WO2008035049A1 - Adamantanyl-(cyclopropyl)-ketones as metabotropic glutamate receptor modulators - Google Patents

Abstract

The invention relates to adamantyl-(cyclopropyl)-ketone derivatives as well as their pharmaceutically acceptable salts. The invention further relates to a process for the preparation of such compounds. The compounds of the invention are Group I mGluR modulators and are therefore useful for the control and prevention of acute and/or chronic neurological disorders.

Description

ADAMANTANYL-(CYCLOPROPYL)-KETONES AS METABOTROPIC GLUTAMATE RECEPTOR MODULATORS

FIELD OF THE INVENTION

[0001] The present invention is concerned with novel metabotropic glutamate receptor (mGluR) modulators, methods for their synthesis and the treatment and/or prevention of neurological disorders by administration of such substances.

BACKGROUND OF THE INVENTION

[0002] Neuronal stimuli are transmitted by the central nervous system (CNS) through the interaction of a neurotransmitter released by a neuron, which neurotransmitter has a specific effect on a neuroreceptor of another neuron.

[0003] L-glutamic acid is considered to be the major excitatory neurotransmitter in the mammalian CNS, consequently playing a critical role in a large number of physiological processes. Glutamate-dependent stimulus receptors are divided into two main groups. The first group comprises ligand-controlled ion channels whereas the second comprises metabotropic glutamate receptors (mGluR). Metabotropic glutamate receptors are a subfamily of G-protein-coupled receptors (GPCR). There is increasing evidence for a peripheral role of both ionotropic and metabotropic glutamate receptors outside the CNS e.g, in chronic pain states.

[0004] At present, eight different members of these mGluRs are known. On the basis of structural parameters such as sequence homology, the second messenger system utilized by these receptors and their different affinity to low- molecular weight compounds, these eight receptors can be divided into three groups: mGluRI and mGluR5 belong to Group I which are positively coupled to phospholipase C and their activation leads to intracellular calcium-ion mobilization. Both mGluR2 and mGluR3 belong to Group Il and mGluR4, mGluR6, mGluR7 and mGluRδ belong to Group III, both of which are negatively coupled to adenyl cyclase, i.e., their activation causes a reduction in second messenger cAMP and, as such, a dampening of neuronal activity.

[0005] Group I mGluR modulators have been shown to modulate the effects of the presynaptically released neurotransmitter glutamate via postsynaptic mechanisms. Moreover, as these Group I modulators can be both positive and/or negative, such modulators may increase or inhibit the effects of these metabotropic receptors. Since a variety of pathophysiological processes and disease states affecting the CNS are thought to be related to abnormal glutamate neurotransmission, and Group I mGluRs are shown to be expressed in several areas of the CNS, modulators of these receptors could be therapeutically beneficial in the treatment of CNS diseases

[0006] Therefore, Group I mGluR modulators may be administered to provide neuroprotection in acute and chronic pathological conditions such as: AIDS- related dementia, Alzheimer's disease, Creutzfeld-Jakob^'s syndrome, bovine spongiform encephalopathy (BSE) or other prion related infections, diseases involving mitochondrial dysfunction, diseases involving β-amyloid and/or tauopathy such as Down's syndrome, hepatic encephalopathy, Huntington's disease, motor neuron diseases such as amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), olivopontocerebellar atrophy, post-operative cognitive deficit (POCD), Parkinson's disease, Parkinson's dementia, mild cognitive impairment, dementia pugilistica, vascular and frontal lobe dementia, cognitive impairment, eye injuries or diseases (e.g. glaucoma, retinopathy, macular degeneration), head and brain and spinal cord injuries / trauma, hypoglycaemia, hypoxia (e.g. perinatal), ischaemia (e.g. resulting from cardiac arrest, stroke, bypass operations or transplants), convulsions, epilepsy, temporal lobe epilepsy, glioma and other tumours, inner ear insult (e.g. in tinnitus, sound- or drug- induced), L-Dopa-induced dyskinesias and tardive dyskinesias.

[0007] Other indications in this context include a symptomatoloqical effect on the following conditions: abuse and addiction (e.g., nicotine, alcohol, opiate, cocaine, amphetamine, obesity and others), amyotrophic lateral sclerosis (ALS), anxiety and panic disorders, attention deficit hyperactivity disorder (ADHD), restless leg syndrome, hyperactivity in children, autism, convulsions, epileptic convulsions, epilepsy, temporal lobe epilepsy, dementia (e.g. in Alzheimer's disease, Korsakoff syndrome, vascular dementia, HIV infections), major depressive disorder or depression (including that resulting from Borna virus infection) and bipolar manic- depressive disorder, drug tolerance (e.g. to opioids), movement disorders, dystonia, dyskinesia (e.g. L-Dopa-induced, tardive dyskinesia or in Huntington's disease), fragile-X syndrome, chorea, Huntington's chorea, irritable bowel syndrome (IBS), migraine, multiple sclerosis (MS), muscle spasms, pain (chronic and acute, e.g. inflammatory pain, neuropathic pain, allodynia, hyperalgesia, nociceptive pain), Parkinson's disease, posttraumatic stress disorder, schizophrenia (positive and negative symptoms), spasticity, tinnitus, Tourette^'s syndrome, urinary incontinence and vomiting, pruritic conditions (e.g. pruritis), sleep disorders, micturition disorders, neuromuscular disorder in the lower urinary tract, gastroesophageal reflux disease (GERD), lower esophageal sphincter (LES) disease, functional gastrointestinal disorders, dyspepsia, regurgitation, respiratory tract infection, bulimia nervosa, chronic laryngitis, asthma (e.g. reflux-related asthma), lung disease, eating disorders, obesity, obesity-related disorders, binge eating disorders, agoraphobia, generalized anxiety disorder, obsessive- compulsive disorder, panic disorder, anxiety disorder, posttraumatic stress disorder, social phobia, substance-induced anxiety disorder, delusional disorder, schizoaffective disorder, schizophreniform disorder, substance-induced psychotic disorder and delirium.

[0008] Yet further indications for Group I mGluR modulators include those indications wherein a particular condition does not necessarily exist but wherein a particular physiological parameter may be improved through administration of the instant compounds, for example cognitive enhancement.

[0009] Positive modulators may be particularly useful in the treatment of positive and negative symptoms in schizophrenia and cognitive deficits in various forms of dementia and mild cognitive impairment. THE PRESENT INVENTION

[001O] We have determined that certain adamantyl-(cyclopropyl)-ketone derivatives are Group I mGluR modulators. Therefore, these substances may be therapeutically beneficial in the treatment of conditions, which involve abnormal glutamate neurotransmission, or in which modulation of Group I mGluR receptors results in therapeutic benefit. These substances may be administered in the form of a pharmaceutical composition, wherein they are present together with one or more pharmaceutically acceptable diluents, carriers, or excipients.

OBJECTS OF THE INVENTION

[0011] It is an object of the present invention to provide novel pharmaceutical compounds, which are Group I mGluR modulators and pharmaceutical compositions thereof. It is a further object of the invention to provide a novel method of treating, eliminating, alleviating, palliating, or ameliorating undesirable CNS disorders which involve abnormal glutamate neurotransmission by employing a compound of the invention or a pharmaceutical composition containing the same. An additional object of the invention is the provision of a process for producing the adamantyl-(cyclopropyl)-ketone active principles. Yet additional objects will become apparent hereinafter, and still further objects will be apparent to one skilled in the art.

SUMMARY OF THE INVENTION

[0012] What we therefore believe to be comprised by our invention may be summarized inter alia in the following words: A compound selected from those of Formula I

wherein

R¹ represents aryl, biaryl, heteroaryl, aryl-heteroaryl, heteroaryl-aryl, or heteroaryl- heteroaryl;

R² represents hydrogen or C_1-6alkyl;

R³ represents hydrogen, cyano, nitro, Ci_-6alkyl, or Ci-₆alkoxyC_1-6alkyl;

and optical isomers, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof;

wherein

the term "aryl" represents phenyl or naphthyl, wherein the aryl group may be optionally substituted by one or more substituents selected independently from halogen, trifluoromethyl, Ci_-6alkyl, C_2-6alkenyl, Ci_-6alkoxy, Ci_-6alkoxy-Ci_-6alkyl, amino, hydroxy, nitro, cyano, d-βalkoxycarbonyl, Ci_-6alkylamino, Ci_-6alkylamino- C_1-6alkyl, di-Ci_-6alkylamino, cycloC₃-i₂alkoxy, aryloxy, cycloCa-^alkylamino, cycloC₃-i₂alkyl-Ci-₆alkylamino, di-Ci-ealkylaminoC-i-βalkyl, arylamino, arylCi_-6alkylamino, arylCi_-6alkoxy, heteroarylCi_-6alkoxy, heteroarylamino, heteroarylCi-₆alkylamino, pyrrolidine, piperidino, morpholino, hexamethyleneimino, -N(R⁵)-C(=O)-R⁴, -N(R⁵)-SO₂-R⁴, -N(R⁵)-C(=O)OR⁴, C(=O)-R⁴, C(=O)N(R⁵)₂, and a bivalent radical selected from -(CH₂)₃-, -(CH₂J₄-, -CH=CH-CH=CH-, -(CHz)₃O-, -OCH₂O-, -O(CH₂)₂O-, and -O(CH₂)₃-;

the term "biaryl" represents biphenylene, including 4,4'-biphenylene, wherein one or both phenyl rings may be optionally substituted by one or more substituents independently selected from halogen, trifluoromethyl, C_halky!, C^alkenyl, Ci_-6alkoxy, C_1-6alkoxyC-i-₆alkyl, amino, hydroxy, nitro, cyano, Ci_-6alkoxycarbonyl, Ci_-6alkylamino, Ci-βalkylamino-Ci-ealkyl, di-Ci_-6alkylamino, cycloC_3-12alkoxy, aryloxy, cycloC_3-i₂alkylamino, cycloCs-^alkyl-Ci-ealkylamino, di-Ci-ealkylaminoCi-ealkyl, arylamino, arylC-i-βalkylamino, heteroarylCi-βalkoxy, heteroarylamino, heteroarylCi_-6alkylamino, pyrrolidine, piperidino, morpholino, hexamethyleneimino, -N(R⁵)-C(=O)-R⁴, -N(R⁵)-SO₂-R⁴, -N(R⁵)-C(=O)OR⁴,

C(=O)-R⁴, C(=O)N(R⁵)₂, and a bivalent radical selected from -(CH₂)₃-, -(CH₂J₄-, -CH=CH-CH=CH-, -(CH₂)₃O-, -OCH₂O-, -O(CH₂)₂O-, and -O(CH₂)₃-; and

the term "heteroaryl" represents an aromatic 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen, or a bicyclic group comprising a 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen fused with a benzene ring or a 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen, wherein the heteroaryl group may be optionally substituted by one or more substituents selected independently from halogen, trifluoromethyl, Ci-βalkyl, C_2-6alkenyl, d_-6alkoxy, C_1-6alkoxyC_1-6alkyl, amino, hydroxy, nitro, cyano, C-i_-6alkoxycarbonyl, Ci.₆alkylamino, Ci-_θalkylamino-Ci-ealkyl, di-C_1-6alkylamino, cycloC_3-i₂alkoxy, aryloxy, cycloCs-^alkylamino, cycloC₃-i₂alkyl-Ci-₆alkylamino, di-Ci-βalkylaminoCi-ealkyl, arylamino, arylC_1-6alkylamino, heteroaryld-βalkoxy, heteroarylamino, heteroarylCi_-6alkylamino, pyrrolidino, piperidino, morpholino, hexamethyleneimino, -N(R⁵)-C(=O)-R⁴, -N(R⁵)-SO₂-R⁴, -N(R⁵)-C(=O)OR⁴, C(=O)-R⁴, C(=O)N(R⁵)_2> and a bivalent radical selected from -(CH₂)₃-, -(CH₂)₄-, -CH=CH-CH=CH-, -(CH₂)₃O-, -OCH₂O-, -O(CH₂)₂O-, and -O(CH₂)₃-;

wherein

R⁴ represents hydrogen, Ci_-6alkyl which may be optionally substituted with one or more halogen atoms, cycloC_3-i₂alkyl, aryl, heteroaryl, adamantyl, carboxyd-βalkyl or CF₃; and

R⁵ represents hydrogen, C_halky!, cycloC_3-i₂alkyl, aryl, heteroaryl, adamantyl, carboxyCi-βalkyl, alkylcarbonyl or CF₃.

Examples of heteroaryl include furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, benzofuryl, benzothienyl, indolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinolyl and isoquinolyl. [0013] Moreover, a pharmaceutical composition comprising, together with one or more pharmaceutically acceptable excipients or vehicles, at least one compound selected from those of Formula I

wherein

R¹ represents aryl, biaryl, heteroaryl, aryl-heteroaryl, heteroaryl-aryl, or heteroaryl-heteroaryl;

R² represents hydrogen or C_1-6alkyl;

R³ represents hydrogen, cyano, nitro, Ci_-6alkyl or Ci_-6alkoxyCi_-6alkyl;

and optical isomers, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof;

wherein

the term "aryl" represents phenyl or naphthyl, wherein the aryl group may be optionally substituted by one or more substituents selected independently from halogen, trifluoromethyl, Ci-βalkyl, C^alkenyl, Ci_-6alkoxy, C_1-6alkoxy-C_1-6alkyl, amino, hydroxy, nitro, cyano, Ci_-6alkoxycarbonyl, Ci-₆alkylamino, Ci-βalkylamino- d-βalkyl, di-Ci_-6alkylamino, cycloC_3-i₂alkoxy, aryloxy, cycloCs-^alkylamino, cycloC_3-12alkyl-Ci_-6alkylamino, di-d-ealkylaminoCi-ealkyl, arylamino, arylC_1-6alkylamino, arylCi_-6alkoxy, heteroarylCi-₆alkoxy, heteroarylamino, heteroarylC_1-6alkylamino, pyrrolidino, piperidino, morpholino, hexamethyleneimino, -N(R⁵)-C(=O)-R⁴, -N(R⁵)-SO₂-R⁴, -N(R⁵)-C(=O)OR⁴, C(O)-R⁴, C(=O)N(R⁵)₂, and a bivalent radical selected from -(CH₂)₃-, -(CH₂)₄-, -CH=CH-CH=CH-, -(CH₂J₃O-, -OCH₂O-, -0(CH₂J₂O-, and -0(CH₂J₃-;

the term "biaryl" represents biphenylene, including 4,4'-biphenylene, wherein one or both phenyl rings may be optionally substituted by one or more substituents independently selected from halogen, trifluoromethyl, C_1-6alkyl, C_2-6alkenyl, C_1-6alkoxy, Ci-₆alkoxyCi_-6alkyl, amino, hydroxy, nitro, cyano, Ci_-6alkoxycarbonyl, Ci-₆alkylamino, Ci-ealkylamino-Ci-ealkyl, di-Ci_-6alkylamino, cycloC_3-i₂alkoxy, aryloxy, cycloCs-^alkylamino, cycloCs-^alkyl-Ci-βalkylamino, di-Ci-βalkylaminoCi-βalkyl, arylamino, arylCi_-6alkylamino, heteroarylCi_-6alkoxy, heteroarylamino, heteroarylCi_-6alkylamino, pyrrolidino, piperidino, morpholino, hexamethyleneimino, -N(R⁵)-C(=O)-R⁴, -N(R⁵J-SO₂-R⁴, -N(R⁵)-C(=O)OR⁴, C(=O)-R⁴, C(=O)N(R⁵)₂, and a bivalent radical selected from -(CH₂J₃-, -(CH₂J₄-, -CH=CH-CH=CH-, -(CH₂J₃O-, -OCH₂O-, -0(CH₂J₂O-, and -0(CH₂J₃-; and

the term "heteroaryl" represents an aromatic 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen, or a bicyclic group comprising a 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen fused with a benzene ring or a 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen, wherein the heteroaryl group may be optionally substituted by one or more substituents selected independently from halogen, trifluoromethyl, C_1-6alkyl, C₂-₆alkenyl, Ci_-6alkoxy, Ci-βalkoxyd-ealkyl, amino, hydroxy, nitro, cyano, C_1-6alkoxycarbonyl, Ci-βalkylamino, Ci-₆alkylamino-Ci_-6alkyl, di-Ci_-6alkylamino, cycloC_3-i₂alkoxy, aryloxy, cycloC_3-i₂alkylamino, cycloCs-^alkyl-d-ealkylamino, di-C_1-6alkylaminoCi_-6alkyl, arylamino, arylCi_-6alkylamino, heteroarylCi_-6alkoxy, heteroarylamino, heteroarylCi_-6alkylamino, pyrrolidino, piperidino, morpholino, hexamethyleneimino, -N(R⁵)-C(=O)-R⁴, -N(R⁵)-SO₂-R⁴, -N(R⁵)-C(=O)OR⁴, C(=O)-R⁴, C(=O)N(R⁵)₂, and a bivalent radical selected from -(CH₂J₃-, -(CH₂J₄-, -CH=CH-CH=CH-, -(CH₂J₃O-, -OCH₂O-, -0(CH₂J₂O-, and -0(CH₂J₃-;

wherein

R⁴ represents hydrogen, C-ι_-6alkyl which may be optionally substituted with one or more halogen atoms, cycloC_3-i₂alkyl, aryl, heteroaryl, adamantyl, carboxyCi-βalkyl or CF₃; and

R⁵ represents hydrogen, C_1-6alkyl, cycloC_3-i₂alkyl, aryl, heteroaryl, adamantyl, carboxyCi_-6alkyl, alkylcarbonyl or CF₃.

Examples of heteroaryl include furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, benzofuryl, benzothienyl, indolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinolyl and isoquinolyl. [0014] Further, a method for treating or preventing a condition or disease associated with abnormal glutamate neurotransmission or a method for modulating Group I mGluR receptors to achieve therapeutic benefit, or a method for enhancing cognition, such method comprising administering to a living animal, including a human, a therapeutically effective amount of a compound selected from those of Formula I

wherein

R¹ represents aryl, biaryl, heteroaryl, aryl-heteroaryl, heteroaryl-aryl, or heteroaryl-heteroaryl;

R² represents hydrogen or C-i-βalkyl;

R³ represents hydrogen, cyano, nitro, Ci_-6alkyl or Ci-₆alkoxyCi_-6alkyl;

and optical isomers, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof;

wherein the term "aryl" represents phenyl or naphthyl, wherein the aryl group may be optionally substituted by one or more substituents selected independently from halogen, trifluoromethyl, C_1-6alkyl, C_2-6alkenyl, Ci_-6alkoxy, Ci.₆alkoxy-Ci_-6alkyl, amino, hydroxy, nitro, cyano, Ci_-6alkoxycarbonyl, d-βalkylamino, Ci_-6alkylamino- Ci_-6alkyl, di-Ci_-6alkylamino, cycloC_3-i₂alkoxy, aryloxy, cycloC_3-12alkylamino, cycloC_3-i₂alkyl-Ci-₆alkylamino, di-Ci-βalkylaminoCi-βalkyl, arylamino, arylC_1-6alkylamino, arylCi_-6alkoxy, heteroarylCi_-6alkoxy, heteroarylamino, heteroarylCi_-6alkylamino, pyrrolidine, piperidino, morpholino, hexamethyleneimino, -N(R⁵J-C(O)-R⁴, -N(R⁵)-SO₂-R⁴, -N(R⁵)-C(=O)OR⁴, C(=O)-R⁴, C(=O)N(R⁵)₂, and a bivalent radical selected from -(CH₂)₃-, -(CH₂J₄-, -CH=CH-CH=CH-, -(CH₂)₃O-, -OCH₂O-, -O(CH₂)₂O-, and -O(CH₂)₃-;

the term "biaryl" represents biphenylene, including 4,4'-biphenylene, wherein one or both phenyl rings may be optionally substituted by one or more substituents independently selected from halogen, trifluoromethyl, C_halky!, C_2-6alkenyl, Ci_-6alkoxy, Ci-₆alkoxyCi-₆alkyl, amino, hydroxy, nitro, cyano, C_1-6alkoxycarbonyl, d-βalkylamino, Ci-ealkylamino-Ci-βalkyl, di-Ci-βalkylamino, cycloC_3-i₂alkoxy, aryloxy, cycloCs-^alkylamino, cycloCs-^alkyl-Ci-βalkylamino, di-Ci-βalkylaminoCi-ealkyl, arylamino, arylCi_-6alkylamino, heteroarylCi_-6alkoxy, heteroarylamino, heteroarylCi_-6alkylamino, pyrrolidine, piperidino, morpholino, hexamethyleneimino, -N(R⁵)-C(=O)-R⁴, -N(R⁵)-SO₂-R⁴, -N(R⁵)-C(=O)OR⁴, C(=O)-R⁴, C(=O)N(R⁵)₂, and a bivalent radical selected from -(CH₂J₃-, -(CH₂J₄-, -CH=CH-CH=CH-, -(CH₂J₃O-, -OCH₂O-, -0(CH₂J₂O-, and -0(CH₂J₃-; and the term "heteroaryl" represents an aromatic 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen, or a bicyclic group comprising a 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen fused with a benzene ring or a 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen, wherein the heteroaryl group may be optionally substituted by one or more substituents selected independently from halogen, trifluoromethyl, C_1-6alkyl, C_2-6alkenyl, d-₆alkoxy, Ci_-6alkoxyCi-₆alkyl, amino, hydroxy, nitro, cyano, d-βalkoxycarbonyl, Ci_-6alkylamino, C-i-ealkylamino-Ci-ealkyl, di-Ci_-6alkylamino, cycloC_3-12alkoxy, aryloxy, cycloCs-^alkylamino, cycloC_3-i₂alkyl-Ci-₆alkylamino, di-C-i-ealkylaminoC-i-βalkyl, arylamino, arylCi_-6alkylamino, heteroarylCi_-6alkoxy, heteroarylamino, heteroarylCi_-6alkylamino, pyrrolidino, piperidino, morpholino, hexamethyleneimino, -N(R⁵)-C(=O)-R⁴, -N(R⁵)-SO₂-R⁴, -N(R⁵)-C(=O)OR⁴, C(=O)-R⁴, C(=O)N(R⁵)₂, and a bivalent radical selected from -(CH₂)₃-, -(CH₂)₄-, -CH=CH-CH=CH-, -(CH₂)₃O-, -OCH₂O-, -O(CH₂)₂O-, and -O(CH₂)₃-;

wherein

R⁴ represents hydrogen, Ci_-6alkyl which may be optionally substituted with one or more halogen atoms, cycloC_3-12alkyl, aryl, heteroaryl, adamantyl, carboxyCi_-6aikyl or CF₃; and

R⁵ represents hydrogen, Ci_-6alkyl, cycloC_3--ι₂alkyl, aryl, heteroaryl, adamantyl, carboxyC-ι_-6alkyl, alkylcarbonyl or CF₃. Examples of heteroaryl include furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, benzofuryl, benzothienyl, indolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinolyl and isoquinolyl.

[0015] Further, the use of at least one compound selected from those of Formula I

wherein

R¹ represents aryl, biaryl, heteroaryl, aryl-heteroaryl, heteroaryl-aryl, or heteroaryl-heteroaryl;

R² represents hydrogen or C_1-6alkyl;

R³ represents hydrogen, cyano, nitro, Ci_-6alkyl, or Ci-₆alkoxyCi-₆alkyl;

and optical isomers, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof;

for the manufacturing of a medicament for the prevention and/or treatment of a condition or disease in an animal including a human being which condition or disease is affected or facilitated by the modulatory effect of Group I mGluR modulators or for the manufacturing of a medicament for enhancing cognition;

wherein

the term "aryl" represents phenyl or naphthyl, wherein the aryl group may be optionally substituted by one or more substituents selected independently from halogen, trifluoromethyl, Ci_-6alkyl, C₂-₆alkenyl, d-βalkoxy, Ci-₆alkoxy-Ci-₆alkyl, amino, hydroxy, nitro, cyano, Ci_₆alkoxycarbonyl, C_1-6alkylamino, Ci_-6alkylamino- C_1-6alkyl, di-C_1-6alkylamino, cycloC_3-i₂alkoxy, aryloxy, cycloC_3-i₂alkylamino, cycloCa-^alkyl-Cvealkylamino, di-Ci-₆alkylaminoC_1-6alkyl, arylamino, arylCi_-6alkylamino, arylCi_-6alkoxy, heteroarylCi_-6alkoxy, heteroarylamino, heteroarylCi-βalkylamino, pyrrolidino, piperidino, morpholino, hexamethyleneimino, -N(R⁵)-C(=O)-R⁴, -N(R⁵)-SO₂-R⁴, -N(R⁵)-C(=O)OR⁴, C(=O)-R⁴, C(=O)N(R⁵)₂, and a bivalent radical selected from -(CH₂)₃-, -(CH₂J₄-, -CH=CH-CH=CH-, -(CH₂J₃O-, -OCH₂O-, -0(CH₂J₂O-, and -0(CH₂J₃-;

the term "biaryl" represents biphenylene, including 4,4'-biphenylene, wherein one or both phenyl rings may be optionally substituted by one or more substituents independently selected from halogen, trifluoromethyl, Ci_-6alkyl, C_2-6alkenyl, C_1-6alkoxy, Ci-6alkoxyCi_-6alkyl, amino, hydroxy, nitro, cyano, d-βalkoxycarbonyl, Ci_-6alkylamino, C_1-6alkylamino-C_1-6alkyl. di-Ci_-6alkylamino, cycloC_3-i₂alkoxy, aryloxy, cycloCs-^alkylamino, cycloC_3--ι₂alkyl-Ci-₆alkylamino, di-CvβalkylaminoCi-βalkyl, arylamino, arylCi_-6alkylamino, heteroarylCi-βalkoxy, heteroarylamino, heteroarylCi_-6alkylamino, pyrrolidino, piperidino, morpholino, hexamethyleneimino, -N(R⁵)-C(=O)-R⁴, -N(R⁵)-SO₂-R⁴, -N(R⁵)-C(=O)OR⁴,

C(=O)-R⁴, C(=O)N(R⁵)₂, and a bivalent radical selected from -(CH₂J₃-, -(CH₂J₄-, -CH=CH-CH=CH-, -(CH₂J₃O-, -OCH₂O-, -0(CH₂J₂O-, and -0(CH₂J₃-; and

the term "heteroaryl" represents an aromatic 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen, or a bicyclic group comprising a 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen fused with a benzene ring or a 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen, wherein the heteroaryl group may be optionally substituted by one or more substituents selected independently from halogen, trifluoromethyl, Ci_-6alkyl, C_2-6alkenyl, C_1-6alkoxy, Ci_-6alkoxyCi-₆alkyl, amino, hydroxy, nitro, cyano, Ci_-6alkoxycarbonyl, C_1-6alkylamino, C-i-ealkylamino-C-i-ealkyl, di-C-ι_-6alkylamino, cycloC_3-i₂alkoxy, aryloxy, cycloC₃-i₂alkylamino, cycloC_3-12alkyl-Ci_-6alkylamino, di-Ci-ealkylaminoCi-βalkyl, arylamino, arylCi_-6alkylamino, heteroarylC-i-βalkoxy, heteroarylamino, heteroarylCi-_θalkylamino, pyrrolidino, piperidino, morpholino, hexamethyleneimino, -N(R⁵)-C(=O)-R⁴, -N(R⁵J-SO₂-R⁴, -N(R⁵)-C(=O)OR⁴, C(=O)-R⁴, C(=O)N(R⁵)₂, and a bivalent radical selected from -(CH₂J₃-, -(CH₂J₄-, -CH=CH-CH=CH-, -(CH₂J₃O-, -OCH₂O-, -0(CH₂J₂O-, and -0(CH₂J₃-;

wherein

R⁴ represents hydrogen, Ci_-6alkyl which may be optionally substituted with one or more halogen atoms, cycloC_3-i₂alkyl, aryl, heteroaryl, adamantyl, carboxyCi-βalkyl or CF₃; and R⁵ represents hydrogen, Ci_-6alkyl, cycloC_3-i₂alkyl, aryl, heteroaryl, adamantyl, carboxyCi_-6alkyl, alkylcarbonyl or CF₃.

Examples of heteroaryl include furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, benzofuryl, benzothienyl, indolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinolyl and isoquinolyl.

[0016] Such a method or such a use wherein the condition associated with abnormal glutamate neurotransmission, or wherein modulation of Group I mGluR receptors results in therapeutic benefit, is selected from: AIDS-related dementia, Alzheimer's disease, Creutzfeld-Jakob^'s syndrome, bovine spongiform encephalopathy (BSE) or other prion related infections, diseases involving mitochondrial dysfunction, diseases involving β-amyloid and/or tauopathy such as Down's syndrome, hepatic encephalopathy, Huntington's disease, motor neuron diseases such as amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), olivoponto-cerebellar atrophy, post-operative cognitive deficit (POCD), Parkinson's disease, Parkinson's dementia, mild cognitive impairment, dementia pugilistica, vascular and frontal lobe dementia, cognitive impairment, eye injuries or diseases, glaucoma, retinopathy, macular degeneration, head and brain and spinal cord injuries / trauma, hypoglycaemia, hypoxia, perinatal hypoxia, ischaemia, ischaemia resulting from cardiac arrest or stroke or bypass operations or transplants, convulsions, epileptic convulsions, epilepsies, temporal lobe epilepsy, glioma and other tumours, inner ear insult, inner ear insult in tinnitus, sound- or drug-induced inner ear insult, L-Dopa-induced and tardive dyskinesias, abuse and addiction, nicotine addiction, nicotine abuse, alcohol addiction, alcohol abuse, opiate addiction, opiate abuse, cocaine addiction, cocaine abuse, amphetamine addiction, amphetamine abuse, obesity addiction, anxiety and panic disorders, attention deficit hyperactivity disorder (ADHD), restless leg syndrome, hyperactivity in children, autism, dementia, dementia in Alzheimer's disease, dementia in Korsakoff syndrome, vascular dementia, dementia in HIV infections, major depressive disorder or depression, depression resulting from Borna virus infection, and bipolar manic-depressive disorder, drug tolerance, drug tolerance to opioids, movement disorders, dystonia, dyskinesia, L-Dopa-induced dyskinesia, tardive dyskinesia or dyskinesia in Huntington's disease, fragile-X syndrome,

Huntington's chorea, chorea, irritable bowel syndrome (IBS), migraine, multiple sclerosis, muscle spasms, pain, chronic pain and acute pain, inflammatory pain, neuropathic pain, allodynia, hyperalgesia, nociceptive pain, posttraumatic stress disorder, schizophrenia, positive or cognitive or negative symptoms of schizophrenia, spasticity, tinnitus, Tourette^'s syndrome, urinary incontinence, vomiting, pruritic conditions, pruritis, sleep disorders, micturition disorders, neuromuscular disorder in the lower urinary tract, gastroesophageal reflux disease

(GERD), lower esophageal sphincter (LES) disease, functional gastrointestinal disorders, dyspepsia, regurgitation, respiratory tract infection, bulimia nervosa, chronic laryngitis, asthma, reflux-related asthma, lung disease, eating disorders, obesity and obesity-related disorders, binge eating disorders, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, anxiety disorder, posttraumatic stress disorder, social phobia, substance-induced anxiety disorder, delusional disorder, schizoaffective disorder, schizophreniform disorder, substance-induced psychotic disorder, delirium, or for cognitive enhancement and/or neuroprotection.

[0017] Such a method or such a use wherein the condition associated with abnormal glutamate neurotransmission, or wherein modulation of Group I mGluR receptors results in therapeutic benefit, is selected from: neuropathic pain, diabetic neuropathic pain (DNP), cancer pain, pain related to rheumathic arthritis, inflammatory pain, L-Dopa-induced and tardive dyskinesias, Parkinson's disease, anxiety disorders, Huntington's chorea and/or epilepsy.

[0018] Specific compounds of Formula I within the present invention include but are not limited to:

Adamantan-1-yl-(2-quinolin-3-yl-cyclopropyl)-methanone,

Adamantan-1-yl-(2-pyridin-2-yl-cyclopropyl)-methanone,

Adamantan-1-yl-(2-pyridin-3-yl-cyclopropyl)-methanone,

Adamantan-1-yl-[2-(6-methoxy-pyridin-3-yl)-cyclopropyl]-methanone,

Adamantan-1-yl-[2-(2-methoxy-pyridin-3-yl)-cyclopropyl)-methanone,

Adamantan-1-yl-[2-(4-methoxy-3-methyl-phenyl)-cyclopropyl]-methanone,

Adamantan-1-yl-[2-(6-morpholin-4-yl-pyridin-3-yl)-cyclopropyl]-methanone,

Adamantan-1-yl-[2-(6-methoxy-quinolin-3-yl)-cyclopropyl]-methanone,

Adamantan-1-yl-(2-quinolin-2-yl-cyclopropyl)-methanone,

Adamantan-1-yl-[2-(4-methoxy-pyhdin-2-yl)-cyclopropyl]-methanone,

Adamantan-1-yl-[2-(6,7-dimethoxy-quinolin-3-yl)-cyclopropyl]-methanone,

Adamantan-1-yl-[2-(2,3-dihydro-[1 ,4]dioxino[2,3-g]quinolin-8-yl)-cyclopropyl]- methanone, Adamantan-1 -yl-(2-[1 ,3]dioxolo[4,5-g]quinolin-7-yl-cyclopropyl)-methanone, and Adamantan-1-yl-[2-(7-methoxy-quinolin-3-yl)-cyclopropyl]-methanone,

and optical isomers, polymorphs and pharmaceutically-acceptable acid and base addition salts, hydrates, and solvates thereof.

DETAILED DESCRIPTION OF THE INVENTION

[0019] For the purpose of the present invention, the carbon atom content of various hydrocarbon-containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix Cμj indicates a moiety of the integer "i" to the integer "j" carbon atoms, inclusive. Thus, for example, (Ci_-3)alkyl refers to alkyl of one to three carbon atoms, inclusive, (i.e., methyl, ethyl, propyl, and isopropyl), straight and branched forms thereof.

[002O] As used herein, the following definitions are applicable unless otherwise described, the term "Ci-₆alkyl" represents straight or branched chain alkyl groups which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, Ci_-6alkoxy, amino, hydroxy, Ci_-6alkylamino, and di-(Ci- ₆alkyl)amino. Examples of such alkyl groups include methyl, ethyl, n-propyl, 2- propyl, n-butyl, tert-butyl, -CF₃, -C₂F₅, -CBr₃ and -CCI₃. The term "C_2-6alkenyl" represents straight or branched chain alkenyl groups. The term "Ci_-6alkoxy" represents straight or branched chain -O-Ci_-6alkyl groups which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, amino, hydroxy, Ci-₆alkylamino and di-(C_1-6alkyl)amino. Examples of such alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, -OCF₃ and -OC2F5. The term "cycloCs-^alkyl" represents monocyclic or bicyclic, or tricyclic alkyl groups, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptyl and adamantanyl, which may be optionally substituted by one or more substituents, which may be the same or different, selected independently from halogen, trifluoromethyl, trifluoromethoxy, Ci_-6alkyl, C₂-₆alkenyl, Ci_-6alkoxy, amino, hydroxy, nitro, cyano, cyanomethyl, Ci_-6alkoxycarbonyl, Ci_-6alkylamino, and di-(Ci- ₆alkyl)amino, Ci_-6alkylcarbonylamino, and Ci_-6alkylenedioxy. The term "aryl" represents phenyl or naphthyl, wherein the phenyl or naphthyl group is optionally substituted by one or more substituents, which may be the same or different, selected independently from halogen, trifluoromethyl, trifluoromethoxy, C-ι_-6alkyl, hydroxyC_1-6alkyl C₂-₆alkenyl, Ci_-6alkoxy, amino, hydroxy, nitro, cyano, cyanomethyl, Ci_-6alkoxycarbonyl, Ci_-6alkylcarbonyloxy, Ci_-6alkylamino, di-(d- ₆alkyl)amino, Ci_-6alkylcarbonylamino, aminocarbonyl, N-Ci-βalkylaminocarbonyl, di-N,N-Ci_-6alkylaminocarbonyl, pyrrolidinyl, piperidinyl, morpholinyl, and piperazinyl, cycloC_3-i₂alkyl or optionally Ci_-6alkylenedioxy. The term "heteroaryl" represents an aromatic 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen, or a bicyclic group comprising a 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen fused with a benzene ring or a 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen, wherein the heteroaryl group may be optionally substituted by one or more substituents, which may be the same or different, selected independently from halogen, trifluoromethyl, trifluoromethoxy, C_1-6alkyl, hydroxyC_1-6alkyl,

C₂-₆alkenyl, Ci_-6alkoxy, amino, hydroxy, nitro, cyano, Ci-βalkoxycarbonyl, C_1-6alkoxycarbonyloxy, Ci_-6alkylamino, and di-(C_1-6alkyl)amino,

C_1-6alkylcarbonylamino, aminocarbonyl, N-Ci-ealkylaminocarbonyl, di-N.N-C-i-ealkylaminocarbonyl, pyrrolidinyl, piperidinyl, morpholinyl, cycloC_3-i₂alkyl, Ci_-6alkylenedioxy and aryl. Representative heteroaryl groups include furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, benzofuryl, benzothienyl, indolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinolinyl and isoquinolinyl; the term "heterocyclyl" represents a saturated or unsaturated non-aromatic 3 to 12 membered ring comprising one to four heteroatoms selected from oxygen, sulfur and nitrogen, and a saturated or unsaturated non-aromatic bicyclic ring system having 3 to 12 members comprising one to six heteroatoms selected from oxygen, sulfur and nitrogen, wherein the heterocyclic ring or ring system is optionally substituted by one or more substituents selected independently from a halogen, trifluoromethyl, Ci_-6alkyl, C_2-6alkenyl, C-ι_-6alkoxy, amino, hydroxy, nitro, cyano, Ci-βalkoxycarbonyl, Ci_-6alkylamino, di-Ci_-6alkylamino, pyrrolidinyl, piperidinyl, morpholinyl, pyridinyl, and aryl; examples of such heterocyclyl groups include piperidinyl, morpholinyl, pyrrolidinyl, or piperazinyl, wherein the heterocyclic ring or ring system is linked to the group to which it is attached optionally via nitrogen or a carbon atom. The term "halogen" represents fluorine, chlorine, bromine and iodine.

[0021] The compounds of the present invention are usually named according to the IUPAC or CAS nomenclature system. Abbreviations which are well known to one of ordinary skill in the art may be used (e.g. "Ph" for phenyl, "Me" for methyl,

"Et" for ethyl, "h" for hour or hours, and "rt" for room temperature). [0022] The term "analog" or "derivative" is used herein in the conventional pharmaceutical sense, to refer to a molecule that structurally resembles a reference molecule, but has been modified in a targeted and controlled manner to replace one or more specific substituents of the referent molecule with an alternate substituent, thereby generating a molecule which is structurally similar to the reference molecule. Synthesis and screening of analogs (e.g., using structural and/or biochemical analysis), to identify slightly modified versions of a known compound which may have improved or biased traits (such as higher potency and/or selectivity at a specific targeted receptor type, greater ability to penetrate blood-brain barriers, fewer side effects, etc.) is a drug design approach that is well known in pharmaceutical chemistry.

[0023] In addition, using methods known to those skilled in the art, analogs and derivatives of the compounds of the invention can be created which have improved therapeutic efficacy, i.e., higher potency and/or selectivity at a specific targeted receptor type, either greater or lower ability to penetrate mammalian blood-brain barriers (e.g., either higher or lower blood-brain barrier permeation rate), fewer side effects, etc.

[0024] The phrase "pharmaceutically acceptable", as used in connection with compositions of the invention, refers to molecular entities and other ingredients of such compositions that are physiologically tolerable and do not typically produce untoward reactions when administered to a mammal (e.g., human). Preferably, as used herein, the term "pharmaceutically acceptable" means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in mammals, and more particularly in humans.

[0025] Compounds of the present invention may be in the form of pharmaceutically acceptable salts. "Pharmaceutically acceptable salts" refers to those salts which possess the biological effectiveness and properties of the parent compound and which are not biologically or otherwise undesirable. The nature of the salt is not critical, provided that it is non-toxic and does not substantially interfere with the desired pharmacological activity.

[0026] It will be appreciated by those skilled in the art that compounds of the invention having a chiral center may exist in and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism. It is to be understood that the present invention encompasses any racemic, optically active, polymorphic, tautomeric, or stereoisomeric form, or mixture thereof, of a compound of the invention, which possesses the useful properties described herein.

[0027] The compounds of general Formula I may be prepared by reacting propenones of formula 3 with dimethylsulfoxonium methylide in an appropriate solvent (Scheme 1). The solvent is a polar solvent, (e.g., dimethylsulfoxide). Dimethylsulfoxonium methylide is prepared by reacting trimethylsulfoxonium salt, such as iodide with a strong base, such as sodium hydride, powdered sodium hydroxide, or KOBu-t, in dimethylsulfoxide. The propenones of formula 3 may be prepared using standard chemistry, for example, reacting a compound of formula 1, where R¹ and R² are as defined above with 1-adamantan-1-yl-ethanone in an appropriate solvent in the presence of base.

Scheme 1 : Synthetic strategy towards compounds of the general Formula I.

[0028] It will be appreciated that in the above transformations it may be necessary or desirable to protect any sensitive groups in the molecule of the compound in question in order to avoid undesirable side reactions.

[0029] It will be apparent to those skilled in the art that the described synthetic procedures are merely representative in nature and that alternative synthetic processes are known to one of ordinary skill in organic chemistry. EXPERIMENTAL PART

[0030] The compounds and their preparation of the present invention will be better understood in connection with the following examples, which are intended as an illustration of and not a limitation upon the scope of the invention.

[0031] Hereinafter, "NaOH" is defined as sodium hydroxide, "HCI" as hydrochloric acid, "DMSO" as dimethylsulfoxide, and "TMS" as tetramethylsilane.

Examples

[0032] The compounds and their preparation of the present invention will be better understood in connection with the following examples, which are intended as an illustration of and not a limitation upon the scope of the invention.

Synthesis of 1-adamantan-1-yl-propenones

General Procedure

[0033] To a solution of 1-adamantan-1-yl-ethanone (1 mmol) in ethanol (5 ml) is added aryl-carbaldehyde (1 mmol) and 1 N aqueous NaOH (1.3 ml). The mixture is stirred for 36 h, then brine (20 ml) is added and the whole is extracted with dichloromethane (30 ml). The organic phase is washed with brine, dried over anhydrous potassium carbonate, filtered and concentrated under reduced pressure. The residue is purified by flash chromatography on silica gel to give the title compound. Preparation 1

[E)-I -Adamantan- 1 -yl-3-quinolin-3-yl-propenone

[0034] In close analogy to the general procedure, 1-adamantan-1-yl-ethanone is reacted with quinoline-3-carbaldehyde to give the title compound as a colorless solid.

Preparation 2

(E)- 1 -Adamantan- 1 -yl-3-(4-methoxy-3-methyl-phenyl)-propenone

[0035] In close analogy to the general procedure, 1-adamantan-1-yl-ethanone is reacted with 4-methoxy-3-methyl-benzaldehyde to yield the title compound as a colorless solid.

Preparation 3

(E)- 1 -Adamantan- 1 -yl-3-pyridin-2-yl-propenone

[0036] In close analogy to the general procedure, 1-adamantan-1-yl-ethanone is reacted with pyridine-2-carbaldehyde to give the title compound. Preparation 4

(E)- 1 -Adamantan- 7 -yl-3~pyridin-3-yl-propenone

[0037] In close analogy to the general procedure, 1-adamantan-1-yl-ethanone is reacted with pyridine-3-carbaldehyde to give the title compound.

Preparation 5

(E)- 1 -Adamantan- 1 -yl-3-(6-methoxy-pyridin-3-yl)-propenone

[0038] In close analogy to the general procedure, 1-adamantan-1-yl-ethanone is reacted with 6-methoxy-pyridine-3-carbaldehyde to give the title compound.

Preparation 6

(E)-1-Adamantan-1-yl-3-(2-methoxy-pyridin-3-yl)-propenone

[0039] In close analogy to the general procedure, 1-adamantan-1-yl-ethanone is reacted with 2-methoxy-pyridine-3-carbaldehyde to give the title compound. Preparation 7

(E)-1-Adamantan-1-yl-3-(6-morpholin-4-yl-pyridin-3-yl)-propenone

[0040] In close analogy to the general procedure, 1-adamantan-1-yl-ethanone is reacted with 6-morpholin-4-yl-pyridine-3-carbaldehyde to give the title compound.

Preparation 8

(E)- 1 -A damantan- 1 -yl-3-(6-methoxy-quinolin-3-yl)-propenone

[0041] In close analogy to the general procedure, 1-adamantan-1-yl-ethanone is reacted with 6-methoxy-quinoline-3-carbaldehyde to give the title compound.

Preparation 9

(E)- 1 -Adamantan- 1 -yl-3-quinolin-2-yl-propenone

[0042] In close analogy to the general procedure, 1-adamantan-1-yl-ethanone is reacted with quinoline-2-carbaldehyde to give the title compound. Preparation 10

(E)-1-Adamantan-1-yl-3-(4-methoxy-pyridin-3-yl)-propenone

[0043] In close analogy to the general procedure, 1-adamantan-1-yl-ethanone is reacted with 4-methoxy-pyridine-3-carbaldehyde to give the title compound.

Preparation 11

(E)-1-Adamantan-1-yl-3-(6,7-dimethoxy-quinolin-3-yl)-propenone

[0044] In close analogy to the general procedure, 1-adamantan-1-yl-ethanone is reacted with 6,7-dimethoxy-quinoline-3-carbaldehyde [Sato, I.; Nakao, T; Sugie, R.; Kawasaki, T.; Soai, K. Synthesis, 2004, 9, 1419-1428.] to give the title compound.

Preparation 12

(E)- 1 -Adamantan- 1 -yl-3-(2, 3-dihydro-[1 , 4]dioxino[2, 3-g]quinolin-8-yl)-propenone

[0045] In close analogy to the general procedure, 1-adamantan-1-yl-ethanone is reacted with 2,3-dihydro-benzo[1 ,4]dioxine-6-carbaldehyde [Sato, I.; Nakao, T;

Sugie, R.; Kawasaki, T.; Soai, K. Synthesis, 2004, 9, 1419-1428.] to yield the title compound as a colorless solid.

Physical characteristics are as follows:

Mp 125-127 ⁰C; ¹H NMR (CDCI₃, TMS) δ: 1.75, 1.87, 2.07, 4.28, 6.85, 7.00, 7.09,

7.11 , and 7.56.

Preparation 13

(E)-1-Adamantan-1-yl-3-[1,3]dioxolo[4,5-g]quinolin-7-yl-propenone

[0046] In close analogy to the general procedure, 1-adamantan-1-yl-ethanone is reacted with [1 ,3]dioxolo[4,5-g]quinoline-7-carbaldehyde [prepared according to Sato, I.; Nakao, T; Sugie, R.; Kawasaki, T.; Soai, K. Synthesis, 2004, 9, 1419- 1428.] to give the title compound.

Preparation 14

(E)-1-Adamantan-1-yl-3-(7-methoxy-quinolin-3-yl)-propenone

[0047] In close analogy to the general procedure, 1-adamantan-1-yl-ethanone is reacted with 7-methoxy-quinoline-3-carbaldehyde [Sato, I.; Nakao, T; Sugie, R.; Kawasaki, T.; Soai, K. Synthesis, 2004, 9, 1419-1428.] to give the title compound.

Example 1

Adamantan-1-yl-(2-quinolin-3-yl-cyclopropyl)-methanone hydrochloride

[0048] To a solution of sodium hydride (60% dispersion in oil, 33 mg, 0.82 mmol) in dry DMSO (4 ml) is added trimethylsulfoxonium iodide (180 mg, 0.82 mmol). After stirring for 15 min, a solution of the 1-adamantan-1-yl-3-quinolin-3-yl- propenone (200 mg, 0.63 mmol) in dry DMSO (10 ml) is added dropwise. The reaction mixture was stirred at room temperature overnight. Then it is quenched with water (10 ml) and extracted with methylene chloride (3 x 10 ml). The combined extracts are dried over magnesium sulphate and evaporated under reduced pressure to give a crude product, which is purified by flash chromatography. Elution with petroleum ether-ethyl acetate (10 : 1 , then 4 : 1) yields adamantan-1-yl-(2-quinolin-3-yl-cyclopropyl)-methanone (162 mg, 78 %) as a colorless solid. The product is dissolved in diethyl ether and a dry hydrogen chloride solution in diethyl ether is added. The mixture is stirred for 15 min and evaporated under reduced pressure to yield a white solid, which is triturated with anhydrous diethyl ether, filtered and washed with ether to yield the title compound (150 mg, 83 %) as a colorless solid. Physical characteristics are as follows: Mp 178-181 ⁰C; ¹H NMR (CDCI₃, TMS) δ: 1.46-1.56, 1.80-1.84 , 1.74, 1.88, 2.08, 2.56-2.73, 7.77, 7.92, 7.96, 8.32, 8.56, and 8.73.

Example 2

Adamantan-1-yl-(2-pyridin-2-yl-cyclopropyl)-methanone hydrochloride

[0049] In close analogy to the procedure described in Example 1, (E)-1- adamantan-1-yl-3-pyridin-2-yl-propenone is reacted with dimethylsulfoxonium methylide to yield the title compound as a colorless solid.

Physical characteristics are as follows:

Mp 48-50 ⁰C; ¹H NMR (CDCI₃, TMS) δ: 1.74, 1.79-1.84, 1.91 , 2.06, 2.20-2.29,

2.76-2.85, 3.72-3.82, 7.68, 7.76, 8.23, and 8.69.

Example 3

Adamantan- 1 -yl-(2-pyridin-3-yl-cyclopropyl)-methanone hydrochloride

[005O] In close analogy to the procedure described in Example 1, (E)-1- adamantan-1-yl-3-pyridin-3-yl-propenone is reacted with dimethylsulfoxonium methylide to yield the title compound as a colorless solid. Physical characteristics are as follows: Mp 90-94 ⁰C; ¹H NMR (CDCI₃, TMS) δ: 1.38-1.48, 1.66-1.80, 1.84-1.85, 2.08, 2.56-2.64, 7.84, 8.19, 8.47, and 8.57-8.62.

Example 4

Adamantan-1-yl-[2-(6-methoxy-pyridin-3-yl)-cyclopropyl]-methanone

[0051] In close analogy to the procedure described in Example 1 , (E)-1- adamantan-1-yl-3-(6-methoxy-pyridin-3-yl)-propenone is reacted with dimethylsulfoxonium methylide to yield the title compound as a colorless solid. Physical characteristics are as follows:

Mp 106-108 ⁰C; ¹H NMR (CDCI₃, TMS) δ: 1.25, 1.54-1.63, 1.64-1.73, 1.85-1.86, 2.05, 2.32, 3.91 , 6.68, 7.29, and 7.99.

Example 5

Adamantan-1-yl-[2-(2-methoxyφyridin-3-yl-cyclopropyl)]-methanone hydrochloride

[0052] In close analogy to the procedure described in Example 1 , (E)-1- adamantan-1-yl-3-(2-methoxy-pyridin-3-yl)-propenone is reacted with dimethylsulfoxonium methylide to yield the title compound as a colorless solid. Physical characteristics are as follows: Mp 112-114 ⁰C; ¹H NMR (CDCI₃, TMS) δ: 1.32-1.42, 1.59-1.71 , 1.68-1.80, 1.84- 1.85, 2.07, 2.27-2.36, 2.48-2.58, 4.52, 7.23, 7.72, and 7.28.

Example 6

Adamantan-1-yl-[2-(4-methoxy-3-methyl-phenyl)-cyclopropyl]-methanone

[0053] In close analogy to the procedure described in Example 1, (E)-1- adamantan-1-yl-3-(-4-methoxy-3-methylphenyl)-propenone is reacted with dimethylsulfoxonium methylide to yield the title compound as a colorless solid. Physical characteristics are as follows:

Mp 70-72 ⁰C; ¹H NMR (CDCI₃, TMS) δ: 1.26, 1.57, 1.71 , 1.86, 2.04, 2.20, 2.31 , 3.81 , 6.74, 6.87, and 6.92.

Example 7

Adamantan-1-yl-[2-(6-morpholin-4-yl-pyridin-3-yl)-cyclopropyl]-methanone

[0054] In close analogy to the procedure described in Example 1 , (E)-1- adamantan-1-yl-3-(6-morpholin-4-yl-2-pyridin-3-yl)-propenone is reacted with dimethylsulfoxonium methylide to yield the title compound as a colorless solid. Physical characteristics are as follows: Mp 139-141 ⁰C; ¹H NMR (CDCI₃, TMS) δ: 1.20-1.27, 1.55-1.65, 1.64-1.82, 1.86, 2.05, 2.24-2.32, 3.44-3.49, 3.79-3.85, 6.59, 7.25, and 8.04.

Example 8

Adamantan-1-yl-[2-(6-methoxy-quinolin-3-yl)-cyclopropyl]-methanone

[0055] In close analogy to the procedure described in Example 1 , (E)-1- adamantan-1-yl-3-(6-methoxy-quinolin-3-yl)-propenone is reacted with dimethylsulfoxonium methylide to yield the title compound as a colorless solid. Physical characteristics are as follows:

Mp 160-162 ⁰C. ¹H NMR (CDCI₃, TMS) δ: 1.43-1.52, 1.65-1.80, 1.87-1.89, 2.06, 2.47-2.58, 3.93, 7.02, 7.32, 7.70, 7.96, and 8.59.

Example 9

Adamantan- 1 -yl-(2-quinolin-2-yl-cyclopropyl)-methanone

[0056] In close analogy to the procedure described in Example 1, (E)-1- adamantan-1-yl-3-(quinolin-2-yl)-propenone is reacted with dimethylsulfoxonium methylide to yield the title compound as a colorless solid. Physical characteristics are as follows: Mp 120-122 ⁰C; ¹H NMR (CDCI₃, TMS) δ: 1.61-1.67, 1.77-1.84, 1.71 , 1.88, 2.03, 2.60-2.69, 2.88-2.94, 7.31 , 7.46, 7.67, 7.76, 7.98, and 8.03.

Example 10

Adamantan-1-yl-[2-(4-methoxy-pyridin-2-yl)-cyclopropyl]-methanone

[0057] In close analogy to the procedure described in Example 1, (E)-1- adamantan-1-yl-3-(4-methoxy-pyridin-2-yl)-propenone is reacted with dimethylsulfoxonium methylide to yield the title compound as a colorless solid. Physical characteristics are as follows:

Mp 101-104 ⁰C; ¹H NMR (CDCI₃, TMS) δ: 1.48-1.64, 1.70-1.72, 1.86, 2.03, 2.37- 2.47, 2.76-2.84, 3.84, 6.63, 6.75, and 8.28.

Example 11

Adamantan- 1 -yl-[2-(6, Y-dimethoxy-quinolin-S-ylj-cyclopropylJ-methanone

[0058] In close analogy to the procedure described in Example 1, (E)-1- adamantan-1-yl-3-(6,7-dimethoxy-quinolin-3-yl)-propenone is reacted with dimethylsulfoxonium methylide to yield the title compound. Physical characteristics are as follows: ¹H NMR (CDCI₃, TMS) δ: 1.40-1.49, 1.66-1.80, 1.87-1.89, 2.05, 2.42-2.56, 4.00, 4.03, 7.00, 7.39, 7.65, and 8.54.

Example 12

Adamantan- 1 -yl-[2-(2, 3-dihydro-[1 , 4]dioxino[2, 3-g]quinolin-8-yl)-cyclopropyl]- methanone

[0059] In close analogy to the procedure described in Example 1, (E)-1- adamantan-1-yl-3-(2,3-dihydro[1 ,4]dioxino[2,3-g]quinolin-8-yl)-propenone is reacted with dimethylsulfoxonium methylide to yield the title compound. Physical characteristics are as follows:

¹H NMR (CDCI₃, TMS) δ: 1.39-1.48, 1.72, 1.88, 2.04, 2.40-2.54, 4.37, 7.15, 7.50, 7.61, and 8.55.

Example 13

Adamantan-1-yl-(2-[1,3]dioxolo[4,5-g]quinolin-7-yl-cyclopropyl)-methanone

[0060] In close analogy to the procedure described in Example 1, (E)-1- adamantan-1-yl-3-[1 ,3]dioxolo[4,5-g]quinolin-7-yl)-propenone is reacted with dimethylsulfoxonium methylide to yield the title compound as a colorless solid. Physical characteristics are as follows:

Mp 173-176 ⁰C; ¹H NMR (CDCI₃, TMS) δ: 1.43-1.48, 1.58-1.72, 1.65, 1.88, 2.05,

2.41-2.55, 6.10, 7.00, 7.35, 7.62, and 8.53.

Example 14

Adamantan-1-yl-[2-(7-methoxy-quinolin-3-yl)-cyclopropyl]-methanone

[0061] In close analogy to the procedure described in Example 1 , (E)-1- adamantan-1-yl-3-(7-methoxy-quinolin-3-yl)-propenone is reacted with dimethylsulfoxonium methylide to yield the title compound as a colorless solid. Physical characteristics are as follows:

Mp 134-136 ⁰C; ¹H NMR (CDCI₃, TMS) δ: 1.41-1.50, 1.72, 1.89, 2.05, 2.42-2.58, 3.95, 7.19, 7.39, 7.64, 7.72, and 8.67.

[0062] Pure stereoisomeric forms of the compounds and the intermediates of this invention may be obtained by the application of art-known procedures. Diastereomers may be separated by physical separation methods such as selective crystallization and chromatographic techniques, e.g. liquid chromatography using chiral stationary phases. Enantiomers may be separated from each other by selective crystallization of their diastereomeric salts with optically active acids. Alternatively, enantiomers may be separated by chromatographic techniques using chiral stationary phases. Said pure stereoisomeric forms may also be derived from the corresponding pure stereoisomer^ form of appropriate starting materials, provided that the reaction occurs stereoselective^. Stereoisomeric forms of Formula I are obviously intended to be included within the scope of this invention.

ADDITION SALTS

[0063] For therapeutic use, salts of the compounds of Formula I are those wherein the counter ion is pharmaceutically acceptable. However, salts of acids and bases, which are non-pharmaceutically acceptable, may also find use, for example, in the preparation and purification of pharmaceutically acceptable compounds. All salts whether pharmaceutically acceptable or not are included within the ambit of the present invention. The pharmaceutically acceptable salts as mentioned above are meant to comprise the therapeutically active non-toxic salt forms, which the compounds of Formula I are able to form. The latter can conveniently be obtained by treating the base form with such appropriate acids as inorganic acids, e.g. hydrohalic acids such as hydrochloric, hydrobromic and the like; sulfuric acid; nitric acid; phosphoric acid and the like; or organic acids such as acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, oxopropanoic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, 2-hydroxy-1 ,2,3- propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4- methylbenzenesulfonic, cyclohexanesulfonic, 2-hydroxybenzoic, 4-amino-2- hydroxybenzoic and the like acids. Conversely, the salt form can be converted by treatment with alkali into the free base form. PHARMACEUTICAL COMPOSITIONS

[0064] The active ingredients of the invention, together with one or more conventional adjuvants, carriers, or diluents, may be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as coated or uncoated tablets or filled capsules, or liquids, such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use; in the form of suppositories or capsules for rectal administration or in the form of sterile injectable solutions for parenteral (including intravenous or subcutaneous) use. Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional or new ingredients in conventional or special proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed. Tablets containing one (1 ) to one hundred (100) milligrams of active ingredient or, more broadly, zero point five (0.5) to five hundred (500) milligrams per tablet, are accordingly suitable representative unit dosage forms.

[0065] The term "carrier" applied to pharmaceutical compositions of the invention refers to a diluent, excipient, or vehicle with which an active compound is administered. Such pharmaceutical carriers can be sterile liquids, such as water, saline solutions, aqueous dextrose solutions, aqueous glycerol solutions, and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. A.R. Gennaro, 20^th Edition, describes suitable pharmaceutical carriers in "Remington: The Science and Practice of Pharmacy".

METHOD OF TREATING

[0066] Due to their high degree of activity and their low toxicity, together presenting a most favorable therapeutic index, the active principles of the invention may be administered to a subject, e.g., a living animal (including a human) body, in need thereof, for the treatment, alleviation, or amelioration, palliation, or elimination of an indication or condition which is susceptible thereto, or representatively of an indication or condition set forth elsewhere in this application, preferably concurrently, simultaneously, or together with one or more pharmaceutically-acceptable excipients, carriers, or diluents, especially and preferably in the form of a pharmaceutical composition thereof, whether by oral, rectal, or parental (including intravenous and subcutaneous) or in some cases even topical route, in an effective amount. Suitable dosage ranges are 1-1000 milligrams daily, preferably 10-500 milligrams daily, and especially 50-500 milligrams daily, depending as usual upon the exact mode of administration, form in which administered, the indication toward which the administration is directed, the subject involved and the body weight of the subject involved, and the preference and experience of the physician or veterinarian in charge.

[0067] The term "therapeutically effective" applied to dose or amount refers to that quantity of a compound or pharmaceutical composition that is sufficient to result in a desired activity upon administration to a living animal body in need thereof. [0068] The active agents of the present invention may be administered orally, topically, parenterally, or mucosally (e.g., buccally, by inhalation, or rectally) in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers. It is usually desirable to use the oral route. The active agents may be administered orally in the form of a capsule, a tablet, or the like (see Remington: The Science and Practice of Pharmacy, 20^th Edition). The orally administered medicaments may be administered in the form of a time-controlled release vehicle, including diffusion-controlled systems, osmotic devices, dissolution-controlled matrices, and erodible/degradable matrices.

[0069] For oral administration in the form of a tablet or capsule, the active drug component may be combined with a non-toxic, pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, sucrose, glucose, mannitol, sorbitol and other reducing and non-reducing sugars, microcrystalline cellulose, calcium sulfate, or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, or silica, steric acid, sodium stearyl fumarate, glyceryl behenate, calcium stearate, and the like); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulphate), coloring and flavoring agents, gelatin, sweeteners, natural and synthetic gums (such as acacia, tragacanth or alginates), buffer salts, carboxymethylcellulose, polyethyleneglycol, waxes, and the like. For oral administration in liquid form, the drug components may be combined with nontoxic, pharmaceutically acceptable inert carriers (e.g., ethanol, glycerol, water), suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats), emulsifying agents (e.g., lecithin or acacia), non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol or fractionated vegetable oils), preservatives (e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid), and the like. Stabilizing agents such as antioxidants (BHA, BHT, propyl gallate, sodium ascorbate, citric acid) may also be added to stabilize the dosage forms.

[0070] The tablets may be coated by methods well known in the art. The compositions of the invention may be also introduced in beads, microspheres or microcapsules, e.g., fabricated from polyglycolic acid/lactic acid (PGLA). Liquid preparations for oral administration may take the form of, for example, solutions, syrups, emulsions or suspensions, or they may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Preparations for oral administration may be suitably formulated to give controlled or postponed release of the active compound.

[0071] The active drugs may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines, as is well known.

[0072] Drugs of the invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. Active drugs may also be coupled with soluble polymers as targetable drug carriers. Such polymers include polyvinyl-pyrrolidone, pyran copolymer, polyhydroxy-propyl methacrylamide-phenol, polyhydroxy-ethyl-aspartamide- phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, active drug may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polyhydropyrans, polycyanoacrylat.es, and cross-linked or amphipathic block copolymers of hydrogels.

[0073] For administration by inhalation, the therapeutics according to the present invention may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, e.g., gelatin for use in an inhaler or insufflator can be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

[0074] The formulations of the invention may be delivered parenterally, i.e., by intravenous (i.v.), intracerebroventricular (i.c.v.), subcutaneous (s.c), intraperitoneal (i.p.), intramuscular (i.m.), subdermal (s.d.), or intradermal (i.d.) administration, by direct injection, via, for example, bolus injection or continuous infusion. Formulations for injection can be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions can take such forms as excipients, suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient can be in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0075] Compositions of the present invention may also be formulated for rectal administration, e.g., as suppositories or retention enemas (e.g., containing conventional suppository bases such as cocoa butter or other glycerides).

[0076] The compositions may, if desired, be presented in a pack or dispenser device, which may contain one or more unit dosage forms containing the active ingredient and/or may contain different dosage levels to facilitate dosage titration. The pack may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. Compositions of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

[0077] As disclosed herein, the dose of the components in the compositions of the present invention is determined to ensure that the dose administered continuously or intermittently will not exceed an amount determined after consideration of the results in test animals and the individual conditions of a patient. A specific dose naturally varies depending on the dosage procedure, the conditions of a patient or a subject animal such as age, body weight, sex, sensitivity, feed, dosage period, drugs used in combination, seriousness of the disease. The appropriate dose and dosage times under certain conditions can be determined by the test based on the above-described indices but may be refined and ultimately decided according to the judgment of the practitioner and each patient's circumstances (age, general condition, severity of symptoms, sex, etc.) according to standard clinical techniques.

[0078] Toxicity and therapeutic efficacy of the compositions of the invention can be determined by standard pharmaceutical procedures in experimental animals, e.g., by determining the LD₅₀ (the dose lethal to 50% of the population) and the ED₅₀ (the dose therapeutically effective in 50% of the population). The dose ratio between therapeutic and toxic effects is the therapeutic index and it may be expressed as the ratio LD_5O/ED₅o. Compositions that exhibit large therapeutic indices are preferred.

EXAMPLES OF REPRESENTATIVE PHARMACEUTICAL COMPOSITIONS

[0079] With the aid of commonly used solvents, auxiliary agents and carriers, the reaction products can be processed into tablets, coated tablets, capsules, drip solutions, suppositories, injection and infusion preparations, and the like and can be therapeutically applied by the oral, rectal, parenteral, and additional routes. Representative pharmaceutical compositions follow.

(a) Tablets suitable for oral administration, which contain the active ingredient, may be prepared by conventional tabletting techniques. (b) For suppositories, any usual suppository base may be employed for incorporation thereinto by usual procedure of the active ingredient, such as a polyethyleneglycol which is a solid at normal room temperature but which melts at or about body temperature.

(c) For parental (including intravenous and subcutaneous) sterile solutions, the active ingredient together with conventional ingredients in usual amounts are employed, such as for example sodium chloride and double-distilled water q.s., according to conventional procedure, such as filtration, aseptic filling into ampoules or IV-drip bottles, and autoclaving for sterility.

[0080] Other suitable pharmaceutical compositions will be immediately apparent to one skilled in the art.

FORMULATION EXAMPLES

[0081] The following examples are again given by way of illustration only and are not to be construed as limiting.

EXAMPLE 1

Tablet Formulation

A suitable formulation for a tablet containing 10 milligrams of active ingredient is as follows: mg

Active Ingredient 10

Lactose 61

Micro-crystalline Cellulose 25

Talcum 2 Magnesium stearate 1

Colloidal silicon dioxide 1

EXAMPLE 2

Tablet Formulation Another suitable formulation for a tablet containing 100 mg is as follows:

mg

Active Ingredient 100

Polyvinylpyrrolidone, crosslinked 10

Potato starch 20

Polyvinylpyrrolidone 19

Magnesium stearate 1 Microcrystalline Cellulose 50

Film coated and colored.

The film coating material consists of:

Hypromellose 10

Microcryst. Cellulose 5

Talcum 5

Polyethylene glycol 2

Color pigments 5

EXAMPLE 3

Capsule Formulation

A suitable formulation for a capsule containing 50 milligrams of active ingredient is as follows:

mg

Active Ingredient 50

Corn starch 26

Dibasic calcium phosphate 50

Talcum 2

Colloidal silicon dioxide 2 filled in a gelatin capsule.

EXAMPLE 4

Solution for injection A suitable formulation for an injectable solution is as follows:

Active Ingredient mg 10

Sodium chloride mg q.s.

Water for Injection ml_ add 1.0

EXAMPLE 5

Liquid oral formulation

A suitable formulation for 1 liter of a an oral solution containing 2 milligrams of active ingredient in one milliliter of the mixture is as follows:

mg

Active Ingredient 2

Saccharose 250

Glucose 300 Sorbitol 150

Orange flavor 10

Colorant q.s.

Purified water add 1000 ml_

EXAMPLE 6

Liquid oral formulation

Another suitable formulation for 1 liter of a liquid mixture containing 20 milligrams of active ingredient in one milliliter of the mixture is as follows:

G

Active Ingredient 20.00

Tragacanth 7.00

Glycerol 50.00

Saccharose 400.00

Methylparaben 0.50

Propylparaben 0.05

Black currant-flavor 10.00

Soluble Red color 0.02

Purified water add 1000 mL EXAMPLE 7

Liquid oral formulation

Another suitable formulation for 1 liter of a liquid mixture containing 2 milligrams of active ingredient in one milliliter of the mixture is as follows:

Active Ingredient 2

Saccharose 400

Bitter orange peel tincture 20

Sweet orange peel tincture 15

Purified water add 1000 mL

EXAMPLE 8

Aerosol formulation 8O g aerosol solution contain:

Active Ingredient 10

Oleic acid 5 Ethanol 81

Purified Water 9

Tetrafluoroethane 75

15 ml of the solution are filled into aluminum aerosol cans, capped with a dosing valve, purged with 3.0 bar.

EXAMPLE 9

TDS formulation 100 g solution contain:

Active Ingredient 10.0

Ethanol 57.5

Propyleneglycol 7.5

Dimethylsulfoxide 5.0

Hydroxyethylcellulose 0.4

Purified water 19.6

1.8 ml of the solution are placed on a fleece covered by an adhesive backing foil. The system is closed by a protective liner which will be removed before use. EXAMPLE 10

Nanoparticle formulation 10 g of polybutylcyanoacrylate nanoparticles contain:

Active Ingredient 1.00

Poloxamer 0.10

Butylcyanoacrylate 8.75

Mannitol 0.10

Sodium chloride 0.05

Polybutylcyanoacrylate nanoparticles are prepared by emulsion polymerization in a water/0.1 N HCI/ethanol mixture as polymerizsation medium. The nanoparticles in the suspension are finally lyophilized under vacuum.

PHARMACOLOGY

[0082] The active principles of the present invention, and pharmaceutical compositions thereof and method of treating therewith, are characterized by unique and advantageous properties, rendering the "subject matter as a whole", as claimed herein, unobvious. The compounds and pharmaceutical compositions thereof exhibit, in standard accepted reliable test procedures, the following valuable properties and characteristics:

METHODS

BINDING ASSAYS FOR THE CHARACTERIZATION OF mGluR5 ANTAGONIST PROPERTIES

[³H]IVIPEP (2-methyl-6-(phenylethynyl)pyridine) binding to transmembrane allosteric modulatory sites of mGluR5 receptors in cortical membranes

Preparation of rat cortical membranes:

[0083] Male Sprague-Dawley rats (200-250 g) are decapitated and their brains are removed rapidly. The cortex is dissected and homogenized in 20 volumes of ice- cold 0.32 M sucrose using a glass-Teflon homogenizer. The homogenate is centrifuged at 1000xg for 10 min. The pellet is discarded and the supernatant centrifuged at 20,000xg for 20 min. The resulting pellet is re-suspended in 20 volumes of distilled water and centrifuged for 20 min at 8000xg. Then the supernatant and the buffy coat are centrifuged at 48,000xg for 20 min in the presence of 50 mM Tris-HCI, pH 8.0. The pellet is then re-suspended and centrifuged two to three more times at 48,000xg for 20 min in the presence of 50 mM Tris-HCI, pH 8.0. All centrifugation steps are carried out at 4°C. After resuspension in 5 volumes of 50 mM Tris-HCI, pH 8.0 the membrane suspension is frozen rapidly at -80⁰C. [0084] On the day of assay the membranes are thawed and washed four times by resuspension in 50 mM Tris-HCI, pH 8.0 and centrifugation at 48,000xg for 20 min. and finally re-suspended in 50 mM Tris-HCI, pH 7.4. The amount of protein in the final membrane preparation (250-500 μg/ml) is determined according to the method of Lowry (Lowry O. H. et al., 1951. J. Biol. Chem. 193, 256-275).

[³H]MPEP Assay

[0085] Incubations are started by adding (³H)-MPEP (50.2 Ci/mmol, 5 nM, Tocris) to vials with 125-250 μg protein (total volume 0.5 ml) and various concentrations of the agents. The incubations are continued at room temperature for 60 min (equilibrium is achieved under the conditions used). Non-specific binding is defined by the addition of unlabeled MPEP (10 μM). Incubations are terminated using a Millipore filter system. The samples are rinsed twice with 4 ml of ice-cold assay buffer over glass fibre filters (Schleicher & Schuell) under a constant vacuum. Following separation and rinse, the filters are placed into scintillation liquid (5 ml Ultima Gold) and radioactivity retained on the filters is determined with a conventional liquid scintillation counter (Hewlett Packard, Liquid Scintillation Analyser).

Characterization

[0086] Specific binding is extremely high i.e. normally > 85% and essentially independent of buffer (Tris or HEPES oth 50 mM) and pH (6.8-8.9). There is a clear saturable protein dependence and the chosen protein concentration used for subsequent assays (250-500 μg/ml) is within the linear portion of this dependence. Cold MPEP displaces hot ligand with an IC₅₀ of 18.8 ± 4.1 nM. The Kd of (³H)-MPEP of 13.6 nM is determined by Scatchard analysis and used according to the Cheng Prussoff relationship to calculate the affinity of displacers as Kd values (IC_5O of cold MPEP equates to a Ki of 13.7 nM). B_max is 0.56 pm / mg protein.

FUNCTIONAL ASSAY OF MGLUR5 RECEPTORS

Materials and Methods Astrocyte culture

[0087] Primary astrocyte cultures are prepared from cortices of newborn rats as described by Booher and Sensenbrenner (1972, Neurobiology 2(3):97-105). Briefly, Sprague-Dawley rat pups (2 - 4 d old) are decapitated and neocortices are dissected, disintegrated with a nylon filter (poresize 80 μm) and carefully triturated. The cell suspension is plated on poly-D-lysine precoated flasks (Costar) and cultivated in Dulbecco's Modified Eagle's Medium (DMEM, InVitrogen) supplemented with 10% heat inactivated fetal calf serum (FCSj, Sigma), 4 ITIM glutamine (Biochrom) and 50 μg/mL gentamycin (Biochrom) at 37°C in a humidified atmosphere of 5% CO₂/95% air for 7 d with exchanging the medium at day 2.

[0088] After 7 DIV, cells are shaken overnight at 250 rpm to remove oligodendrocytes and microglia. The next day, astrocytes are rinsed twice with CMF-PBS, trypsinized and subplated on poly-D-lysine precoated 96-well plates (Becton Dickinson #6516 or #6640) at a density of 40,000 - 45,000 cells/well. 24 h after establishing the secondary culture the astrocytes are rinsed with PBS⁺⁺ and fed with astrocyte-defined medium (ADM) consisting of DMEM containing 1x G5-supplement (InVitrogen), 0.5 μg/mL heparan sulfate (Sigma), and 1.5 μg/ ml_ fibronectin (Sigma) (Miller et al., (1993) Brain Res. 618(1):175-8). 3 d later the medium is exchanged and the cells incubated for another 2-3 d, so that at the time of experiments astrocytes are 14-15 DIV.

lmmunocytochemistry

[0089] lmmunostaining is performed to confirm the presence of classical astrocytic markers such as GFAP as well the expression of mGluRδ receptors.

Accumulation of [³H]-lnositol Phosphates

[0090] After astrocytes are cultured for 12 d ADM is removed and inositol-free DMEM (ICN) supplemented with [³H]myo-inositol (0.5 μCi / well; Perkin Elmer), and the ADM chemicals is added. After 48 h the medium is replaced with 100 μl_ Locke^'s buffer (plus 20 mM Li⁺, pH 7.4) and incubated for 15 min at 37°C before replacement with agonists / antagonists in Locke^'s buffer. The incubation (45 min at 37 ⁰C) is terminated by replacing the Locke's solutions with 100 μL 0.1 M HCI (10 min on ice). The 96 well plates can be frozen at -20⁰C at this stage until further analysis. Home made resin exchange columns (AG1-X8 Biorad, 140- 14444) are used to separate labeled inositol phosphates. On the day of assay, columns are washed with 1 ml of 0.1 M formic acid followed by 1 ml of distilled water. The contents of each assay well are then added to one column and washed with 1 ml distilled water followed by 1 ml of 5 mM sodium tetraborate / 60 mM sodium formate. The retained radioactive inositol phosphates are then eluted with 2 * 1ml of 1 M ammonium formate / 0.1 M formic acid into 24-well visiplates. Scintillation liquid (UltimaFlow AF, Perkin Elmer) is added, the plate sealed and vortexed before radioactivity is determined by conventional liquid scintillation counting (Microbeta, Perkin Elmer) as disintegration per minute (DPM).

Calcium FLIPR studies

[0091] Cultured astrocytes express mGluR5 receptors as shown by immunostaining. The increase of intracellular calcium after stimulation with the mGluR5 agonist DHPG or L-quisqualate is measured using the fluorometric imaging plate reader (FLIPR) and the Ca-Kit (both Molecular Devices, CA). Prior to addition of agonist or antagonist the medium is aspirated and cells are loaded for 2 h at RT with 150 μL of loading buffer consisting of Ca-sensitive dye (MD # R8033) reconstituted in sodium chloride (123 mM), potassium chloride (5.4 mM), magnesium chloride (0.8 mM), calcium chloride (1.8 mM), D-glucose (15 mM), and HEPES (20 mM), pH 7.3. Subsequently, plates are transferred to FLIPR to detect calcium increase with the addition of DHPG (300 μM) or L-quisqualate (100 nM) measured as relative fluorescence units (RFU). If antagonists are tested, these compounds are pre-incubated for 10 min at RT before addition of the respective agonist.

[0092] For positive modulators, concentration-response curves for quisqualate are performed in the presence and absence of 10 μM modulator to determine the extent of potentiation / agonist potency increase. Thereafter, concentration- response curves for the positive modulator are performed in the presence of a fixed concentration of quisqualate showing the biggest window for potentiation (normally 10-3O nM).

Data analysis

[0093] The fluorescence signal increases after addition of agonist reflects the increase of intracellular calcium. Inconsistencies in the amount of cells per well are normalised by using the spatial uniformity correction of the FLIPR software. The mean of replicated temporal data (n=5) is calculated and used for graphical representation. For the evaluation of the pharmacology, the calcium changes in response to different concentrations of agonist or antagonist are determined using a maximum minus minimum (MaxMin) calculation.

[0094] All responses (DPM- or RFU-values) are determined as percentage of control (= maximum response at 100 nM quisqualate).

EC₅₀ and IC₅₀ are calculated according the logistic equation using GraFit 5.0 (Erithacus Software).

FUNCTIONAL ASSAY OF mGluRI RECEPTORS IN CEREBELLAR GRANULE CELLS - RADIOACTIVE ASSAY FOR CHANGES IN IP3 LEVELS

Preparation of cerebellar granule cells

[0095] Cerebellar cortici are obtained from P8 postnatal Sprague Dawley rats, mechanically disrupted into small pieces with forceps and then transferred to Ca²⁺ and Mg²⁺ free Hank's buffered salt solution (HBSS-CMF) on ice. After three washes in HBSS-CMF, the tissue pieces are incubated 37°C for 8 minutes in the presence of 0.25% trypsin / 0.05% DNase. The enzymatic reaction is stopped with 0.016% DNAase / 0.1% ovomucoid before centrifugation at 800 rpm for 5 minutes. The supernatant is replaced twice with NaHCOa/HEPES-buffered basal Eagle medium (BME) plus 20 mM KCI. Cells are mechanically dissociated in 2 ml of BME by trituration through three Pasteur pipettes of successively decreasing tip diameter and then filtered through a 48 μM gauge filter. Cells are plated at a density of 150,000 cells in 50 μl in each well of poly-L-Lysin pre-coated 96 well plates (Falcon). The cells are nourished with BEM supplemented with 10% foetal calf serum, 2 mM glutamine (Biochrom), 20 mM KCI and gentamycin (Biochrom) and incubated at 36 ⁰C with 5% CO₂ at 95% humidity. After 24 h, cytosine-β-D- arabinofuranoside (AraC, 10 μM) is added to the medium.

IP₃ assay with [³H]myo-inositol

[0096] After 6 DIV the culture medium is replaced completely with inositol free DMEM (ICN) containing [³H]myo-inositol (Perkin Elmer) at a final concentration of 0.5 μCi / 100 μl / well and incubated for a further 48 hours. The culture medium in each well is replaced with 100 μL Locke^'s buffer (containing in (mM) NaCI (156), KCI (5.6), NaHCO₃ (3.6), MgCI₂ (1.0), CaCI₂ (1.3), Glucose (5.6), HEPES (10)) with additional (20 mM Li⁺, pH 7.4) and incubated for 15 min at 37°C. Locke's buffer is replaced with agonists / agonists / putative mGluRI ligands in Locke's buffer and incubated for 45 min. These solutions are then replaced by 100 μL 0.1 M HCI in each well and incubated for a further 10 mins on ice. The 96 well plates can be frozen at -20⁰C at this stage until further analysis. Home made resin exchange columns (AG1-X8 Biorad, 140-14444) are used to separate labeled inositol phosphates. On the day of assay, columns are washed with 1 ml of 0.1 M formic acid followed by 1 ml of distilled water. The contents of each assay well are then added to one column and washed with 1 ml distilled water followed by 1 ml of 5 mM sodium tetraborate / 60 mM sodium formate. The retained radioactive inositol phosphates are then eluted with 2 * 1 ml of 1 M ammonium formate / 0.1 M formic acid into 24-well visiplates. Scintillation liquid (UltimaFlow AF, Perkin Elmer) is added, the plate sealed and vortexed before radioactivity is determined by conventional liquid scintillation counting (Microbeta, Perkin Elmer) as disintegration per minute (DPM). Unless otherwise stated, all reagents are obtained from Sigma.

[0097] Compounds of the present invention have a potency (EC₅₀ or IC₅₀, respectively) range of about 0.5 nM to about 100 μM. CONCLUSIONS

[0098] In conclusion, from the foregoing, it is apparent that the present invention provides novel, valuable, and unpredictable applications and uses of the compounds of the present invention, which compounds comprise the active principle according to the present invention, as well as novel pharmaceutical compositions thereof and methods of preparation thereof and of treating therewith, all possessed of the foregoing more specifically-enumerated characteristics and advantages.

[0099] The high order of activity of the active agent of the present invention and compositions thereof, as evidenced by the tests reported, is indicative of utility based on its valuable activity in human beings as well as in lower animals. Clinical evaluation in human beings has not been completed, however. It will be clearly understood that the distribution and marketing of any compound or composition falling within the scope of the present invention for use in human beings will of course have to be predicated upon prior approval by governmental agencies, such as the U.S. Federal Food and Drug Administration, which are responsible for and authorized to pass judgment on such questions.

[00100] The instant compounds represent a novel class of Group I mGluR modulators. In view of their potency, they will be useful therapeutics in a wide range of CNS disorders which involve abnormal glutamate neurotransmission. [00101] These compounds accordingly find application in the treatment of the following disorders of a living animal body, especially a human: AIDS-related dementia, Alzheimer's disease, Creutzfeld- Jakob^'s syndrome, bovine spongiform encephalopathy (BSE) or other prion related infections, diseases involving mitochondrial dysfunction, diseases involving β-amyloid and/or tauopathy such as Down's syndrome, hepatic encephalopathy, Huntington's disease, motor neuron diseases such as amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), olivoponto-cerebellar atrophy, post-operative cognitive deficit (POCD), Parkinson's disease, Parkinson's dementia, mild cognitive impairment, dementia pugilistica, vascular and frontal lobe dementia, cognitive impairment, eye injuries or diseases (e.g. glaucoma, retinopathy, macular degeneration), head and brain and spinal cord injuries / trauma, hypoglycaemia, hypoxia (e.g. perinatal), ischaemia (e.g. resulting from cardiac arrest, stroke, bypass operations or transplants), convulsions, glioma and other tumours, inner ear insult (e.g. in tinnitus, sound or drug-induced), L-Dopa-induced dyskinesias and tardive dyskinesias.

[00102] These compounds also find application in the treatment of the following disorders of a living animal body, especially a human: abuse and addiction (e.g., nicotine, alcohol, opiate, cocaine, amphetamine, obesity and others), amyotrophic lateral sclerosis (ALS), anxiety and panic disorders, attention deficit hyperactivity disorder (ADHD), restless leg syndrome, hyperactivity in children, autism, convulsions / epilepsy, dementia (e.g. in Alzheimer's disease, Korsakoff syndrome, vascular dementia, HIV infections), major depressive disorder or depression (including that resulting from Borna virus infection) and bipolar manic-depressive disorder, drug tolerance (e.g. to opioids), movement disorders, dystonia, dyskinesia (e.g. L-Dopa-induced, tardive dyskinesia or in Huntington's disease), fragile-X syndrome, Huntington's chorea, irritable bowel syndrome (IBS), migraine, multiple sclerosis, muscle spasms, pain (chronic and acute, e.g. inflammatory pain, neuropathic pain, allodynia, hyperalgesia, nociceptive pain), Parkinson's disease, posttraumatic stress disorder, schizophrenia (positive, cognitive and negative symptoms), spasticity, tinnitus, Tourette^'s syndrome, urinary incontinence and vomiting, pruritic conditions (e.g. pruritis), sleep disorders, micturition disorders, neuromuscular disorder in the lower urinary tract, gastroesophageal reflux disease (GERD), lower esophageal sphincter (LES) disease, functional gastrointestinal disorders, dyspepsia, regurgitation, respiratory tract infection, bulimia nervosa, chronic laryngitis, asthma (e.g. reflux-related asthma), lung disease, eating disorders, obesity and obesity-related disorders, agoraphobia, generalized anxiety disorder, obsessive- compulsive disorder, panic disorder, posttraumatic stress disorder, social phobia, substance-induced anxiety disorder, delusional disorder, schizoaffective disorder, schizophreniform disorder, substance-induced psychotic disorder, delirium, or for cognitive enhancement and/or neuroprotection.

[00103] These compounds also find application in the treatment of indications in a living animal body, especially a human, wherein a particular condition does not necessarily exist but wherein a particular physiological parameter may be improved through administration of the instant compounds, including cognitive enhancement. [00104] The method-of-treating a living animal body with a compound of the invention, for the inhibition of progression or alleviation of the selected ailment therein, is as previously stated by any normally-accepted pharmaceutical route, employing the selected dosage which is effective in the alleviation of the particular ailment desired to be alleviated.

[00105] Use of the compounds of the present invention in the manufacture of a medicament for the treatment of a living animal for inhibition of progression or alleviation of selected ailments or conditions, particularly ailments or conditions susceptible to treatment with a Group I mGluR modulator is carried out in the usual manner comprising the step of admixing an effective amount of a compound of the invention with a pharmaceutically-acceptable diluent, excipient, or carrier, and the method-of-treating, pharmaceutical compositions, and use of a compound of the present invention in the manufacture of a medicament.

[00106] Representative pharmaceutical compositions prepared by admixing the active ingredient with a suitable pharmaceutically-acceptable excipient, diluent, or carrier, include tablets, capsules, solutions for injection, liquid oral formulations, aerosol formulations, TDS formulations, and nanoparticle formulations, thus to produce medicaments for oral, injectable, or dermal use, also in accord with the foregoing.

_{* * * * *} [00107] The present invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description.

[00108] All patents, applications, publications, test methods, literature, and other materials cited herein are hereby incorporated by reference.

Claims

CLAIMSWe claim:

1. A compound selected from those of Formula I

wherein

R¹ represents aryl, biaryl, heteroaryl, aryl-heteroaryl, heteroaryl-aryl, or heteroaryl-heteroaryl;

R² represents hydrogen or C-ι_-6alkyl;

R³ represents hydrogen, cyano, nitro, d-βalkyl or Ci_-6alkoxyCi_-6alkyl;

and optical isomers, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof;

wherein

the term "aryl" represents phenyl or naphthyl, wherein the aryl group may be optionally substituted by one or more substituents selected independently from halogen, trifluoromethyl, Ci_-6alkyl, Ca-βalkenyl, Ci_-6alkoxy, Ci_-6alkoxy-Ci-₆alkyl, amino, hydroxy, nitro, cyano, Ci-βalkoxycarbonyl, Ci_-6alkylamino, Ci-βalkylamino-Ci-ealkyl, di-Ci-₆alkylamino, cycloC_3-12alkoxy, aryloxy, cycloCs-^alkylamino, cycIoC₃-i₂alkyl-C_1-6alkylamino, di-Ci-ealkylaminoC-i-βalkyl, arylamino, arylCi_-6alkylamino, arylCi_-6alkoxy, heteroarylC-i-βalkoxy, heteroarylamino, heteroarylCi-βalkylamino, pyrrolidine, piperidino, morpholino, hexamethyleneimino, -N(R⁵)-C(=O)-R⁴, -N(R⁵)-SO₂-R⁴, -N(R⁵)-C(=O)OR⁴, C(=O)-R⁴, C(=O)N(R⁵)₂, and a bivalent radical selected from -(CH₂J₃-, -(CH₂J₄-, -CH=CH-CH=CH-, -(CH₂)₃O-, -OCH₂O-, -0(CH₂J₂O-, and -0(CH₂J₃-;

the term "biaryl" represents biphenylene, wherein one or both phenyl rings may be optionally substituted by one or more substituents independently selected from halogen, trifluoromethyl, Ci_₆alkyl, C_2-6alkenyl, Ci_-6alkoxy, Ci-₆alkoxyCi_-6alkyl, amino, hydroxy, nitro, cyano, Ci-βalkoxycarbonyl, Ci-₆alkylamino, Ci-ealkylamino-Ci-_δalkyl, di-Ci-₆alkylamino, cycloC_3-i₂alkoxy, aryloxy, cycloC_3-i₂alkylamino, cycloC_3-i₂alkyl-C-i_-6alkylamino, di-Ci-βalkylaminoCi-βalkyl, arylamino, arylCi-₆alkylamino, heteroarylCi_-6alkoxy, heteroarylamino, heteroarylCi_-6alkylamino, pyrrolidino, piperidino, morpholino, hexamethyleneimino, -N(R⁵)-C(=O)-R⁴, -N(R⁵J-SO₂-R⁴, -N(R⁵J- C(=O)OR⁴, C(=O)-R⁴, C(=O)N(R⁵) ₂, and a bivalent radical selected from -(CH₂J₃-, -(CH₂J₄-, -CH=CH-CH=CH-, -(CH₂J₃O-, -OCH₂O-, -^Q(CH₂J₂O-, and -0(CH₂J₃-; and the term "heteroaryl" represents an aromatic 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen, or a bicyclic group comprising a 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen fused with a benzene ring or a 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen, wherein the heteroaryl group may be optionally substituted by one or more substituents selected independently from halogen, trifluoromethyl, Ci_-6alkyl, C^alkenyl, Ci_-6alkoxy, C_1-6alkoxyCi-₆alkyl, amino, hydroxy, nitro, cyano, Ci_-6alkoxycarbonyl, Ci-₆alkylamino, Ci-ealkylamino-Ci-ealkyl, di-Ci_-6alkylamino, cycloC_3-12alkoxy, aryloxy, cycloCs-^alkylamino, cycloC_3-i₂alkyl-

Ci_-6alkylamino, di-C_1-6alkylaminoC_1-6alkyl, arylamino, arylCi-₆alkylamino, heteroarylC_1-6alkoxy, heteroarylamino, heteroarylC-ι-6alkylamino, pyrrolidino, piperidino, morpholino, hexamethyleneimino, -N(R⁵)-C(=O)-R⁴, -N(R⁵)-SO₂-R⁴,

-N(R⁵)-C(=O)OR⁴, C(=O)-R⁴, C(=O)N(R⁵)₂, and a bivalent radical selected from -(CH₂)₃-, -(CH₂)₄-, -CH=CH-CH=CH-, -(CH₂)₃O-, -OCH₂O-, -O(CH₂)₂O-, and -O(CH₂)₃-;

wherein

R⁴ represents hydrogen, Ci-₆alkyl which may be optionally substituted with one or more halogen atoms, cycloC_3-i₂alkyl, aryl, heteroaryl, adamantyl, carboxyCi_-6alkyl or CF₃; and R⁵ represents hydrogen, C_1-6alkyl, cycloC_3-i2alkyi, aryl, heteroaryl, adamantyl, carboxyCi.₆alkyl, alkylcarbonyl or CF₃.

2. A pharmaceutical composition comprising as active ingredient at least one compound of Claim 1 together with one or more pharmaceutically acceptable excipients or vehicles.

3. A method for treating or preventing a condition or disease associated with abnormal glutamate neurotransmission or a method for modulating Group I mGluR receptors to achieve therapeutic benefit, or a method for enhancing cognition, such method comprising the step of administering to a living animal, including a human, a therapeutically effective amount of a compound of Claim 1.

4. Use of at least one compound of Claim 1 for the manufacturing of a medicament for the prevention and/or treatment of a condition or disease in an animal including a human being which condition or disease is affected or facilitated by the modulatory effect of Group I mGluR modulators or for the manufacturing of a medicament for enhancing cognition.

5. The method of Claim 3 or the use of Claim 4, wherein the condition associated with abnormal glutamate neurotransmission, or wherein modulation of Group I mGluR receptors results in therapeutic benefit, is selected from: AIDS-related dementia, Alzheimer's disease, Creutzfeld- Jakob^'s syndrome, bovine spongiform encephalopathy (BSE) or other prion related infections, diseases involving mitochondrial dysfunction, diseases involving β-amyloid and/or tauopathy such as Down's syndrome, hepatic encephalopathy, Huntington's disease, motor neuron diseases such as amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), olivopontocerebellar atrophy, post-operative cognitive deficit (POCD), Parkinson's disease, Parkinson's dementia, mild cognitive impairment, dementia pugilistica, vascular and frontal lobe dementia, cognitive impairment, eye injuries or diseases, glaucoma, retinopathy, macular degeneration, head and brain and spinal cord injuries / trauma, hypoglycaemia, hypoxia, perinatal hypoxia, ischaemia, ischaemia resulting from cardiac arrest or stroke or bypass operations or transplants, convulsions, epileptic convulsions, epilepsies, temporal lobe epilepsy, glioma and other tumours, inner ear insult, inner ear insult in tinnitus, sound- or drug-induced inner ear insult, L-Dopa-induced and tardive dyskinesias, abuse and addiction, nicotine addiction, nicotine abuse, alcohol addiction, alcohol abuse, opiate addiction, opiate abuse, cocaine addiction, cocaine abuse, amphetamine addiction, amphetamine abuse, obesity addiction, anxiety and panic disorders, attention deficit hyperactivity disorder (ADHD), restless leg syndrome, hyperactivity in children, autism, dementia, dementia in Alzheimer's disease, dementia in Korsakoff syndrome, vascular dementia, dementia in HIV infections, major depressive disorder or depression, depression resulting from Borna virus infection, and bipolar manic-depressive disorder, drug tolerance, drug tolerance to opioids, movement disorders, dystonia, dyskinesia, L-Dopa-induced dyskinesia, tardive dyskinesia or dyskinesia in Huntington's disease, fragile-X syndrome, Huntington's chorea, chorea, irritable bowel syndrome (IBS), migraine, multiple sclerosis, muscle spasms, pain, chronic pain and acute pain, inflammatory pain, neuropathic pain, allodynia, hyperalgesia, nociceptive pain, posttraumatic stress disorder, schizophrenia, positive or cognitive or negative symptoms of schizophrenia, spasticity, tinnitus, Tourette^'s syndrome, urinary incontinence, vomiting, pruritic conditions, pruritis, sleep disorders, micturition disorders, neuromuscular disorder in the lower urinary tract, gastroesophageal reflux disease (GERD), lower esophageal sphincter (LES) disease, functional gastrointestinal disorders, dyspepsia, regurgitation, respiratory tract infection, bulimia nervosa, chronic laryngitis, asthma, reflux- related asthma, lung disease, eating disorders, obesity and obesity-related disorders, binge eating disorders, agoraphobia, generalized anxiety disorder, obsessive- compulsive disorder, panic disorder, anxiety disorder, posttraumatic stress disorder, social phobia, substance-induced anxiety disorder, delusional disorder, schizoaffective disorder, schizophreniform disorder, substance-induced psychotic disorder, delirium, or for cognitive enhancement and/or neuroprotection.

6. The method of Claim 3 or the use of Claim 4, wherein the condition associated with abnormal glutamate neurotransmission, or wherein negative modulation of Group I mGluR receptors results in therapeutic benefit, is selected from: neuropathic pain, diabetic neuropathic pain (DNP), cancer pain, pain related to rheumathic arthritis, inflammatory pain, L-Dopa-induced and tardive dyskinesias, Parkinson's disease, anxiety disorders, Huntington's chorea and/or epilepsy.

7. The method of Claim 3 or the use of Claim 4, wherein the condition associated with abnormal glutamate neurotransmission, or wherein positive modulation of Group I mGluR receptors results in therapeutic benefit, is selected from: Alzheimer's disease, positive and/or negative symptoms of schizophrenia, cognitive impairment, or for cognitive enhancement and/or neuroprotection.