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Definitions

• the present invention relates to pyrazolopyrimidine derivatives, which can act as novel metabotropic glutamate receptor (mGluR) modulators, methods for their synthesis and their use as a medicament for the treatment of various diseases and/or prevention of disorders, e.g. neurological disorders, by administration of such substances.
• mGluR metabotropic glutamate receptor
• 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.
• L-glutamic acid is considered to be a 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 other 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.
• MGluR1 and mGluR5 belong to Group I which are positively coupled to phospholipase C and their activation leads to a mobilization of intracellular calcium ions.
• MGluR2 and mGluR3 belong to Group II and mGluR4, mGluR6, mGluR7 and mGluR8 belong to Group III, both of which are negatively coupled to adenylyl cyclase, i.e., their activation causes a reduction in second messenger cAMP and thus a dampening of neuronal activity.
• the mGluR5 modulators have been shown to modulate the effects of the presynaptically released neurotransmitter glutamate via postsynaptic mechanisms. Moreover, as these modulators can be both positive and/or negative mGluR5 modulators, such modulators may increase or inhibit the effects mediated through these metabotropic glutamate receptors.
• modulators which are negative mGluR5 modulators.
• Such modulators decrease the effects mediated through metabotropic glutamate receptors. Since a variety of patho-physiological processes and disease states affecting the CNS are thought to be related to abnormal glutamate neurotransmission, and mGluR5 receptors 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.
• mGluR5 positive or negative modulators may be administered to provide neuroprotection and/or disease modification in the following acute or chronic pathological conditions or to provide a symptomatological effect on the following conditions:
• Alzheimer's disease Creutzfeld-Jakob's syndrome/disease, bovine spongiform encephalopathy (BSE), prion related infections, diseases involving mitochondrial dysfunction, diseases involving ⁇ -amyloid and/or tauopathy, Down's syndrome, hepatic encephalopathy, Huntington's disease, motor neuron diseases, amyotrophic lateral sclerosis (ALS), olivoponto-cerebellar atrophy, post-operative cognitive deficit (POCD), systemic lupus erythematosus, systemic sclerosis, Sjogren's syndrome, Neuronal Ceroid Lipofuscinosis, neurodegenerative cerebellar ataxias, Parkinson's disease, Parkinson's dementia, mild cognitive impairment, cognitive deficits in various forms of mild cognitive impairment, cognitive deficits in various forms of dementia, dementia pugilistica, vascular and frontal lobe dementia, cognitive impairment, learning impairment, eye injuries, eye diseases, eye disorders, glaucoma, retinopathy, macular degeneration
• the mGluR5 negative or positive modulators may also be administered to provide inhibition of tumour cell growth, migration, invasion, adhesion and toxicity in the peripheral tissues, peripheral nervous system and CNS.
• MGluR5 modulators may be administered to provide therapeutic intervention in neoplasia, hyperplasia, dysplasia, cancer, carcinoma, sarcoma, oral cancer, squamous cell carcinoma (SCC), oral squamous cell carcinoma (SCC), lung cancer, lung adenocarcinoma, breast cancer, prostate cancer, gastric cancer, liver cancer, colon cancer, colorectal carcinoma, rhabdomyosarcoma, brain tumour, tumour of a nerve tissue, glioma, malignant glioma, astroglioma, neuroglioma, neuroblastoma, glioblastoma, medulloblastoma, cancer of skin cells, melanoma, malignant melanoma, epithelial neoplasm, lymphom
• mGluR5 negative or positive 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, learning impairment and/or neuroprotection.
• 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.
• pyrazolopyrimidines of formula (XXII) which can act as small molecule immune potentiators (SMIP) and which can be used e.g. for cancer treatment.
• SMIP small molecule immune potentiators
• pyrazolo(1,5-a)pyrimidine derivates of the following general formula (C) are disclosed:
• This compound however has only a limited activity as metabotropic glutamate receptor (mGluR5) modulator and furthermore is not selective.
• heterocyclic compounds which can contain a carboxylic acid amid function are disclosed which have an activity at dopamine receptors and which can be used for the treatment of CNS-diseases.
• pyrazolopyrimidines are mentioned.
• pyrazolopyrimidine derivatives which differ in structure from the known pyrazolopyrimidines, are potent mGluR5 modulators. Therefore, these substances may be therapeutically beneficial in the treatment of conditions which involve abnormal glutamate neurotransmission or in which modulation of mGluR5 receptors results in therapeutic benefit.
• These substances are preferably administered in the form of a pharmaceutical composition, wherein they are present together with one or more pharmaceutically acceptable diluents, carriers, or excipients.
• An additional object of the invention is the provision of processes for producing the pyrazolopyrimidine derivatives.
• the invention in general deals with: A compound selected from those of formula (Ig)
• R 1 defined by Formula (Ig) and Formula (IgA) may represent bromo.
• R 1 defined by Formula (Ig) and Formula (IgA) may represent chloro. It will be apparent to those skilled in the art that the invention also includes optical isomers, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs of the described compounds.
• the invention deals with a pharmaceutical composition
• a pharmaceutical composition comprising, together with one or more pharmaceutically acceptable excipients or vehicles, at least one compound of formula (Ig) or of formula (IgA), wherein the substituents are as defined above, or optical isomers, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.
• a method for treating or preventing a condition or disease associated with abnormal glutamate neurotransmission or a method for modulating mGluR5 receptors to achieve therapeutic benefit, or a method for enhancing cognition comprising the step of administering to a living animal, including a human, a therapeutically effective amount of a compound selected of those of formula (Ig) or formula (IgA).
• the invention in particular relates to a compound selected from those of formula (I)
• R 1 represents chloro or bromo
• R 2 represents hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl or trifluoromethyl
• R 3 represents hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl or trifluoromethyl
• R 4 represents hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl or trifluoromethyl
• R 5 represents hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl or trifluoromethyl
• R 6 represents hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl or trifluoromethyl
• R 7 represents hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl or trifluoromethyl.
• R 1 represents chloro or bromo
• R 2 represents hydrogen, C 1-6 alkyl or trifluoromethyl
• R 3 represents hydrogen, C 1-6 alkyl or trifluoromethyl
• R 4 represents hydrogen, C 1-6 alkyl or trifluoromethyl
• R 5 represents hydrogen, C 1-6 alkyl or trifluoromethyl
• R 6 represents hydrogen, C 1-6 alkyl or trifluoromethyl
• R 7 represents hydrogen, C 1-6 alkyl or trifluoromethyl.
• R 10 is hydrogen
• R 10 is hydrogen and R 9 is in 4-position of the tetrahydropyridine-ring and represents a substituted phenyl ring.
• a further embodiment of the invention relates to compounds of formula (I), wherein R 2 , R 3 , R 4 , R 5 , R 6 and R 7 independently represent hydrogen, C 1-6 -alkyl, C 3-7 cycloalkyl or trifluoromethyl; and one of the radicals R 8 represents hydrogen or methyl and the other radical R 8 represents a phenyl, thiophene, pyrrole, tetrazole, furan, pyridine or pyrimidine ring, wherein the ring system may be substituted by one substituent selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, C 1-6 alkyl and C 1-6 alkoxy.
• the invention also relates to a compound of formula (I), wherein one of the radicals R 8 represents hydrogen and the other radical R 8 represents a phenyl, thiophene, pyrrole, tetrazole, furan, pyridine or a pyrimidine ring which may be optionally substituted by one substituent selected from halogen, amino, hydroxyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, C 1-6 alkyl, hydroxyC 1-6 alkyl and C 1-6 alkoxy.
• a further embodiment of the invention relates to a compound of formula (I), wherein one of the radicals R 8 represents hydrogen and the other radical R 8 represents a phenyl, thiophene, pyrrole, furan, pyridine or pyrimidine ring.
• a further embodiment of the invention relates to a compound of formula (I), wherein R 6 and R 7 represent hydrogen.
• a further embodiment of the invention relates to compound of formula (I), wherein R 2 , R 3 , R 4 and R 5 independently represent hydrogen, methyl, ethyl or trifluoromethyl; and R 6 and R 7 represent hydrogen or methyl.
• a further embodiment of the invention relates to compound of formula (I), wherein R 2 , R 3 , R 4 , R 5 , R 6 and R 7 independently represent hydrogen, methyl or ethyl.
• a further embodiment of the invention relates to compound of formula (I), wherein R 2 and R 3 independently represent hydrogen, methyl or ethyl.
• a further embodiment of the invention relates to compound of formula (I) wherein R 2 represent methyl or ethyl and R 3 represent hydrogen and which has at least one chiral carbon atom.
• a further embodiment of the invention relates to compound of formula (I), wherein R 2 represent hydrogen or methyl and R 3 , R 4 , R 5 , R 6 and R 7 represent hydrogen.
• a further embodiment of the invention relates to compound of formula (I), wherein R 1 represents chloro.
• a further embodiment of the invention relates to compound of formula (I), wherein R 1 represents bromo.
• a further embodiment of the invention relates to a compound of formula (I), wherein R 2 , R 3 , R 4 , R 5 , R 6 and R 7 represent hydrogen.
• a further embodiment of the invention relates to a compound of formula (I), wherein R 2 , R 3 , R 4 , R 5 , R 6 and R 7 represent hydrogen, and the radical R 8 which is in 3-position of the dihydro-pyridin-ring system also represents hydrogen.
• a further embodiment of the invention relates to a compound of formula (I), wherein the radical R 8 which is in 4-position of the dihydro-pyridin-ring represents a phenyl, thiophene, pyrrole, tetrazole, furane, pyridine or pyrimidine ring, wherein the ring system may be optionally substituted by one substituent selected from halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, C 1-6 alkyl and C 1-6 alkoxy.
• a further embodiment of the invention relates to a compound of formula (I), wherein the radical R 8 which is in 3-position of the dihydro-pyridin-ring represents hydrogen, and the radical R 8 which is in 4-position of the dihydro-pyridin-ring represents a phenyl, thiophene, pyrrole, furane, pyridine or pyrimidine ring.
• the invention includes compounds of formula (I) selected from the following compounds (or salts thereof) and having the following chemical names:
• the invention also relates to compounds of the formula (I) which are marked by radioactive atoms.
• Typical compounds include those where one or more hydrogens are substituted by tritium, where one or more C 12 are substituted by C 14 , where one or more fluor atoms are substituted by F 18 or other isotopes. These can be used for the treatment of diseases (e.g. cancer) but also for diagnostic purposes.
• the radioactive atoms exchanged in the molecule are often isotopes of carbon, hydrogen, halogen, sulphur or phosphor.
• the invention in general relates to the use of a metabotropic glutamate receptor modulator (and in particular of a mGluR5 modulator) for the preparation of a medicament and for the treatment of various diseases as mentioned hereunder in a mammal, including humans.
• the invention relates to the use of a compound of formula (I) or of formula (Ia) as defined above or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof for the preparation of a medicament and for the treatment of a mammal, including humans.
• the invention relates to the use of a compound for the preparation of a medicament for treating or preventing a condition or disease associated with abnormal glutamate neurotransmission.
• a use includes the use of a compound for the preparation 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 negative modulatory effect of mGluR5 modulators.
• the invention is dealing with the use of a mGluR5 modulator and in particular a compound according to formula (I), for the preparation of a medicament, including for the conditions or diseases selected from those mentioned earlier in the description.
• the invention also relates to the use of a mGluR5 modulator, in particular a compound according to formula (I), wherein the condition associated with abnormal glutamate neurotransmission is selected from those mentioned earlier in the description.
• a compound wherein the condition associated with abnormal glutamate neurotransmission 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, epilepsy, Alzheimer's disease, positive and negative symptoms of schizophrenia, cognitive impairment, reflux, migraine or for cognitive enhancement and/or neuroprotection.
• DNP diabetic neuropathic pain
• cancer pain pain related to rheumathic arthritis
• inflammatory pain pain
• L-dopa-induced and tardive dyskinesias Parkinson's disease
• Parkinson's disease anxiety disorders
• Huntington's chorea epilepsy
• Alzheimer's disease positive and negative symptoms of schizophrenia, cognitive impairment, reflux, migraine or for cognitive enhancement and/or neuroprotection.
• the invention relates to a pharmaceutical composition
• a pharmaceutical composition comprising as active ingredient at least one compound of formula (I) as defined above or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof, together with one or more pharmaceutically acceptable excipients.
• the invention also relates to the process for the synthesis or preparation of a compound of formula (I)
• a further embodiment of the invention relates to an amine compound of formula (VII)
• a further embodiment of the invention relates to a process for the synthesis of a compound of formula (I)
• the mGluR modulators as described above are expected to have a high activity when administered in combination with other substances exhibiting neurological effects via different mechanisms.
• the invention also relates to a pharmaceutical composition
• a pharmaceutical composition comprising at least two different active ingredients, containing at least one compound of formula (I) as defined above, and furthermore containing at least one NMDA receptor antagonist, together with one or more pharmaceutically acceptable excipients.
• These compositions can be used for the treatment of CNS-related diseases, cognitive enhancement and for neuro-protection.
• the combined therapy exhibits a greater neuroprotective effect than monotherapy with either an mGluR modulator or an NMDA receptor antagonist.
• an NMDA receptor antagonist As particularly active NMDA receptor antagonist, the compound Memantine can be named, which is also known as 1-amino-3,5-dimethyladamantane (see U.S. Pat. No. 4,122,193; U.S. Pat. No. 4,273,774; and U.S. Pat. No. 5,061,703).
• Neramexane which also is known as 1-amino-1,3,3,5,5-pentamethylcyclohexane, is a further active NMDA receptor antagonist and is disclosed in detail in U.S. Pat. No. 6,034,134 and U.S. Pat. No. 6,071,966.
• Memantine and Neramexane are systemically-active noncompetitive NMDA receptor antagonists having moderate affinity for the receptor. They exhibit strong voltage dependent characteristics and fast blocking/unblocking kinetics (see e.g. Görtelmeyer et al., Arzneim-Forsch/Drug Res., 1992, 42:904-913; Winblad et al., Int. J. Geriat.
• NMDA antagonists with mGluR5 modulators can be realized in a single pharmaceutical composition (as principally described in the prior art) comprising a mGluR5 modulator of the present invention and an NMDA receptor antagonist, in one pharmaceutical formulation, or in two separate pharmaceutical compositions or formulations, one comprising a mGluR5 modulator of the present invention and one comprising an NMDA receptor antagonist in a pharmaceutical formulation, to be administered conjointly (simultaneously or sequentially).
• the mGluR5 modulator of the present invention and the NMDA receptor antagonist must be administered separated by a time interval that still permits the resultant beneficial effect in a mammal.
• the mGluR5 modulator of the present invention and the NMDA receptor antagonist must be administered on the same day (e.g., each—once or twice daily), preferably within an hour of each other, and most preferably simultaneously.
• This invention also relates to a pharmaceutical composition
• a pharmaceutical composition comprising a combination of a compound of formula (I) as described above and an NMDA receptor antagonist.
• an NMDA receptor antagonist is selected from Memantine and Neramexane (or a combination thereof) and pharmaceutically acceptable salts, polymorphs, hydrates and solvates thereof.
• the invention also relates to a pharmaceutical composition
• a pharmaceutical composition comprising at least two different active ingredients, containing at least one compound of formula (I) as defined above, and furthermore containing at least one of L-DOPA, another dopaminomimetics (in particular an antiparkinsonian dopaminomimetics e.g. bromocriptine, cabergolin, ropinirole, pramiperole, pergolide, rotigotine), and a neuroleptic (in particular a classical neuroleptic, e.g. haloperidol, perphenazin, chlorpromazine, metoclopramide).
• another dopaminomimetics in particular an antiparkinsonian dopaminomimetics e.g. bromocriptine, cabergolin, ropinirole, pramiperole, pergolide, rotigotine
• a neuroleptic in particular a classical neuroleptic, e.g. haloperidol, perphenazin, chlorpromazine
• combination products can e.g. be used for the treatment of CNS-related disorders and diseases.
• drug induced dyskinesias can be treated in addition to the conditions which are typically treated with L-Dopa, dopaminomimetics or neuroleptics.
• the invention also relates to a method of providing neuroprotection to a living animal, including a human, comprising the step of administering to a living animal, including a human, a therapeutically effective amount of a composition as described.
• This invention is also dealing with the compounds of formula (I) for the use as a medicament. Furthermore, the invention relates to the use of a compound of formula (I) for the manufacture of a medicament for the treatment of the diseases and conditions mentioned above.
• the invention relates to the use of a composition as described for the manufacture of a medicament to provide neuroprotection in an animal, including a human.
• the invention relates to the use of a compound of formula (I) in the manufacture of a medicament for treatment of a condition associated with abnormal glutamate neurotransmission or in which modulation of mGluR5 receptors results in therapeutic benefit.
• a condition associated with abnormal glutamate neurotransmission or in which modulation of mGluR5 receptors results in therapeutic benefit include:
• mGluR5 modulators chronic pain, neuropathic pain, diabetic neuropathic pain (DNP), cancer pain, pain related to rheumathic arthritis, inflammatory pain, L-dopa-induced dyskinesias, dopaminomimetic-induced dyskinesias, L-dopa-induced dyskinesias in Parkinson's disease therapy, dopaminomimetic-induced dyskinesias in Parkinson's disease therapy, tardive dyskinesias, Parkinson's disease, anxiety disorders, panic disorders, anxiety and panic disorders, social anxiety disorder (SAD), generalized anxiety disorder, substance-induced anxiety disorder, eating disorders, obesity, binge eating disorders, Huntington's chorea, epilepsy, Alzheimer's disease, positive and negative symptoms of schizophrenia, cognitive impairment, functional gastrointestinal disorders, gastroesophageal reflux disease (GERD), migraine, irritable bowel syndrome (IBS), or for cognitive enhancement and/or neuroprotection.
• DNP diabetic neuropathic pain
• IBS
• mGluR5 chronic pain, neuropathic pain, diabetic neuropathic pain (DNP), cancer pain, pain related to rheumathic arthritis, inflammatory pain, L-dopa-induced dyskinesias, dopaminomimetic-induced dyskinesias, L-dopa-induced dyskinesias in Parkinson's disease therapy, dopaminomimetic-induced dyskinesias in Parkinson's disease therapy, tardive dyskinesias, Parkinson's disease, anxiety disorders, panic disorders, anxiety and panic disorders, social anxiety disorder (SAD), generalized anxiety disorder, substance-induced anxiety disorder, eating disorders, obesity, binge eating disorders, migraine, irritable bowel syndrome (IBS), functional gastrointestinal disorders, gastroesophageal reflux disease (GERD), Huntington's chorea and/or epilepsy.
• DNP diabetic neuropathic pain
• IBS irritable bowel syndrome
• GSD gastroesophageal reflux disease
• mGluR5 For positive modulation of mGluR5: Alzheimer's disease, positive and/or negative symptoms of schizophrenia, cognitive impairment, or for cognitive enhancement and/or neuroprotection.
• mGluR5 negative modulators in general and in particular the compounds of formula (I) according to the invention can be used for the treatment of binge eating disorders.
• 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 C i-j indicates a moiety of the integer “i” to the integer “j” carbon atoms, inclusive.
• (C 1-3 )alkyl refers to alkyl of one to three carbon atoms (i.e. 1, 2 or 3 carbon atoms), inclusive, (methyl, ethyl, propyl, and isopropyl), straight and branched forms thereof, (C 1-6 ) for instance refers to a radical of one to six carbon atoms (i.e. 1, 2, 3, 4, 5 or 6 carbon atoms).
• C 1-6 alkyl represents straight or branched chain alkyl groups which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, C 1-6 alkoxy, amino, hydroxy, C 1-6 alkylamino, and di-(C 1-6 alkyl)amino.
• substituents selected from halogen, trifluoromethyl, C 1-6 alkoxy, amino, hydroxy, C 1-6 alkylamino, and di-(C 1-6 alkyl)amino.
• alkyl groups include methyl, ethyl, n-propyl, 2-propyl, n-butyl, tert-butyl, —CF 3 , —C 2 F 5 , —CBr 3 and —CCl 3 .
• C 2-6 alkenyl represents straight or branched chain alkenyl groups.
• C 1-6 alkoxy represents straight or branched chain —O—C 1-6 alkyl groups which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, amino, hydroxy, C 1-6 alkylamino and di-(C 1-6 alkyl)amino. Examples of such alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, —OCF 3 and —OC 2 F 5 .
• cycloC 3-12 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, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, amino, hydroxy, nitro, cyano, cyanomethyl, C 1-6 alkoxycarbonyl, C 1-6 alkylamino, and di-(C 1-6 alkyl)amino, C 1-6 alkylcarbonylamino, and C 1-6 alkylenedioxy.
• 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 1-6 alkyl, hydroxyC 1-6 alkyl C 2-6 alkenyl, C 1-6 alkoxy, amino, hydroxy, nitro, cyano, cyanomethyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonyloxy, C 1-6 alkylamino, di-(C 1-6 alkyl)amino, C 1-6 alkylcarbonylamino, aminocarbonyl, N—C 1-6 alkylaminocarbonyl, di-N,N—C 1-6 alkylaminocarbonyl, pyrrolidinyl, piperidinyl, morpholinyl, and piperazinyl, cycloC 3-12 alkyl or optionally C 1-6 substituent
• acyl includes —(C ⁇ O)-alkyl; —(C ⁇ O)aryl; —(C ⁇ O)-aralkyl, —(C ⁇ O)-heterocyclyl, C 1-6 -alkylcarbonyl, C 3-7 cycloalkylcarbonyl, C 2-6 alkenylcarbonyl, C 2-6 alkynylcarbonyl, arylcarbonyl, heteroarylcarbonyl or heterocyclylcarbonyl, wherein the terms alkyl, aryl and heterocyclyl are defied as above. Examples are acetyl, propionyl, benzoyl or pivaloyl.
• 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 1-6 alkyl, hydroxyC 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, amino, hydroxy, nitro, cyano, C 1-6 alkoxycarbonyl, C 1-6 alkoxycarbonyloxy, C 1-6 alkylamino, and di-(C 1-6 alkyl)amino, C 1-6 alkylcarbonylamin
• heteroaryl groups include furanyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thiazolyl, imidazolyl, oxadiazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrazolyl, benzofuryl, benzothienyl, indolyl, indolizinyl, isoindolyl, indolinyl, indazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinolinyl, quinazolinyl, quinoxalinyl, cinnolinyl, naphtyridinyl, and isoquinolinyl. Examples are pyridy
• 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, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, amino, hydroxy, nitro, cyano, C 1-6 alkoxycarbonyl, C 1-6 alkylamino, di-C 1-6 alkylamino, pyrrolidinyl, piperidinyl, morpholinyl, pyridinyl, and aryl; examples of such heterocyclyl groups include piperidinyl, morpholinyl, thiomorpholinyl, imidazolid
• halogen represents fluorine, chlorine, bromine and iodine.
• 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).
• 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.
• 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.
• 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).
• 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.
• compositions 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.
• the compounds containing one or more chiral centers can be prepared as racemates or mixtures of various stereoisomers and then separated. However, they also can be prepared by a special enantioselective synthesis.
• the enantiomers differ in pharmacological activity.
• 5-Nitro-1H-pyrazole-3-carboxylic acid 1 is reduced under standard conditions, such as treatment with hydrogen in the presence of palladium(0) on carbon in a solvent such as methanol, to yield 5-amino-1H-pyrazole-3-carboxylic acid 2.
• Compound 2 is reacted with di-aldehyde 3, carrying a bromo or chloro substituent at the R 1 position, under acid conditions, such as acetic acid, at elevated temperatures to give 6-bromo- or 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (4).
• a compound of Formula I is prepared from 4 via reaction with an appropriate secondary amine 5 in the presence of a condensation agent, including, for example, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (“TBTU”) or N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC).
• a condensation agent including, for example, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (“TBTU”) or N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC).
• the amines (5) are commercially available or may be prepared according to literature procedures (see, for example, Bull. Soc. Chim. Belg., v. 71, 1962; p. 592; US 2002/049223 A1 (2002/04/25); Chem. Ber., 84, 1951, p. 795-798; Bull. Soc. Chim. Fr. 5, 4, 1937, p. 1265-1269; Zh. Obshch. Khim., 7, 1937, p. 1999-2004; Chem. Pharm. Bull., EN, 31, 8, 1983, p. 2583-2592; Tetrahedron, 28, 1972, p. 5999-6004; J. Org. Chem., 34, 8, 1969, p. 2478; Pharm. Chem. J. (Engl. Tran.); 5; 5; 1971, p. 260; Khfzan; Khim. Famm. Zh., 5, 5, 1971, p. 13).
• 5-Nitro-3-pyrazole carboxylic acid 1 is dissolved in an alcoholic solvent, e.g. methanol or ethanol, and reacted with thionyl chloride to give compound 1a bearing an alkyl ester group.
• PG denotes any C 1-6 alkyl chain, including branched alkyl chains, for example, methyl and ethyl groups.
• 5-Nitro-3-pyrazole-carboxylic acid alkyl ester 1a is reduced under standard conditions, such as treatment with hydrogen in the presence of palladium(0) on carbon in a solvent such as methanol, to yield 5-amino-1H-pyrazole-3-carboxylic acid alkyl ester 2a.
• Compound 2a is reacted with di-aldehyde 3, carrying a bromo or chloro substituent at the R 1 position, under acid conditions, such as acetic acid, at elevated temperatures to give 6-bromo- or 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid alkyl ester (4a).
• the ester 4a is hydrolyzed under acidic conditions such as sulphuric acid (30%) to yield 6-bromo- or 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid 4.
• a compound of Formula I is prepared from 4 via reaction with an appropriate secondary amine 5 as shown in Scheme 1.
• Ethyl 3-cyano-2-oxopropionate sodium salt (“NaCOPE”) 6 is treated with methyl hydrazino formiate to yield ethyl 5-aminopyrazole-3-carboxylate 7.
• Compound 7 is reacted with dialdehyde 3, carrying a bromo or chloro substituent at the R 1 position, under acidic conditions, to yield ethyl 6-bromo- or 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylate 8.
• the ester 8 is hydrolyzed under acidic conditions to yield 6-bromo- or 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid 4.
• a compound of Formula I is prepared from 4 via reaction with an appropriate secondary amine 5 as shown in Scheme 1.
• DMF is defined as N,N-dimlethylformamide
• HCl as hydrochloric acid
• DMSO dimethylsulfoxide
• TBTU O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate.
• 5-Nitro-3-pyrazol carboxylic acid (21.44 g, 136.5 mmol) is dissolved in dry methanol (200 mL). Then, thionyl chloride (9.9 mL, 136.5 mmol) is added slowly in a drop wise manner at RT. The reaction mixture is heated over night under reflux and under argon atmosphere. After cooling down, the solvent is evaporated under vacuum and the crude material is heated with boiling hexane (200 ml). After cooling down and removal of the hexane, the material is washed two times with 200 ml pentane. Then, the solvent is removed and the product is dried under vacuum to give 5-nitro-3-pyrazole-carboxylic acid methyl ester (22.35 g, 95.7%).
• 5-Nitro-3-pyrazole-carboxylic acid methyl ester (22.35 g, 130.61 mmol) is dissolved in each 160 mL THF und glacial acetic acid. Then, Pd—C (10%, 4.36 g) are added and the reaction is stirred for 6 days under hydrogen atmosphere at RT. Then, the mixture is filtered over celite and the solvent is removed under vacuum. The crude material is dissolved in methylene chloride (800 mL) and sodium hydrogen carbonate (200 g) are added, filtered and the solvent is again removed under vacuum. This procedure is repeated until the acetic acid smell is lost. 5-Amino-3-pyrazole-carboxylic acid methyl ester is isolated in high yields (16.91 g, 91.7%).
• 5-Amino-3-pyrazolcarboxylic acid methyl ester (16.91 g, 119.8 mmol) is dissolved in ethanol (2.4 L) and hydrochloric acid (37%, 12.5 mL, 150 mmol) is added. Then, a solution of 2-bromo-malonealdehyde (18.9 g, 125.2 mmol) is dissolved in ethanol (1.4 L) and is quickly added in a drop wise manner at RT. After 30 min, a precipitation is observed; after 6 hours the precipitate is removed and washed with 50 ml ethanol and thereafter with 50 ml diethyl ether. Here, 4.19 g of the clean product are isolated.
• 6-Bromopyrazolo[1,5a]pyrimidin-2-carboxylic acid methyl ester (3.76 g, 14.68 mmol) is heated in 600 mL water, 190 mL sulphuric acid (30%) and 50 mL of the methanol/water mixture is removed from the reaction mixture via distillation. After cooling down, 50 mL water is added, the mixture is heated again and 50 mL of the alcohol-water mixture is removed. This cycle is repeated 6 times, the reaction mixture is cooled to RT and filtered over a glass filter.
• a 10 L three-necked flask is equipped with mechanical stirrer, reflux condenser and nitrogen inlet.
• NaCOPE ethyl 3-cyano-2-oxopropionate sodium salt
• 585 mL of water, 3.6 L of ethanol and 350 mL of hydrochloric acid (12N; 4.2 mol) are added.
• the resulting suspension is stirred at RT for 15 min.
• methyl hydrazino formiate 356.0 g; 3.95 mol
• a slightly exothermic reaction occurs.
• a 2 L Schlenk flask equipped with a 500 mL addition funnel is charged with mucochloric acid (100.0 g; 592.0 mmol) dissolved in 400 mL of ethanol. Then, a solution of aniline (108 mL; 1.18 mmol) in 400 mL of ethanol is added over a period of 5 min. The reaction proceeds exothermic via the formation of large amounts of carbon dioxide. Thereafter, the orange solution is heated to reflux for 5 min and then cooled down to RT. Overnight, a yellow precipitate is formed. 500 mL of HCl (1N) are added and the suspension is filtered with suction. The residue is washed with 200 mL of ethanol and 500 mL of ether.
• the suspensions are cooled by means of an ice-water bath and filtered with suction.
• the residues are washed with water, acetone and ether. After drying at 40° C./1 Torr the 6-halogenopyrazolo[1,5a]pyrimidine-2-carboxylic acids (6) are examined by HPLC.
• 3′,6′-Dihydro-2′H-[3,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (0.2 mmol) is dissolved in a 20% mixture (1 mL) of trifluoroacetic acid in dry methylene chloride. The reaction solution is stirred for 1 h at room temperature, and then evaporated in vacuo. The resulting amine salt is sufficiently pure for the next transformation.
• 2-Methyl-4-phenyl-3,6-dihydro-2H-pyridine-1-carboxylic acid phenyl ester is dissolved in a mixture of 2 mL of isopropyl alcohol and 2 mL of 2 M aqueous LiOH solution. The resulting reaction mixture is refluxed for 48 hrs. The solution is concentrated in vacuo and extracted with diethyl ether. Combined organic phase is washed with brine and dried over NaOH pellets. Solvent is evaporated and resulting product is used without further purification.
• Acid A (1 equiv., 0.4 mmol) is mixed with TBTU (1.1 equiv., 0.145 g, 0.45 mmol) in dry CH 3 CN. Then, Et 3 N (2.5 equiv., 0.14 mL, 1 mmol) is added. The corresponding amine (1 equiv., 0.4 mmol) is added. The reaction is stirred at 50° C. for 2 h to adjust full resolution of the acid. Then, the reaction is carried out at room temperature. The reaction is monitored with TLC. When the reaction is over, some water is added to the reaction mixture. If a precipitate formed it is filtered off, washed with 5% ammonia solution and ether. If an oil formed it is extracted with methylene chloride and separated on a column (different systems) providing the final compounds in good to moderate yields.
• the stereo-isomers of this compound are separated.
• the S-configurated compound has a different activity than the R-configurated isomer.
• the stereo-isomers of this compound are separated.
• the S-configurated compound has a different activity than the R-configurated isomer.
• the stereo-isomers of this compound are separated.
• the S-configurated compound has a different activity than the R-configurated isomer.
• the stereo-isomers of this compound are separated.
• the S-configurated compound has a different activity than the R-configurated isomer.
• the stereo-isomers of this compound are separated.
• the S-configurated compound has a different activity than the R-configurated isomer.
• the stereo-isomers of this compound are separated.
• the S-configurated compound has a different activity than the R-configurated isomer.
• the stereo-isomers of this compound are separated.
• the S-configurated compound has a different activity than the R-configurated isomer.
• the stereo-isomers of this compound are separated.
• the S-configurated compound has a different activity than the R-configurated isomer.
• the stereo-isomers of this compound are separated.
• the S-configurated compound has a different activity than the R-configurated isomer.
• the stereo-isomers of this compound are separated.
• the S-configurated compound has a different activity than the R-configurated isomer.
• the stereo-isomers of this compound are separated.
• the S-configurated compound has a different activity than the R-configurated isomer.
• the stereo-isomers of this compound are separated.
• the S-configurated compound has a different activity than the R-configurated isomer.
• the stereo-isomers of this compound are separated.
• the S-configurated compound has a different activity than the R-configurated isomer.
• the stereo-isomers of this compound are separated.
• the S-configurated compound has a different activity than the R-configurated isomer.
• the stereo-isomers of this compound are separated.
• the S-configurated compound has a different activity than the R-configurated isomer.
• the stereo-isomers of this compound are separated.
• the S-configurated compound has a different activity than the R-configurated isomer.
• the stereo-isomers of this compound are separated.
• the S-configurated compound has a different activity than the R-configurated isomer.
• the stereo-isomers of this compound are separated.
• the S-configurated compound has a different activity than the R-configurated isomer.
• the stereo-isomers of this compound are separated.
• the S-configurated compound has a different activity than the R-configurated isomer.
• the stereo-isomers of this compound are separated.
• the S-configurated compound has a different activity than the R-configurated isomer.
• the stereo-isomers of this compound are separated.
• the S-configurated compound has a different activity than the R-configurated isomer.
• the stereo-isomers of this compound are separated.
• the S-configurated compound has a different activity than the R-configurated isomer.
• the stereo-isomers of this compound are separated.
• the S-configurated compound has a different activity than the R-configurated isomer.
• the stereo-isomers of this compound are separated.
• the S-configurated compound has a different activity than the R-configurated isomer.
• the stereo-isomers of this compound are separated.
• the S-configurated compound has a different activity than the R-configurated isomer.
• the stereo-isomers of this compound are separated.
• the S-configurated compound has a different activity than the R-configurated isomer.
• the stereo-isomers of this compound are separated.
• the S-configurated compound has a different activity than the R-configurated isomer.
• the stereo-isomers of this compound are separated.
• the S-configurated compound has a different activity than the R-configurated isomer.
• the stereo-isomers of this compound are separated.
• the S-configurated compound has a different activity than the R-configurated isomer.
• the stereo-isomers of this compound are separated.
• the S-configurated compound has a different activity than the R-configurated isomer.
• the stereo-isomers of this compound are separated.
• the S-configurated compound has a different activity than the R-configurated isomer.
• the stereo-isomers of this compound are separated.
• the S-configurated compound has a different activity than the R-configurated isomer.
• the stereo-isomers of this compound are separated.
• the S-configurated compound has a different activity than the R-configurated isomer.
• the stereo-isomers of this compound are separated.
• the S-configurated compound has a different activity than the R-configurated isomer.
• the stereo-isomers of this compound are separated.
• the S-configurated compound has a different activity than the R-configurated isomer.
• the stereo-isomers of this compound are separated.
• the S-configurated compound has a different activity than the R-configurated isomer.
• the stereo-isomers of this compound are separated.
• the S-configurated compound has a different activity than the R-configurated isomer.
• the stereo-isomers of this compound are separated.
• the S-configurated compound has a different activity than the R-configurated isomer.
• the stereo-isomers of this compound are separated.
• the S-configurated compound has a different activity than the R-configurated isomer.
• the stereo-isomers of this compound are separated.
• the S-configurated compound has a different activity than the R-configurated isomer.
• the stereo-isomers of this compound are separated.
• the S-configurated compound has a different activity than the R-configurated isomer.
• the stereo-isomers of this compound are separated.
• the S-configurated compound has a different activity than the R-configurated isomer.
• the stereo-isomers of this compound are separated.
• the S-configurated compound has a different activity than the R-configurated isomer.
• the stereo-isomers of this compound are separated.
• the S-configurated compound has a different activity than the R-configurated isomer.
• the stereo-isomers of this compound are separated.
• the S-configurated compound has a different activity than the R-configurated isomer.
• the stereo-isomers of this compound are separated.
• the S-configurated compound has a different activity than the R-configurated isomer.
• the stereo-isomers of this compound are separated.
• the S-configurated compound has a different activity than the R-configurated isomer.
• the stereo-isomers of this compound are separated.
• the S-configurated compound has a different activity than the R-configurated isomer.
• the stereo-isomers of this compound are separated.
• the S-configurated compound has a different activity than the R-configurated isomer.
• the stereo-isomers of this compound are separated.
• the S-configurated compound has a different activity than the R-configurated isomer.
• the stereo-isomers of this compound are separated.
• the S-configurated compound has a different activity than the R-configurated isomer.
• the stereo-isomers of this compound are separated.
• the S-configurated compound has a different activity than the R-configurated isomer.
• the stereo-isomers of this compound are separated.
• the S-configurated compound has a different activity than the R-configurated isomer.
• the pure stereoisomeric forms (including optical isomers) 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 (optically active isomers) may be separated from each other by selective crystallization of their diastereomeric salts with optically active acids.
• enantiomers may be separated by chromatographic techniques using chiral stationary phases.
• Said pure stereoisomeric forms may also be derived from the corresponding pure stereoisomeric form of appropriate starting materials, provided that the reaction occur stereoselectively.
• Stereoisomeric forms of Formula (I) are included within the scope of this invention.
• salts of the compounds of Formula I are those wherein the counterion is pharmaceutically acceptable.
• 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, cyclohexane-sulfonic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids.
• the salt form can be
• the active ingredients of formula (I) of the invention 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.
• 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”.
• the active principles of formula (I) 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.
• terapéuticaally 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.
• the active agents of formula (I) 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.
• the active drug component of formula (I) 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 a
• the drug components may be combined with non-toxic, 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.
• the tablets containing as active compound a compound of formula (I) may be coated by methods well known in the art.
• the compositions of the invention containing as active compound a compound of formula (I) 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.
• the active drugs of formula (I) 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.
• Drugs of the invention containing as active compound a compound of formula (I) 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.
• 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, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels.
• 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, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels.
• the therapeutics according to the present invention containing as active compound a compound of formula (I) 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, dichlorotetra-fluoroethane, carbon dioxide, or other suitable gas.
• a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetra-fluoroethane, carbon dioxide, or other suitable gas.
• 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.
• the formulations of the invention containing a compound of formula (I) 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.
• 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.
• the active ingredient can be in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
• compositions of the present invention containing a compound of formula (I) 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).
• rectal administration e.g., as suppositories or retention enemas (e.g., containing conventional suppository bases such as cocoa butter or other glycerides).
• compositions containing a compound of formula (I) 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.
• 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.
• 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 LD 50 (the dose lethal to 50% of the population) and the ED 50 (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 ED 50 /LD 50 .
• Compositions that exhibit large therapeutic indices are preferred.
• 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 containing a compound of formula (I) according to the present invention follow:
• Tablets suitable for oral administration which contain the active ingredient may be prepared by conventional tabletting techniques.
• 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.
• a suitable formulation for a tablet containing 10 milligrams of active ingredient is as follows: mg Active Ingredient 10 Lactose 61 Microcrystalline Cellulose 25 Talcum 2 Magnesium stearate 1 Colloidal silicon dioxide 1
• 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
• 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
• This formulation is filled in a gelatin capsule.
• 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
• a suitable formulation for 1 liter of 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
• 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
• 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: g Active Ingredient 2 Saccharose 400 Bitter orange peel tincture 20 Sweet orange peel tincture 15 Purified water add 1000 ml
• the aerosol solution contain: g Active Ingredient 10 Oleic acid 5 Ethanol 81 Purified Water 9 Tetrafluoroethane 75
• 100 g of the solution contain: g Active Ingredient 10.0 Ethanol 57.5 Propyleneglycol 7.5 Dimethylsulfoxide 5.0 Hydroxyethylcellulose 0.4 Purified water 19.6
• polybutylcyanoacrylate nanoparticles contain: g 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 HCl/ethanol mixture as polymerization medium. The nanoparticles in the suspension are finally lyophilized under vacuum.
• 1.0 g of the suspension contains the following: g Active Ingredient 0.10 Hypromellose 0.01 Purified water Ad 1.0 g
• Hypromellose is dispersed in water homogeneously with a high speed mixer/blender. After about one hour of hydration time of the hypromellose, the active ingredient is blended homogeneously into the hypromellose solution. The viscosity of the suspension can be adjusted by the amount of hypromellose, resulting in a very stable suspension with a very slow tendency of particle sedimentation and particle agglomeration.
• 1.0 ml of solution contain: g Active Ingredient 0.05 Mannitol q.s. DMSO 0.10 Water for injection Ad 1.0 ml
• the active ingredient is dissolved in DMSO by stirring and heating (solution 1).
• the mannitol is dissolved in WFI (solution 2).
• solution 1 is mixed with solution 2 by continuous stirring.
• the solution is sterilized by filtration of by autoclaving.
• the active principles of the present invention, and pharmaceutical compositions containing them and method of treating therewith, are characterized by unique and advantageous properties.
• the compounds and pharmaceutical compositions thereof exhibit, in standard accepted reliable test procedures, the following valuable properties and characteristics
• [ 3 H]-MPEP (2-methyl-6-(phenylethynyl)pyridine binding to transmembrane allosteric modulatory sites of mGluR5 receptors in cortical membranes.
• the pellet is then re-suspended and centrifuged two to three more times at 48,000 ⁇ g for 20 minutes in the presence of 50 mM Tris-HCl, pH 8.0. All centrifugation steps are carried out at 4° C. After resuspension in 5 volumes of 50 mM Tris-HCl, pH 8.0 the membrane suspension is frozen rapidly at ⁇ 80° C.
• the membranes are thawed and washed four times by resuspension in 50 mM Tris-HCl, pH 8.0 and centrifugation at 48,000 ⁇ g for 20 minutes and finally re-suspended in 50 mM Tris-HCl, pH 7.4.
• the amount of protein in the final membrane preparation (500-700 ⁇ g/ml) is determined according to the method of Lowry (Lowry 0. H. et al. 1951. J. Biol. Chem. 193, 256-275).
• Incubations are started by adding [ 3 H]-MPEP (50.2 Ci/mmol, 5 nM, Tocris, GB) to vials with 125-250 ⁇ g protein (total volume 0.25 ml) and various concentrations of the agents.
• assays are performed with [ 3 H]-MMPEP (2-(3-methoxyphenylethynyl)-6-methylpyridine hydrochloride) as radioligand.
• the incubations are continued at room temperature for 60 minutes (equilibrium is achieved under the conditions used). Non-specific binding is defined by the addition of unlabeled MPEP (10 ⁇ M). 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, Germany) under a constant vacuum. Following separation and rinse, the filters are placed into scintillation liquid (5 ml Ultima Gold, Perkin Elmer, Germany) and radioactivity retained on the filters is determined with a conventional liquid scintillation counter (Canberra Packard, Germany).
• scintillation liquid 5 ml Ultima Gold, Perkin Elmer, Germany
• CHO-K1 cells Chinese hamster ovary cells (CHO-K1 cells), stably transfected for inducible expression of a human metabotropic glutamate receptor mGluR5, are seeded into black clear bottom 96 well plates at a density of 35.000 cells per well.
• the standard growth medium used (Dulbecco's modified Eagle Medium, DMEM plus L-proline) contains the appropriate inducer isopropyl- ⁇ -D-thiogalactopyranosid (IPTG) to achieve optimal receptor expression.
• IPTG inducer isopropyl- ⁇ -D-thiogalactopyranosid
• One day after seeding the growth medium is exchanged for reconstituted Ca-Kit (Molecular Devices, USA) and incubated for one hour.
• Ca-Kit is reconstituted in an assay buffer containing 20 mM HEPES pH 7.4, glutamic-pyruvate transaminase, pyridoxal phosphate and sodium pyruvate in Hank's balanced salt solution (HBBS).
• HBBS Hank's balanced salt solution
• Agonistic compounds to the receptor elicit increases in cytosolic calcium which can be measured as increases in fluorescence signals by use of a fluorescence imaging plate reader (Molecular Devices).
• a fluorescence imaging plate reader Molecular Devices.
• To analyze their potency to modulate the Ca-response test compounds dissolved in a final DMSO concentration of 0.5%, are added on-line 5 minutes before the agonist to the receptor (L-quisqualic acid at a concentration giving ⁇ 80% of the maximal signal).
• 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 (pore size 80 ⁇ m) and carefully triturated.
• the cell suspension is plated on poly-D-lysine pre-coated flasks (Costar, Netherlands) and cultivated in Dulbecco's Modified Eagle's Medium (DMEM, Invitrogen, Germany) supplemented with 10% foetal calf serum (FCS, Sigma, Germany), 4 mM glutamine and 50 ⁇ g/ml gentamycin (both Biochrom, Germany) at 37° C. in a humidified atmosphere of 5% CO 2 /95% air for 7 d with exchanging the medium at day 2 and 6.
• DMEM Dulbecco's Modified Eagle's Medium
• FCS foetal calf serum
• FCS foetal calf serum
• astrocytes are rinsed twice with CMF-PBS (calcium- and magnesium-free phosphate buffered saline, Biochrom, Germany), trypsinized and subplated on poly-D-lysine pre-coated 96-well plates (Greiner, Germany) at a density of 40,000 cells/well.
• CMF-PBS calcium- and magnesium-free phosphate buffered saline, Biochrom, Germany
• astrocytes are rinsed with PBS ++ (phosphate buffered saline, Biochrom, Germany) and fed with astrocyte-defined medium (ADM) consisting of DMEM containing 1 ⁇ G5-supplement (Invitrogen, Germany), 0.5 ⁇ g/ml heparan sulfate, and 1.5 ⁇ g/ml fibronectin (both Sigma, Germany) (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.
• ADM astrocyte-defined medium
• Immunostaining is performed to confirm the presence of astrocytic markers such as the glial fibrillary acidic protein (GFAP) as well as to monitor the expression of mGluR5 receptors.
• astrocytic markers such as the glial fibrillary acidic protein (GFAP) as well as to monitor the expression of mGluR5 receptors.
• the increase of cytosolic calcium after stimulation with the mGluR5 agonist L-quisqualate is measured using a fluorometric imaging plate reader (FLIPR) and the Ca-Kit (both Molecular Devices).
• FLIPR fluorometric imaging plate reader
• the medium Prior to addition of agonist or antagonist the medium is aspirated and cells are loaded for 2 h at RT with 150 ⁇ l of loading buffer consisting of Ca-sensitive dye 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.
• concentration-response curves for quisqualate are performed in the presence and absence of 10 ⁇ M 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 10-30 nM).
• MaxMin maximum minus minimum
• EC 50 and IC 50 are calculated according the logistic equation using GraFit 5.0 (Erithacus Software, GB) or Prism 4.0 (GraphPad Software, USA).
• the compounds of the present invention have a potency (IC 50 ) within a range of about 0.5 nM to about 100 ⁇ M.
• the present invention provides novel and valuable 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.
• the instant compounds of formula (I) represent a novel class of mGluR5 modulators. In view of their potency, they will be useful therapeutics in a wide range of disorders, in particular CNS disorders, which involve excessive glutamate induced excitation.
• Neuroprotection as well as cognitive enhancement can also be achieved by combining application of these compounds with NMDA receptor antagonists like Memantine and Neramexane.
• 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.
• 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.
• 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.

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• 2007
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  • 2007-08-03 MX MX2009001036A patent/MX2009001036A/es active IP Right Grant
• 2008
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• 2011
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