium hydroxide, 0.1-3% of citric acid, 0.05-0.2% of nipagin (sodium methyl 4-hydroxybenzoate), 0.005-0.02% of propyl nipagin, 0.01-0.5% of carbopol (polyacrylic acid), 0.1-5% of 96% of ethanol, 0.1-1% of flavoring agent, 20-70% of sorbitol (70% water solution) and 30-50% of distilled water.

Under vigorous stirring, an aliquot of carbopol was added to a solution of parabens and citric acid in 20ml of distilled water and the solution was allowed to stand for 10-12 h. Then add sodium hydroxide in 1ml distilled water, aqueous sorbitol solution with stirring and finally add ethanolic raspberry flavor. The active ingredient is added to the vehicle in small portions and suspended using a dip homogenizer. Finally, the suspension was brought to the desired final volume with distilled water and the suspension syrup was passed through a colloid mill apparatus.

e) Suppository:

for each suppository, 0.01-15% of the active ingredient of formula (I) and 1-20% of lactose are mixed thoroughly, then 50-95% of the pre-suppository lard (e.g. Witepsol 4) is melted and cooled to 35 ℃, and the mixture of active ingredient and lactose is mixed therein with a homogenizer. The resulting mixture was cooled and molded.

f) Lyophilized powder ampoule composition:

a 5% mannitol or lactose solution was prepared with redistilled water for injection, and the solution was filtered to obtain a sterile solution. A 0.01-5% solution of the active ingredient of formula (I) is also prepared with redistilled water for injection and the solution is filtered to obtain a sterile solution. The two solutions were mixed under sterile conditions, filled into ampoules in 1ml, the ampoule contents lyophilized, and the ampoules sealed under nitrogen. Immediately before use, the contents of the ampoule are dissolved in sterile water or 0.9% (physiological) sterile aqueous sodium chloride solution.

Example 9

3- (3, 4-difluoro-benzenesulfonyl) -7-nitro-quinolin-4-ol (intermediate)

The title compound was prepared from 2- (3, 4-difluoro-benzenesulfonyl) -3-ethoxy-acrylic acid methyl ester (3.49g, 11.4mmol) and 3-nitroaniline (1.57g, 11.4mmol) using the procedure described in example 4. The yield was 1.6g (38.3%).

MS(EI)M⁺＝367.2。

Prepared in the same way: for example 3- (3-cyano-5-fluoro-benzenesulfonyl) -8-nitro-quinolin-4-ol (MS (EI) M⁺＝374.3)。

Example 10

4-bromo-3- (3, 4-difluoro-benzenesulfonyl) -7-nitro-quinoline (intermediate)

A mixture of 3- (3, 4-difluoro-benzenesulfonyl) -7-nitro-quinolin-4-ol (1.6g, 4.37mmol) and phosphoryl bromide (V) (2.5g, 8.72mmol) in DMF (16ml) was stirred at 65 ℃ for 1 hour. The reaction mixture was diluted with water (100ml) and the pH was adjusted to 10 with aqueous sodium hydroxide solution. After cooling, the precipitate was filtered and washed with water. The crude product obtained was purified by crystallization from ethanol to yield 1.25g of the title compound in 67% yield.

MS(EI)M⁺＝430.9。

The following compounds were prepared using the procedure described above: for example 4-bromo-3- (3-cyano-5-fluoro-benzenesulfonyl) -8-nitro-quinoline (MS (EI) M⁺＝437.2)。

Example 11

3- (3, 4-difluoro-benzenesulfonyl) -4- (3-fluoro-phenyl) -7-nitro-quinoline (intermediate)

The title compound was prepared from 4-bromo-3- (3, 4-difluoro-benzenesulfonyl) -7-nitro-quinoline (0.53g, 1.23mmol) and 3-fluorophenylboronic acid (0.21g, 1.5mmol) using the procedure described in example 7. The crude product was purified by column chromatography on silica gel (Kieselgel 60, eluent: chloroform) and crystallized from methanol to yield 0.31g of the title compound in 57% yield.

MS(EI)M⁺＝445.3。

Prepared in the same way: for example 3- (3-cyano-5-fluoro-benzenesulfonyl) -4- (4-fluoro-phenyl) -8-nitro-quinoline (MS (EI) M⁺452.3); 3- (3-cyano-5-fluoro-benzenesulfonyl) -4- (3-fluoro-phenyl) -8-nitro-quinoline (MS (EI) M⁺＝452.3)。

Example 12

7-amino-3- (3, 4-difluoro-benzenesulfonyl) -4- (3-fluoro-phenyl) -quinoline

Compound 264 of table I

A mixture of 3- (3, 4-difluoro-benzenesulfonyl) -4- (3-fluoro-phenyl) -7-nitro-quinoline (0.31g, 0.69mmol) and iron powder (0.15g, 2.6mmol) in acetic acid was stirred at 60 ℃ for 30 minutes. The reaction mixture was diluted with water (5 ml). The precipitate was filtered and washed with water (2X 5 ml). The crude product obtained was purified by crystallization from methanol to yield 0.12g of the title compound in 42% yield.

MS(EI)M⁺＝415.1。

The following compounds were prepared using the procedure described above: for example 7-amino-3- (3-chloro-5-fluoro-benzenesulfonyl) -4- (4-fluoro-phenyl) -quinoline (MS (EI) M⁺422.1); 7-amino-3- (3-chloro-5-fluoro-benzenesulfonyl) -4- (3-fluoro-phenyl) -quinoline (MS (EI) M⁺＝422.1)。

Claims (13)

1. A compound having the formula (I):

wherein

Ar₁Represents phenyl optionally substituted by one or more substituents selected from hydrogen, fluoro, chloro, cyano, methyl, methoxy, or thienyl optionally substituted by one or more substituents selected from hydrogen, fluoro, chloro;

Ar₂represents phenyl substituted by one or more substituents selected from fluoro, chloro, cyano, methyl, methoxy, or pyridinyl optionally substituted by one or more substituents selected from hydrogen, fluoro, chloro;

R₁，R₂，R₃and R₄Independently represent a substituent selected from hydrogen, fluorine, chlorine, cyano, methyl, methoxy, hydroxy, trifluoromethyl, amino, methylamino, dimethylamino, aminomethyl, methylaminomethyl, dimethylaminomethyl,

and/or salts thereof.

2. The compound of claim 1 selected from the group consisting of:

4- (4-chloro-phenyl) -3- (4-methyl-benzenesulfonyl) -quinoline,

7-chloro-3- (4-chloro-benzenesulfonyl) -4- (4-fluoro-phenyl) -quinoline,

8-chloro-4- (3-chloro-phenyl) -3- (3, 4-dichloro-benzenesulfonyl) -quinoline,

7-fluoro-3- (4-fluoro-benzenesulfonyl) -4- (3-fluoro-phenyl) -quinoline,

4- (4-chloro-phenyl) -7-fluoro-3- (4-methoxy-benzenesulfonyl) -quinoline,

7-fluoro-3- (4-methoxy-benzenesulfonyl) -4- (4-methoxy-phenyl) -quinoline,

7-fluoro-3- (3-fluoro-benzenesulfonyl) -4- (3-fluoro-phenyl) -quinoline,

7-fluoro-3- (3-fluoro-benzenesulfonyl) -4- (4-fluoro-phenyl) -quinoline,

4- (3-chloro-phenyl) -3- (3, 4-dimethyl-benzenesulfonyl) -7-fluoro-quinoline,

3- (3, 4-dimethyl-benzenesulfonyl) -7-fluoro-4- (3-fluoro-phenyl) -quinoline,

3- (3, 4-dimethyl-benzenesulfonyl) -7-fluoro-4- (3-methoxy-phenyl) -quinoline,

4- (3-chloro-phenyl) -8-fluoro-3- (4-fluoro-benzenesulfonyl) -quinoline,

4- (4-chloro-phenyl) -8-fluoro-3- (4-fluoro-benzenesulfonyl) -quinoline,

8-fluoro-3- (4-fluoro-benzenesulfonyl) -4- (3-fluoro-phenyl) -quinoline,

8-fluoro-3- (4-fluoro-benzenesulfonyl) -4- (3-methoxy-phenyl) -quinoline,

4- (4-chloro-phenyl) -6-fluoro-3- (4-methoxy-benzenesulfonyl) -quinoline,

4- (4-chloro-phenyl) -3- (3, 4-dimethyl-benzenesulfonyl) -6-fluoro-quinoline,

4- (4-chloro-phenyl) -3- (3, 5-difluoro-benzenesulfonyl) -7-fluoro-quinoline,

3- (3, 5-difluoro-benzenesulfonyl) -7-fluoro-4- (4-fluoro-phenyl) -quinoline,

4- (4-chloro-phenyl) -3- (3-cyano-benzenesulfonyl) -7-fluoro-quinoline,

3- (3-cyano-benzenesulfonyl) -7-fluoro-4- (3-fluoro-phenyl) -quinoline,

3- (3-cyano-benzenesulfonyl) -7-fluoro-4- (4-fluoro-phenyl) -quinoline,

7-fluoro-3- (4-fluoro-benzenesulfonyl) -4- (4-fluoro-phenyl) -quinoline,

4- (4-chloro-phenyl) -7-fluoro-3- (3-fluoro-benzenesulfonyl) -quinoline,

4- (3-chloro-phenyl) -7-fluoro-3- (3-methoxy-benzenesulfonyl) -quinoline,

7-fluoro-4- (4-fluoro-phenyl) -3- (3-methoxy-benzenesulfonyl) -quinoline,

4- (4-chloro-phenyl) -3- (3, 4-dimethyl-benzenesulfonyl) -7-fluoro-quinoline,

3- (3, 4-dimethyl-benzenesulfonyl) -7-fluoro-4- (4-fluoro-phenyl) -quinoline,

4- (3-chloro-phenyl) -3- (3-chloro-4-methoxy-benzenesulfonyl) -7-fluoro-quinoline,

3- (3-chloro-4-methoxy-benzenesulfonyl) -7-fluoro-4- (3-fluoro-phenyl) -quinoline,

3- (3-chloro-4-methoxy-benzenesulfonyl) -7-fluoro-4- (4-fluoro-phenyl) -quinoline,

3- (3, 5-dichloro-benzenesulfonyl) -8-fluoro-4- (4-fluoro-phenyl) -quinoline,

3- (3, 5-difluoro-benzenesulfonyl) -8-fluoro-4- (3-fluoro-phenyl) -quinoline,

8-fluoro-3- (4-fluoro-benzenesulfonyl) -4- (4-methoxy-phenyl) -quinoline,

4- (3-chloro-phenyl) -8-fluoro-3- (4-methoxy-benzenesulfonyl) -quinoline,

4- (4-chloro-phenyl) -8-fluoro-3- (4-methoxy-benzenesulfonyl) -quinoline,

8-fluoro-3- (4-methoxy-benzenesulfonyl) -4- (4-methoxy-phenyl) -quinoline,

8-fluoro-3- (4-methoxy-benzenesulfonyl) -4- (3-methoxy-phenyl) -quinoline,

4- (3-chloro-phenyl) -8-fluoro-3- (3-fluoro-benzenesulfonyl) -quinoline,

4- (4-chloro-phenyl) -8-fluoro-3- (3-fluoro-benzenesulfonyl) -quinoline,

8-fluoro-3- (3-fluoro-benzenesulfonyl) -4- (3-fluoro-phenyl) -quinoline,

8-fluoro-3- (3-fluoro-benzenesulfonyl) -4- (4-methoxy-phenyl) -quinoline,

8-fluoro-3- (3-fluoro-benzenesulfonyl) -4- (3-methoxy-phenyl) -quinoline,

8-fluoro-3- (3-fluoro-benzenesulfonyl) -4- (4-fluoro-phenyl) -quinoline,

3- (3-cyano-benzenesulfonyl) -6-fluoro-4- (3-fluoro-phenyl) -quinoline,

3- (3-cyano-benzenesulfonyl) -6-fluoro-4- (3-methoxy-phenyl) -quinoline,

3- (3-cyano-benzenesulfonyl) -6-fluoro-4- (4-fluoro-phenyl) -quinoline,

4- (3-chloro-phenyl) -6-fluoro-3- (3-methoxy-benzenesulfonyl) -quinoline,

6-fluoro-4- (4-fluoro-phenyl) -3- (3-methoxy-benzenesulfonyl) -quinoline,

3- (3-chloro-4-methoxy-benzenesulfonyl) -6-fluoro-4- (4-methoxy-phenyl) -quinoline,

3- (3-chloro-4-methoxy-benzenesulfonyl) -6-fluoro-4- (3-methoxy-phenyl) -quinoline,

4- (4-chloro-phenyl) -7-fluoro-3- (4-fluoro-benzenesulfonyl) -quinoline,

3- (3, 4-dimethyl-benzenesulfonyl) -7-fluoro-4- (4-methoxy-phenyl) -quinoline,

3- (3-chloro-4-methoxy-benzenesulfonyl) -4- (4-chloro-phenyl) -6-fluoro-quinoline,

3- (3-chloro-4-methoxy-benzenesulfonyl) -6-fluoro-4- (3-fluoro-phenyl) -quinoline,

3- (3, 5-dichloro-benzenesulfonyl) -7-fluoro-4- (4-methoxy-phenyl) -quinoline,

3- (3, 5-dichloro-benzenesulfonyl) -7-fluoro-4- (3-methoxy-phenyl) -quinoline,

3- (3, 5-difluoro-benzenesulfonyl) -7-fluoro-4- (4-fluoro-phenyl) -quinoline,

4- (3-chloro-phenyl) -7-fluoro-3- (3-fluoro-4-methyl-benzenesulfonyl) -quinoline,

7-fluoro-3- (3-fluoro-4-methyl-benzenesulfonyl) -4- (3-fluoro-phenyl) -quinoline,

7-fluoro-3- (3-fluoro-4-methyl-benzenesulfonyl) -4- (4-fluoro-phenyl) -quinoline,

3- (3, 5-difluoro-benzenesulfonyl) -7-fluoro-4- (3-fluoro-phenyl) -quinoline,

3- (3, 5-difluoro-benzenesulfonyl) -7-fluoro-4- (4-methoxy-phenyl) -quinoline,

3- (3, 5-difluoro-benzenesulfonyl) -7-fluoro-4- (3-methoxy-phenyl) -quinoline,

4- (3-chloro-phenyl) -3- (3-cyano-benzenesulfonyl) -7-fluoro-quinoline,

3- (3-cyano-benzenesulfonyl) -7-fluoro-4- (4-methoxy-phenyl) -quinoline,

3- (3-cyano-benzenesulfonyl) -7-fluoro-4- (3-methoxy-phenyl) -quinoline,

3- (3-chloro-4-methyl-benzenesulfonyl) -7-fluoro-4- (3-fluoro-phenyl) -quinoline,

3- (3, 4-difluoro-benzenesulfonyl) -7-fluoro-4- (3-fluoro-phenyl) -quinoline,

3- (3, 4-difluoro-benzenesulfonyl) -7-fluoro-4- (4-methoxy-phenyl) -quinoline,

3- (3, 4-difluoro-benzenesulfonyl) -7-fluoro-4- (3-methoxy-phenyl) -quinoline,

3- (3, 4-difluoro-benzenesulfonyl) -7-fluoro-4- (4-fluoro-phenyl) -quinoline,

3- (3-chloro-4-fluoro-benzenesulfonyl) -4- (4-chloro-phenyl) -7-fluoro-quinoline,

3- (3-chloro-4-fluoro-benzenesulfonyl) -7-fluoro-4- (3-fluoro-phenyl) -quinoline,

3- (3-chloro-4-fluoro-benzenesulfonyl) -7-fluoro-4- (4-methoxy-phenyl) -quinoline,

3- (3-chloro-4-fluoro-benzenesulfonyl) -7-fluoro-4- (4-fluoro-phenyl) -quinoline,

3- (3, 5-dichloro-benzenesulfonyl) -8-fluoro-4- (3-fluoro-phenyl) -quinoline,

3- (3, 5-dichloro-benzenesulfonyl) -8-fluoro-4- (4-methoxy-phenyl) -quinoline,

3- (3, 5-dichloro-benzenesulfonyl) -8-fluoro-4- (3-methoxy-phenyl) -quinoline,

4- (3-chloro-phenyl) -8-fluoro-3- (3-fluoro-4-methyl-benzenesulfonyl) -quinoline,

4- (4-chloro-phenyl) -8-fluoro-3- (3-fluoro-4-methyl-benzenesulfonyl) -quinoline,

8-fluoro-3- (3-fluoro-4-methyl-benzenesulfonyl) -4- (3-fluoro-phenyl) -quinoline,

8-fluoro-3- (3-fluoro-4-methyl-benzenesulfonyl) -4- (4-methoxy-phenyl) -quinoline,

8-fluoro-3- (3-fluoro-4-methyl-benzenesulfonyl) -4- (3-methoxy-phenyl) -quinoline,

8-fluoro-3- (3-fluoro-4-methyl-benzenesulfonyl) -4- (4-fluoro-phenyl) -quinoline,

4- (3-chloro-phenyl) -3- (3, 5-difluoro-benzenesulfonyl) -8-fluoro-quinoline,

4- (4-chloro-phenyl) -3- (3, 5-difluoro-benzenesulfonyl) -8-fluoro-quinoline,

3- (3, 5-difluoro-benzenesulfonyl) -8-fluoro-4- (4-methoxy-phenyl) -quinoline,

3- (3, 5-difluoro-benzenesulfonyl) -8-fluoro-4- (3-methoxy-phenyl) -quinoline,

3- (3, 5-difluoro-benzenesulfonyl) -8-fluoro-4- (4-fluoro-phenyl) -quinoline,

4- (4-chloro-phenyl) -3- (3, 4-difluoro-benzenesulfonyl) -8-fluoro-quinoline,

3- (3, 4-difluoro-benzenesulfonyl) -8-fluoro-4- (3-fluoro-phenyl) -quinoline,

3- (3, 4-difluoro-benzenesulfonyl) -8-fluoro-4- (4-methoxy-phenyl) -quinoline,

3- (3, 4-difluoro-benzenesulfonyl) -8-fluoro-4- (4-fluoro-phenyl) -quinoline,

3- (3, 5-dichloro-benzenesulfonyl) -6-fluoro-4- (3-fluoro-phenyl) -quinoline,

3- (3, 5-dichloro-benzenesulfonyl) -6-fluoro-4- (4-methoxy-phenyl) -quinoline,

3- (3, 5-dichloro-benzenesulfonyl) -6-fluoro-4- (3-methoxy-phenyl) -quinoline,

4- (3-chloro-phenyl) -6-fluoro-3- (3-fluoro-4-methyl-benzenesulfonyl) -quinoline,

6-fluoro-3- (3-fluoro-4-methyl-benzenesulfonyl) -4- (3-fluoro-phenyl) -quinoline,

6-fluoro-3- (3-fluoro-4-methyl-benzenesulfonyl) -4- (4-methoxy-phenyl) -quinoline,

6-fluoro-3- (3-fluoro-4-methyl-benzenesulfonyl) -4- (3-methoxy-phenyl) -quinoline,

6-fluoro-3- (3-fluoro-4-methyl-benzenesulfonyl) -4- (4-fluoro-phenyl) -quinoline,

4- (3-chloro-phenyl) -3- (3-cyano-benzenesulfonyl) -6-fluoro-quinoline,

4- (4-chloro-phenyl) -3- (3-cyano-benzenesulfonyl) -6-fluoro-quinoline,

3- (3-cyano-benzenesulfonyl) -6-fluoro-4- (4-methoxy-phenyl) -quinoline,

3- (3-chloro-4-methyl-benzenesulfonyl) -4- (3-chloro-phenyl) -6-fluoro-quinoline,

3- (3-chloro-4-methyl-benzenesulfonyl) -4- (4-chloro-phenyl) -6-fluoro-quinoline,

3- (3-chloro-4-methyl-benzenesulfonyl) -6-fluoro-4- (3-fluoro-phenyl) -quinoline,

3- (3-chloro-4-methyl-benzenesulfonyl) -6-fluoro-4- (3-methoxy-phenyl) -quinoline,

3- (3-chloro-4-methyl-benzenesulfonyl) -6-fluoro-4- (4-fluoro-phenyl) -quinoline,

4- (4-chloro-phenyl) -6-fluoro-3- (3-methoxy-benzenesulfonyl) -quinoline,

3- (3, 4-dimethyl-benzenesulfonyl) -6-fluoro-4- (3-fluoro-phenyl) -quinoline,

3- (3, 4-dimethyl-benzenesulfonyl) -6-fluoro-4- (4-methoxy-phenyl) -quinoline,

3- (3, 4-dimethyl-benzenesulfonyl) -6-fluoro-4- (4-fluoro-phenyl) -quinoline,

3- (3, 4-difluoro-benzenesulfonyl) -6-fluoro-4- (3-fluoro-phenyl) -quinoline,

3- (3, 4-difluoro-benzenesulfonyl) -6-fluoro-4- (4-fluoro-phenyl) -quinoline,

3- (3-chloro-4-fluoro-benzenesulfonyl) -4- (4-chloro-phenyl) -6-fluoro-quinoline,

3- (3-chloro-4-fluoro-benzenesulfonyl) -6-fluoro-4- (3-methoxy-phenyl) -quinoline,

3- (3-chloro-4-fluoro-benzenesulfonyl) -6-fluoro-4- (4-fluoro-phenyl) -quinoline,

4- (3-chloro-phenyl) -3- (3, 5-dichloro-benzenesulfonyl) -7-fluoro-quinoline,

4- (4-chloro-phenyl) -3- (3, 5-dichloro-benzenesulfonyl) -7-fluoro-quinoline,

4- (3-chloro-phenyl) -3- (3, 5-dichloro-benzenesulfonyl) -8-fluoro-quinoline,

4- (4-chloro-phenyl) -3- (3, 5-dichloro-benzenesulfonyl) -8-fluoro-quinoline,

4- (3-chloro-phenyl) -3- (3, 5-dichloro-benzenesulfonyl) -6-fluoro-quinoline,

4- (4-chloro-phenyl) -3- (3, 5-dichloro-benzenesulfonyl) -6-fluoro-quinoline,

6-fluoro-3- (4-methoxy-benzenesulfonyl) -4- (4-methoxy-phenyl) -quinoline,

7-chloro-4- (4-chloro-phenyl) -3- (3, 5-difluoro-benzenesulfonyl) -quinoline,

7-chloro-4- (4-chloro-phenyl) -3- (3, 4-difluoro-benzenesulfonyl) -quinoline,

7-chloro-4- (4-chloro-phenyl) -3- (3-cyano-benzenesulfonyl) -quinoline,

7-chloro-3- (3, 5-dichloro-benzenesulfonyl) -4- (4-fluoro-phenyl) -quinoline,

7-chloro-3- (4-fluoro-benzenesulfonyl) -4- (4-fluoro-phenyl) -quinoline,

7-chloro-3- (3-fluoro-benzenesulfonyl) -4- (4-fluoro-phenyl) -quinoline,

7-chloro-3- (3, 4-difluoro-benzenesulfonyl) -4- (4-fluoro-phenyl) -quinoline,

7-chloro-3- (3-chloro-4-fluoro-benzenesulfonyl) -4- (4-fluoro-phenyl) -quinoline,

7-chloro-3- (3-cyano-5-fluoro-benzenesulfonyl) -4- (4-fluoro-phenyl) -quinoline,

3- (3-chloro-4-fluoro-benzenesulfonyl) -7-cyano-4- (2-fluoro-phenyl) -quinoline,

7-chloro-3- (3, 4-difluoro-benzenesulfonyl) -8-fluoro-4- (3-fluoro-phenyl) -quinoline,

7-chloro-3- (3-chloro-4-fluoro-benzenesulfonyl) -4- (4-fluoro-phenyl) -8-fluoro-quinoline,

7-chloro-3- (3-chloro-4-fluoro-benzenesulfonyl) -8-fluoro-4- (3-fluoro-phenyl) -quinoline,

7-chloro-4- (4-chloro-phenyl) -3- (3, 4-difluoro-benzenesulfonyl) -8-fluoro-quinoline,

7-chloro-3- (3-chloro-4-fluoro-benzenesulfonyl) -8-fluoro-4- (4-fluoro-phenyl) -quinoline,

3- (3-cyano-4-fluoro-benzenesulfonyl) -4- (3-fluoro-phenyl) -quinoline,

3- (3-cyano-5-fluoro-benzenesulfonyl) -4- (3-fluoro-phenyl) -quinoline,

3- (3-chloro-4-fluoro-benzenesulfonyl) -4- (4-chloro-phenyl) -8-fluoro-quinoline,

3- (3-chloro-4-fluoro-benzenesulfonyl) -8-fluoro-4- (2-fluoro-phenyl) -quinoline,

3- (3-chloro-4-fluoro-benzenesulfonyl) -8-fluoro-4- (3-fluoro-phenyl) -quinoline,

3- (3-cyano-4-fluoro-benzenesulfonyl) -4- (4-fluoro-phenyl) -quinoline,

3- (3-chloro-4-fluoro-benzenesulfonyl) -8-fluoro-4- (4-fluoro-phenyl) -quinoline,

3- (3-cyano-benzenesulfonyl) -8-fluoro-4- (2-fluoro-phenyl) -quinoline,

3- (3-cyano-benzenesulfonyl) -4- (3-fluoro-phenyl) -quinoline,

3- (3-cyano-benzenesulfonyl) -8-fluoro-4- (3-fluoro-phenyl) -quinoline,

3- (3-cyano-4-fluoro-benzenesulfonyl) -7-fluoro-4- (3-fluoro-phenyl) -quinoline,

4- (3-chloro-phenyl) -3- (3-cyano-4-fluoro-benzenesulfonyl) -quinoline,

3- (3-cyano-5-fluoro-benzenesulfonyl) -7-fluoro-4- (4-fluoro-phenyl) -quinoline,

7-chloro-3- (3-cyano-4-fluoro-benzenesulfonyl) -4- (3-fluoro-phenyl) -quinoline,

3- (3, 5-dichloro-benzenesulfonyl) -4- (3, 4-difluoro-phenyl) -8-fluoro-quinoline,

7-chloro-3- (3-cyano-5-fluoro-benzenesulfonyl) -4- (3-fluoro-phenyl) -quinoline,

3- (3-cyano-benzenesulfonyl) -8-fluoro-4- (4-fluoro-phenyl) -quinoline,

3- (3, 5-dichloro-benzenesulfonyl) -8-fluoro-4- (2-fluoro-phenyl) -quinoline,

3- (3-chloro-4-fluoro-benzenesulfonyl) -7-fluoro-4- (2-fluoro-phenyl) -quinoline,

4- (4-chloro-phenyl) -3- (3-cyano-benzenesulfonyl) -8-fluoro-quinoline,

4- (3-chloro-phenyl) -3- (3-cyano-5-fluoro-benzenesulfonyl) -quinoline,

7-chloro-3- (3-cyano-benzenesulfonyl) -4- (2-fluoro-phenyl) -quinoline,

3- (3-cyano-5-fluoro-benzenesulfonyl) -7-fluoro-4- (3-fluoro-phenyl) -quinoline,

3- (3-chloro-4-fluoro-benzenesulfonyl) -4- (3-chloro-phenyl) -8-fluoro-quinoline,

3- (3-cyano-benzenesulfonyl) -7-fluoro-4- (2-fluoro-phenyl) -quinoline,

3- (3-cyano-5-fluoro-benzenesulfonyl) -4- (3, 4-difluoro-phenyl) -7-fluoro-quinoline,

3- (3-cyano-4-fluoro-benzenesulfonyl) -4- (3, 4-dichloro-phenyl) -quinoline,

7-chloro-3- (3-chloro-4-fluoro-benzenesulfonyl) -4- (2-fluoro-phenyl) -quinoline,

7-chloro-3- (3-cyano-benzenesulfonyl) -4- (3-fluoro-phenyl) -quinoline,

4- (3-chloro-phenyl) -3- (3-cyano-4-fluoro-benzenesulfonyl) -7-fluoro-quinoline,

3- (3, 4-difluoro-benzenesulfonyl) -4- (3, 5-difluoro-phenyl) -8-fluoro-quinoline,

3- (3, 4-difluoro-benzenesulfonyl) -4- (4-fluoro-phenyl) -quinoline,

3- (3, 4-difluoro-benzenesulfonyl) -4- (3, 4-difluoro-phenyl) -8-fluoro-quinoline,

3- (3, 5-dichloro-benzenesulfonyl) -4- (3, 4-difluoro-phenyl) -7-fluoro-quinoline,

3- (3, 4-difluoro-benzenesulfonyl) -4- (3-fluoro-phenyl) -quinoline,

7-chloro-3- (3-cyano-benzenesulfonyl) -4- (4-fluoro-phenyl) -quinoline,

7-chloro-4- (3-chloro-phenyl) -3- (3-cyano-4-fluoro-benzenesulfonyl) -quinoline,

3- (3, 4-difluoro-benzenesulfonyl) -8-fluoro-4- (2-fluoro-phenyl) -quinoline,

4- (3-chloro-phenyl) -3- (3-cyano-5-fluoro-benzenesulfonyl) -7-fluoro-quinoline,

3- (3-cyano-benzenesulfonyl) -4- (3, 5-difluoro-phenyl) -7-fluoro-quinoline,

4- (3-chloro-phenyl) -3- (3-cyano-benzenesulfonyl) -8-fluoro-quinoline,

4- (4-chloro-phenyl) -3- (3, 4-difluoro-benzenesulfonyl) -7-fluoro-quinoline,

7-chloro-3- (3, 4-dichloro-benzenesulfonyl) -4- (3, 4-difluoro-phenyl) -quinoline,

3- (3, 5-dicyano-benzenesulfonyl) -7-fluoro-4- (4-fluoro-phenyl) -quinoline,

3- (3, 4-difluoro-benzenesulfonyl) -4- (3, 4-difluoro-phenyl) -7-fluoro-quinoline,

7-chloro-4- (3-chloro-phenyl) -3- (3, 5-dichloro-benzenesulfonyl) -8-fluoro-quinoline,

7-chloro-4- (3-chloro-phenyl) -3- (3-cyano-benzenesulfonyl) -8-fluoro-quinoline,

7-chloro-4- (3-chloro-phenyl) -3- (3-cyano-benzenesulfonyl) -quinoline,

7-chloro-3- (3, 5-dichloro-benzenesulfonyl) -4- (2-fluoro-phenyl) -quinoline,

3- (3, 5-dicyano-benzenesulfonyl) -4- (3, 4-difluoro-phenyl) -7-fluoro-quinoline,

3- (3, 5-dichloro-benzenesulfonyl) -7-fluoro-4- (2-fluoro-phenyl) -quinoline,

3- (3-chloro-4-fluoro-benzenesulfonyl) -4- (3-chloro-phenyl) -7-fluoro-quinoline,

4- (3-chloro-phenyl) -3- (3, 4-difluoro-benzenesulfonyl) -8-fluoro-quinoline,

4- (3, 4-dichloro-phenyl) -3- (3, 4-difluoro-benzenesulfonyl) -quinoline,

3- (3, 4-difluoro-benzenesulfonyl) -7-fluoro-4- (2-fluoro-phenyl) -quinoline,

7-chloro-3- (3-chloro-4-fluoro-benzenesulfonyl) -4- (3, 5-difluoro-phenyl) -quinoline,

7-chloro-4- (3-chloro-phenyl) -3- (3, 5-dichloro-benzenesulfonyl) -quinoline,

7-amino-3- (3, 4-difluoro-benzenesulfonyl) -4- (3-fluoro-phenyl) -quinoline,

4- (3-chloro-phenyl) -3- (3-cyano-benzenesulfonyl) -quinoline,

3- (3-cyano-5-fluoro-benzenesulfonyl) -4- (3, 4-difluoro-phenyl) -quinoline,

3- (3-cyano-5-fluoro-benzenesulfonyl) -7-fluoro-4- (4-fluoro-phenyl) -quinoline,

4- (4-chloro-phenyl) -3- (3-cyano-5-fluoro-benzenesulfonyl) -7-fluoro-quinoline,

7-chloro-3- (3-chloro-4-fluoro-benzenesulfonyl) -4- (4-fluoro-phenyl) -quinoline, and

7-chloro-3- (3-chloro-4-fluoro-benzenesulfonyl) -4- (4-chloro-phenyl) -quinoline,

and/or salts thereof.

3. A process for preparing a compound of formula (I) and/or a salt thereof:

wherein Ar is₁，Ar₂，R₁，R₂，R₃And R₄As defined in claim 1, wherein the first and second groups are,

a，

a1. the method comprises the following steps: reacting a compound of formula (II):

wherein R is₁，R₂，R₃And R₄As defined in claim 1, with a compound of formula (III):

Ar₁-S^-M⁺

(III)

wherein Ar is₁As defined in claim 1, M is selected from alkali metals or alkaline earth metals, giving compounds of formula (IV):

wherein Ar is₁，R₁，R₂，R₃And R₄As defined in claim 1, thereafter oxidizing the compound of formula (IV) to obtain the compound of formula (V):

wherein Ar is₁，R₁，R₂，R₃And R₄As defined in claim 1, thereafter oxidizing the compound of formula (V) to obtain the compound of formula (VI):

wherein Ar is₁，R₁，R₂，R₃And R₄As defined in claim 1, or

a2.

Reacting a compound of formula (IX) by:

Ar₁-SO₂Na

(IX)

wherein Ar is₁As defined in claim 1, with α -halo-acetates of formula (X):

Hlg-CH₂-COOR₅

(X)

wherein Hlg is halogen and R₅Ethyl or methyl to give a compound of formula (XI):

Ar₁-SO₂-CH₂-COOR₅

(XI)

wherein Ar is₁As defined in claim 1 and R₅Is ethyl or methyl, after which the compound of formula (XI) is reacted with a trialkyl orthoformate of formula (XII):

CH(OR₆)₃

(XII)

wherein R is₆Ethyl or methyl to give a compound of formula (XIII):

wherein Ar is₁As defined in claim 1, R₅And R₆Independently selected from ethyl or methyl, after which the compound of formula (XIII) is reacted with an aniline derivative of formula (XIV):

wherein R is₁，R₂，R₃And R₄As defined in claim 1, to give a compound of formula (VI):

wherein Ar is₁，R₁，R₂，R₃And R₄As defined in claim 1, wherein the first and second groups are,

thereafter converting the compound of formula (VI) to a compound of formula (VII):

wherein Ar is₁，R₁，R₂，R₃And R₄As defined in claim 1, X is selected from the group consisting of chloro, bromo, benzenesulfonyloxy, 4-fluoro-benzenesulfonyloxy, 4-methyl-benzenesulfonyloxy, methanesulfonyloxy or trifluoromethanesulfonyloxy,

thereafter reacting the compound of formula (VII) obtained with a boronic acid derivative of formula (VIII) in the presence of a base and a catalyst in a solvent:

Ar₂-B(OH)₂

(VIII)

wherein Ar is₂As defined in claim 1, wherein the first and second groups are,

and optionally thereafter forming a salt of the compound of formula (I).

4. A compound of formula (VII):

wherein

Ar₁，R₁，R₂，R₃And R₄As defined in claim 1, X is selected from the group consisting of chloro, bromo, benzenesulfonyloxy, 4-fluoro-benzenesulfonyloxy, 4-methyl-benzenesulfonyloxy, methanesulfonyloxy or trifluoromethanesulfonyloxy,

and/or salts thereof.

5. A pharmaceutical formulation comprising a compound of formula (I):

wherein

Ar₁Represents phenyl optionally substituted by one or more substituents selected from hydrogen, fluoro, chloro, cyano, methyl, methoxy, or thienyl optionally substituted by one or more substituents selected from hydrogen, fluoro, chloro;

Ar₂represents phenyl substituted by one or more substituents selected from fluoro, chloro, cyano, methyl, methoxy, or pyridinyl optionally substituted by one or more substituents selected from hydrogen, fluoro, chloro;

R₁，R₂，R₃and R₄Independently represent a substituent selected from hydrogen, fluorine, chlorine, cyano, methyl, methoxy, hydroxy, trifluoromethyl, amino, methylamino, dimethylamino, aminomethyl, methylaminomethyl, dimethylaminomethyl,

and/or a salt thereof, and/or a pharmaceutically acceptable salt thereof,

and one or more physiologically acceptable diluents, excipients and/or inert carriers.

6. Use of a pharmaceutical formulation according to claim 5 in the manufacture of a medicament for the prevention and/or treatment of mGluR1 and mGluR5 receptor mediated disorders.

7. Use of a compound of formula (I) and/or a salt thereof in the manufacture of a medicament for the treatment and/or prevention of mGluR1 and mGluR5 receptor mediated disorders:

wherein

Ar₁Represents an optionally substituted one or more groups selected from hydrogen, fluoro, chloro, cyano, methyl, methoxyPhenyl substituted with a substituent(s) of (a), or thienyl optionally substituted with one or more substituents selected from hydrogen, fluoro, chloro;

Ar₂represents phenyl substituted by one or more substituents selected from fluoro, chloro, cyano, methyl, methoxy, or pyridinyl optionally substituted by one or more substituents selected from hydrogen, fluoro, chloro;

R₁，R₂，R₃and R₄Independently represent a substituent selected from hydrogen, fluorine, chlorine, cyano, methyl, methoxy, hydroxy, trifluoromethyl, amino, methylamino, dimethylamino, aminomethyl, methylaminomethyl, dimethylaminomethyl.

8. The use of a compound according to claim 7, wherein the mGluR1 and mGluR5 receptor mediated disorder is a psychiatric disorder.

9. The use of a compound according to claim 7, wherein the mGluR1 and mGluR5 receptor mediated disorder is a neurological disorder.

10. The use of a compound according to claim 7, wherein the mGluR1 and mGluR5 receptor mediated disorders are chronic and acute pain.

11. The use of a compound according to claim 7, wherein the mGluR1 and mGluR5 receptor mediated disorder is neuromuscular dysfunction of the lower urinary tract.

12. The use of a compound according to claim 7, wherein the mGluR1 and mGluR5 receptor mediated disorder is gastrointestinal reflux disease and irritable bowel syndrome.

13. The use of a compound according to claim 7, wherein the mGluR1 and mGluR5 receptor mediated disorder is substance abuse and withdrawal.