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• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/08—Antiepileptics; Anticonvulsants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered

Definitions

• the present invention relates to ethynyl derivatives of formula I
• the compounds of general formula I are allosteric modulators of the metabotropic glutamate receptor subtype 5 (mGluR5) which show advantageous biochemical-, physicochemical- and pharmacodynamic-properties compared to compounds of prior art.
• mGluR5 metabotropic glutamate receptor subtype 5
• the transmission of stimuli takes place by the interaction of a neurotransmitter, which is sent out by a neuron, with a neuroreceptor.
• Glutamate is the major excitatory neurotransmitter in the brain and plays a unique role in a variety of central nervous system (CNS) functions.
• the glutamate-dependent stimulus receptors are divided into two main groups.
• the first main group namely the ionotropic receptors, forms ligand-controlled ion channels.
• the metabotropic glutamate receptors (mGluR) belong to the second main group and, furthermore, belong to the family of G-protein coupled receptors.
• these eight receptors can be sub-divided into three sub-groups:
• mGluR1 and mGluR5 belong to group I
• mGluR2 and mGluR3 belong to group II
• mGluR4 mGluR6, mGluR7 and mGluR8 belong to group III.
• Ligands of metabotropic glutamate receptors belonging to the first group can be used for the treatment or prevention of acute and/or chronic neurological disorders such as psychosis, epilepsy, schizophrenia, Alzheimer's disease, cognitive disorders and memory deficits, as well as chronic and acute pain.
• acute and/or chronic neurological disorders such as psychosis, epilepsy, schizophrenia, Alzheimer's disease, cognitive disorders and memory deficits, as well as chronic and acute pain.
• treatable indications in this connection are restricted brain function caused by bypass operations or transplants, poor blood supply to the brain, spinal cord injuries, head injuries, hypoxia caused by pregnancy, cardiac arrest and hypoglycaemia.
• Further treatable indications are ischemia, Huntington's chorea, amyotrophic lateral sclerosis (ALS), tuberous sclerosis (TSC), dementia caused by AIDS, eye injuries, retinopathy, idiopathic parkinsonism or parkinsonism caused by medicaments as well as conditions which lead to glutamate-deficiency functions, such as e.g. muscle spasms, convulsions, migraine, urinary incontinence, nicotine addiction, opiate addiction, anxiety, vomiting, dyskinesia and depressions.
• ALS amyotrophic lateral sclerosis
• TSC tuberous sclerosis
• dementia caused by AIDS
• eye injuries eye injuries
• retinopathy idiopathic parkinsonism or parkinsonism caused by medicaments as well as conditions which lead to glut
• Disorders mediated full or in part by mGluR5 are for example acute, traumatic and chronic degenerative processes of the nervous system, such as Alzheimer's disease, senile dementia, Parkinson's disease, Huntington's chorea, amyotrophic lateral sclerosis and multiple sclerosis, psychiatric diseases such as schizophrenia and anxiety, depression, pain and drug dependency ( Expert Opin. Ther. Patents (2002), 12, (12)).
• Allosteric modulators of mGluR5 have emerged recently as novel pharmaceutical entities offering this attractive alternative. Allosteric modulators have been described, for example in WO2008/151184, WO2006/048771, WO2006/129199, WO2005/044797 and in particular WO2011/128279 as well as in Molecular Pharmacology, 40, 333-336, 1991 ; The Journal of Pharmacology and Experimental Therapeutics, Vol 313 , No. 1, 199-206, 2005 ; Nature, 480 (7375), 63-68, 2012;
• Described in the prior art are positive allosteric modulators. They are compounds that do not directly activate receptors by themselves, but markedly potentiate agonist-stimulated responses, increase potency and maximum of efficacy. The binding of these compounds increases the affinity of a glutamate-site agonist at its extracellular N-terminal binding site. Allosteric modulation is thus an attractive mechanism for enhancing appropriate physiological receptor activation. There is a scarcity of selective allosteric modulators for the mGluR5 receptor. Conventional mGluR5 receptor modulators typically lack drug safety, which lead to more side effects of the drug.
• the compounds of the invention all have similar potencies compared to the reference compounds. Additionally they all show efficacies well below 60% compared to much higher values of the reference compounds (above 80%) which is a criteria with respect to tolerability issues of mGluR5 positive allosteric modulators. Compounds with high efficacy values above 60% show severe CNS related side-effects after oral dosing (seizures) at doses close to those where the desired therapeutic effects are observed (low therapeutic window). Compounds with efficacies below 60% are well tolerated at doses which may be 30 to 1000 times higher than the therapeutic dose while maintaining their desired therapeutic effects. Generally speaking, compounds of the present invention therefore have a clear advantage with respect to drug safety due to their efficacy values below 60% which correlates with the absence of severe CNS side-effect liabilities compared to structurally similar compounds of prior art.
• Compounds of formula I are distinguished by having valuable therapeutic properties. They can be used in the treatment or prevention of disorders, relating to allosteric modulators for the mGluR5 receptor.
• the most preferred indications for compounds which are allosteric modulators are schizophrenia and cognition.
• the present invention relates to compounds of formula I and to their pharmaceutically acceptable salts, to these compounds as pharmaceutically active substances, to the processes for their production as well as to the use in the treatment or prevention of disorders, relating to allosteric modulators for the mGluR5 receptor, such as schizophrenia and cognition and to pharmaceutical compositions containing the compounds of formula I.
• halogen denotes chlorine or fluorine
• pharmaceutically acceptable salt or “pharmaceutically acceptable acid addition salt” embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane-sulfonic acid, p-toluenesulfonic acid and the like.
• R 1 is phenyl which is optionally substituted by 1-2 fluorine atoms; or a pharmaceutically acceptable acid addition salt, in enantiomerically pure form with the absolute configuration as shown in formula I.
• Compounds of formula I-A are the followings:
• the compounds of formula I can be manufactured by the methods given below, by the methods given in the examples or by analogous methods. Appropriate reaction conditions for the individual reaction steps are known to a person skilled in the art.
• the reaction sequence is not limited to the one displayed in the schemes, however, depending on the starting materials and their respective reactivity the sequence of reaction steps can be freely altered. Starting materials are either commercially available or can be prepared by methods analogous to the methods given below, by methods described in references cited in the description or in the examples, or by methods known in the art.
• X is a halogen atom selected from bromine or iodine
• the compound of formula II is a racemic mixture or in enantiomerically pure form with a suitable aryl-acetylene of formula III
• a halo-pyridine compound of formula II can be obtained by a base catalyzed reaction of an appropriate di-halogenated pyridine such as 2-fluoro-5-iodo-pyridine and an appropriate bicyclic urea of formula 4 (scheme 1).
• the compound of formula 4 can be obtained starting from racemic keto-acid of formula I by reaction with enantiomerically pure (R)-phenylalaminol to form the optically pure tricyclic intermediate 2 where all stereocenters are formed under complete stereocontrol using a procedure from M. Jida & al., Green Chem. 12, 961 (2010).
• the tricyclic intermediate 2 is transformed into 4 using an analogous procedure to that described by Dubuffet & Lecouve in EP1354875 for a 6-membered carbocyclic ring analogue.
• Compound 2 is treated with borontrifluoride etherate under reductive conditions to form compound 3 (an N-benzyl-protected derivative of 4) which is de-protected via a chlorination-elimination sequence followed by hydrolysis of the enamine formed to yield enantiomerically pure bicyclic amide 4.
• Other synthetic procedures leading to racemic or enantiomerically pure 4 have also been published (J. Boivin & al., Tetrahedron, 51(23), 6517 (1995); S. Knapp; A.
• Lactam 4 is then condensed with a dihalo pyridine such as 2-Fluoro-5-iodopyridine under base catalyzed conditions (NaH/DMF; or Cs 2 CO 3 /Toluene) to form a compound of formula II where X is iodine.
• a dihalo pyridine such as 2-Fluoro-5-iodopyridine under base catalyzed conditions (NaH/DMF; or Cs 2 CO 3 /Toluene
• Reaction of lactam 4 with a dihalopyridine such as 2-iodo-5-bromopyridine using Palladium catalyzed reaction conditions (Buchwald) can also form a compound of formula II where X is bromine.
• the compound of formula I as described herein as well as its pharmaceutically acceptable salt is used in the treatment or prevention of psychosis, epilepsy, schizophrenia, Alzheimer's disease, cognitive disorders and memory deficits, chronic and acute pain, restricted brain function caused by bypass operations or transplants, poor blood supply to the brain, spinal cord injuries, head injuries, hypoxia caused by pregnancy, cardiac arrest and hypoglycaemia, ischemia, Huntington's chorea, amyotrophic lateral sclerosis (ALS), dementia caused by AIDS, eye injuries, retinopathy, idiopathic parkinsonism or parkinsonism caused by medicaments, muscle spasms, convulsions, migraine, urinary incontinence, gastrointestinal reflux disorder, liver damage or failure whether drug or disease induced, Fragile-X syndrome, Down syndrome, autism, nicotine addiction, opiate addiction, anxiety, vomiting, dyskinesia, eating disorders, in particular bulimia or anorexia nervosa, and depressions, particularly for the treatment and prevention of acute and/or chronic neurological disorders,
• the preferred indications are schizophrenia and cognitive disorders.
• Present invention further relates to the use of a compound of formula I as described herein, as well as its pharmaceutically acceptable salt, for the manufacture of a medicament, preferably for the treatment and prevention of the above-mentioned disorders.
• a monoclonal HEK-293 cell line stably transfected with a cDNA encoding for the human mGlu5a receptor was generated; for the work with mGlu5 Positive Allosteric Modulators (PAMs), a cell line with low receptor expression levels and low constitutive receptor activity was selected to allow the differentiation of agonistic versus PAM activity.
• PAMs mGlu5 Positive Allosteric Modulators
• Cells were cultured according to standard protocols (Freshney, 2000) in Dulbecco's Modified Eagle Medium with high glucose supplemented with 1 mM glutamine, 10% (vol/vol) heat-inactivated bovine calf serum, Penicillin/Streptomycin, 50 ⁇ g/ml hygromycin and 15 ⁇ g/ml blasticidin (all cell culture reagents and antibiotics from Invitrogen, Basel, Switzerland).
• the cells were transferred into a Functional Drug Screening System 7000 (Hamamatsu, Paris, France), and 11 half logarithmic serial dilutions of test compound at 37° C. were added and the cells were incubated for 10-30 min. with on-line recording of fluorescence.
• the agonist L-glutamate was added to the cells at a concentration corresponding to EC 20 (typically around 80 ⁇ M) with on-line recording of fluorescence; in order to account for day-to-day variations in the responsiveness of cells, the EC 20 of glutamate was determined immediately ahead of each experiment by recording of a full dose-response curve of glutamate.
• the compounds of formula (I) and pharmaceutically acceptable salts thereof can be used as medicaments, e.g. in the form of pharmaceutical preparations.
• the pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions.
• the administration can also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.
• the compounds of formula (I) and pharmaceutically acceptable salts thereof can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations.
• Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragées and hard gelatine capsules.
• Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like; depending on the nature of the active substance no carriers are, however, usually required in the case of soft gelatine capsules.
• Suitable carriers for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like.
• Adjuvants such as alcohols, polyols, glycerol, vegetable oils and the like, can be used for aqueous injection solutions of water-soluble salts of compounds of formula (I), but as a rule are not necessary.
• Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
• the pharmaceutical preparations can contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
• medicaments containing a compound of formula (I) or pharmaceutically acceptable salts thereof and a therapeutically inert excipient are also an object of the present invention, as is a process for the production of such medicaments which comprises bringing one or more compounds of formula I or pharmaceutically acceptable salts thereof and, if desired, one or more other therapeutically valuable substances into a galenical dosage form together with one or more therapeutically inert carriers.
• the dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case.
• the effective dosage for oral or parenteral administration is between 0.01-20 mg/kg/day, with a dosage of 0.1-10 mg/kg/day being preferred for all of the indications described.
• Step 1 (1S,5aR)—(R)-3-Phenyl-hexahydro-1-oxa-3a-aza-cyclopenta[c]pentalen-4-one
• Step 2 (R)-1-((R)-Hydroxy-1-(R)-phenethyl)-hexahydro-cyclopenta[b]pyrrol-2-one
• Step 3 (R)-1-((R)-Chloro-1-(R)-phenethyl)-hexahydro-cyclopenta[b]pyrrol-2-one
• Step 4 (3aR,6aR)-1-(1-phenylvinyl)hexahydrocyclopenta[b]pyrrol-2(1H)-one
• Step 6 (3aR,6aR)-1-(5-iodopyridin-2-yl)hexahydrocyclopenta[b]pyrrol-2(1H)-one
• Step 7 ( ⁇ )-(3aR,6aR)-1-(5-(phenylethynyl)pyridin-2-yl)hexahydrocyclopenta[b]pyrrol-2 (1H)-one
• Ethynylbenzene (59.9 mg, 64.5 ⁇ l, 587 ⁇ mol, 1.8 equiv.), triethylamine (99.0 mg, 136 ⁇ l, 978 ⁇ mol, 3.0 equiv.), bis(triphenylphosphine)palladium(II) chloride (13.7 mg, 19.6 ⁇ mol, 0.06 equiv.), triphenylphosphine (1.71 mg, 6.52 ⁇ mol, 0.02 equiv.), and copper (I) iodide (1.86 mg, 9.78 ⁇ mol, 0.03 equiv.) were added. The dark brown solution was stirred at 50° C. for 2 h.

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