US20060167002A1 - Aza-bicycloalkyl ethers and their use as alpha7-nachr agonists - Google Patents
Aza-bicycloalkyl ethers and their use as alpha7-nachr agonists Download PDFInfo
- Publication number
- US20060167002A1 US20060167002A1 US10/526,759 US52675905A US2006167002A1 US 20060167002 A1 US20060167002 A1 US 20060167002A1 US 52675905 A US52675905 A US 52675905A US 2006167002 A1 US2006167002 A1 US 2006167002A1
- Authority
- US
- United States
- Prior art keywords
- aza
- formula
- phenyl
- acid addition
- unsubstituted
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- LPVVVCBDJJRLHT-UHFFFAOYSA-N COC1=CN=C(C)C=C1 Chemical compound COC1=CN=C(C)C=C1 LPVVVCBDJJRLHT-UHFFFAOYSA-N 0.000 description 18
- RCEYXLPKIJSYEM-UHFFFAOYSA-N CC1=CC=C(C)N=N1.CC1=CN=C(C)C=C1.CC1=CN=C(C)N=C1 Chemical compound CC1=CC=C(C)N=N1.CC1=CN=C(C)C=C1.CC1=CN=C(C)N=C1 RCEYXLPKIJSYEM-UHFFFAOYSA-N 0.000 description 8
- 0 *[Y]OC1CN2CCC1CC2.CC1=CC=C(C)N=N1.CC1=CN=C(C)C=C1.CC1=CN=C(C)N=C1 Chemical compound *[Y]OC1CN2CCC1CC2.CC1=CC=C(C)N=N1.CC1=CN=C(C)C=C1.CC1=CN=C(C)N=C1 0.000 description 7
- BGVTUIRPHLSMJU-UHFFFAOYSA-N CC1=CC=C(C)N=N1 Chemical compound CC1=CC=C(C)N=N1 BGVTUIRPHLSMJU-UHFFFAOYSA-N 0.000 description 3
- HBZVJDGWJKDLLX-UHFFFAOYSA-N CC1=CN=C(C)C=C1.CC1=CN=C(C)N=C1 Chemical compound CC1=CN=C(C)C=C1.CC1=CN=C(C)N=C1 HBZVJDGWJKDLLX-UHFFFAOYSA-N 0.000 description 2
- NFQGQMBFMIIIOR-UHFFFAOYSA-N COC1=NC=C(C)C=C1 Chemical compound COC1=NC=C(C)C=C1 NFQGQMBFMIIIOR-UHFFFAOYSA-N 0.000 description 2
- IVLICPVPXWEGCA-UHFFFAOYSA-N OC1CN2CCC1CC2 Chemical compound OC1CN2CCC1CC2 IVLICPVPXWEGCA-UHFFFAOYSA-N 0.000 description 2
- VKSYPKJFCQVBDU-UHFFFAOYSA-N CC1=CC=C(C)N=N1.CC1=CN=C(C)C=C1 Chemical compound CC1=CC=C(C)N=N1.CC1=CN=C(C)C=C1 VKSYPKJFCQVBDU-UHFFFAOYSA-N 0.000 description 1
- ZWWMOLIAJVGEKZ-UHFFFAOYSA-N CCOC1CN2CCC1CC2 Chemical compound CCOC1CN2CCC1CC2 ZWWMOLIAJVGEKZ-UHFFFAOYSA-N 0.000 description 1
- ZNYOMHPJDRUTIS-UHFFFAOYSA-N COC1=NN=C(C)C=N1 Chemical compound COC1=NN=C(C)C=N1 ZNYOMHPJDRUTIS-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- A61K31/439—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 the ring forming part of a bridged ring system, e.g. quinuclidine
-
- 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
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
-
- 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
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- 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
- A61P25/20—Hypnotics; Sedatives
-
- 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
- A61P25/22—Anxiolytics
-
- 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
- A61P25/24—Antidepressants
-
- 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
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/34—Tobacco-abuse
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P33/06—Antimalarials
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
- C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/08—Bridged systems
Definitions
- the present invention relates to novel 1-aza-bicycloalkyl derivatives, to processes for their production, their use as pharmaceuticals and to pharmaceutical compositions comprising them.
- a compound of formula I wherein X is CH 2 or a single bond; Y is a group of formula R is a substituted or unsubstituted C 5 -C 10 aryl or substituted or unsubstituted hetero-C 5 -C 10 aryl, N(R 1 )(R 4 ), or N(R 2 )(CHR 3 R 4 ); each of R 1 , R 2 and R 3 is independently H, C 1 -C 4 alkyl, or CF 3 ; R 4 is a substituted or unsubstituted C 5 -C 10 aryl or substituted or unsubstituted hetero-C 5 -C 10 aryl; in free base or acid addition salt form.
- C 5 -C 10 aryl and hetero-C 5 -C 10 aryl as used herein mean especially partially or fully unsaturated, e.g. aromatic, residues optionally substituted by one or more substituents, preferably up to three substituents, selected from halogen, e.g. F, Cl, Br, I; CN; C 1 -C 4 alkyl, such as methyl, ethyl or propyl, C 2 -C 4 alkenyl, such as vinyl, C 2 -C 4 alkinyl, which radicals themselves can be unsubstituted or substituted by halogen, e.g.
- C 1 -C 4 alkoxy which radical itself can be unsubstituted or substituted by halogen, e.g. trifluoromethoxy; formyl, acetyl; C 1 -C 3 alkoxycarbonyl; N,N-di-(C 1 -C 3 alkyl) carbamoyl; phenyl, phenoxy; or which substituents can be condensed, e.g. to a benzo[1,3]dioxole or 2,3-dihydrobenzo[1,4]dioxine and/or to a further heterocyclic ring.
- halogen e.g. trifluoromethoxy
- formyl acetyl
- C 1 -C 3 alkoxycarbonyl N,N-di-(C 1 -C 3 alkyl) carbamoyl
- phenyl, phenoxy or which substituents can be condensed, e.g. to a benzo[
- Hetero-C 5 -C 10 aryl is an aromatic heterocyclic system comprising one, two or three hetero atoms selected from N, O, S, e.g. a 5 or 7 membered aromatic heterocyclic residue optionally condensed, e.g. to 1 or 2 phenyl rings and/or to a further heterocyclic ring.
- Examples of C 5 -C 10 aryl or hetero-C 5 -C 10 aryl residues as mentioned above include phenyl, naphthyl, tetrahydronaphthyl such as tetralinyl, indanyl, thienyl, benzothienyl, furanyl, benzofuranyl and isobenzofuranyl.
- C 5 -C 10 aryl and hetero-C 5 -C 10 aryl as used herein mean partially or fully unsaturated, e.g. aromatic, residues optionally substituted by one or more substituents, preferably up to three substituents, selected from halogen, e.g. F, Cl, Br, I; CN; C 1 -C 4 alkyl, such as methyl, ethyl or propyl, which radical itself can be unsubstituted or substituted by halogen, e.g. difluoromethyl or trifluoromethyl; C 1 -C 4 alkoxy, which radical itself can be unsubstituted or substituted by halogen, e.g.
- Hetero-C 5 -C 10 aryl is an aromatic heterocyclic system comprising one, two or three hetero atoms selected from N, O, S, e.g. a 5 or 7 membered aromatic heterocyclic residue optionally condensed, e.g. to 1 or 2 phenyl rings and/or to a further heterocyclic ring.
- C 5 -C 10 aryl or hetero-C 5 -C 10 aryl residues as mentioned above include phenyl, naphthyl, indanyl, tetralinyl, thienyl, benzothienyl, furanyl, benzofuranyl and isobenzofuranyl.
- Acid addition salts are especially pharmaceutically acceptable salts of compounds of formula I.
- pharmaceutically unacceptable salts for example picrates or perchlorates.
- pharmaceutically acceptable salts or free compounds are employed (where applicable in the form of pharmaceutical preparations), and these are therefore preferred.
- the compounds may exist in optically active form or in form of mixtures of optical isomers, e.g. in form of racemic mixtures. All optical isomers and their mixtures including the racemic mixtures are part of the present invention.
- X is CH 2 ;
- R is 1-isobenzofuranyl or substituted or unsubstituted phenyl, e.g. monosubstituted by a chlorine or fluorine in position 2, 3 or 4, CF 3 in position 2 or 3, methoxy in position 2; trifluoromethoxy in position 3; benzo[1,3]-dioxole; 2,3-dihydrobenzo[1,4]-dioxine; cyano; or disubstituted, e.g. by a fluorine in position 2 and 5, 3 and 5 or chlorine in position 2 and fluorine in position 6.
- X is CH 2 or a single bond
- Y is a group of formula and R is phenyl, naphthyl, tetrahydronaphthyl, indanyl, thienyl, benzothienyl, furanyl, benzofuranyl and isobenzofuranyl, which in each case can be unsubstituted or mono-, di- or trisubstituted by halogen, cyano, formyl, acetyl, C 1 -C 3 alkoxycarbonyl, N,N-di-(C 1 -C 3 alkyl) carbamoyl, phenyl, phenoxy, methylendioxy, ethylendioxy; or C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkinyl or C 1 -C 4 alkoxy, which radicals themselves can be unsubstituted or mono-, di- or trisubstituted by halogen.
- X is CH 2 or a single bond
- Y is a group of formula and R is (a) phenyl which is unsubstituted or mono-, di- or trisubstituted by halogen, cyano, methylendioxy, C 1 -C 4 alkyl, which is unsubstituted or mono-, di- or trisubstituted by halogen, or C 1 -C 4 alkoxy, which is unsubstituted or mono-, di- or trisubstituted by halogen, (b) naphthyl, indanyl, tetralinyl or (c) furanyl, benzofuranyl, isobenzofuranyl, benzothienyl or thienyl, in free base or acid addition salt form.
- X is CH 2 or a single bond
- Y is a group of formula and R is (a) phenyl which is unsubstituted or mono-, di- or trisubstituted by halogen, cyano, methylendioxy, C 1 -C 4 alkyl, which is unsubstituted or mono-, di- or trisubstituted by halogen, or C 1 -C 4 alkoxy, which is unsubstituted or mono-, di- or trisubstituted by halogen, (b) naphthyl, or (c) furanyl, benzofuranyl, isobenzofuranyl, or thienyl, in free base or acid addition salt form.
- the present invention also provides a process for the production of a compound of formula I, which process comprises the step of reacting a compound of formula II z-Y—R (II); wherein Y and R are as defined above and z is a leaving group, e.g. F, Cl, Br, I or OSO 2 CF 3 , with a compound of formula III wherein X Is as defined above for a compound of formula I, and recovering the so obtained compound of formula I in free base or acid addition salt form.
- reaction may be carried out in accordance with standard procedures, for instance, as illustrated in the Examples.
- the compounds of formula I′ wherein X and R are as defined above and Y′ is can be produced by a process comprising the step of reacting a compound of formula IV wherein Y′, z and X are as defined above, with a compound of formula V wherein R is as defined above for a compound of formula I, and recovering the so obtained compound of formula I′ in free base or acid addition salt form.
- a compound of formula VI e.g. unsubstituted or substituted phenylboronic acids
- a compound of formula VI, R—Br (VI) wherein R has the meaning as provided for a compound of formula I can be reacted with a trialkyl borate in an inert solvent such as benzene, toluene, tetrahydrofuran or mixtures thereof by the addition of butyl lithium at a temperature of between about ⁇ 78° C. and 31 25° C., e.g. about ⁇ 40° C., for a period of about 1 hour to 6 hours, furnishing a compound of formula V.
- an inert solvent such as benzene, toluene, tetrahydrofuran or mixtures thereof
- Acid addition salts may be produced from the free bases in known manner, and vice-versa.
- Suitable acid addition salts for use in accordance with the present invention include, for example, the hydrochloride and the formate.
- Stereoisomeric mixtures e.g. mixtures of diastereomers
- Diastereomeric mixtures for example may be separated into their individual diastereomers by means of fractionated crystallization, chromatography, solvent distribution, and similar procedures. This separation may take place either at the level of a starting compound or in a compound of formula I itself.
- Enantiomers may be separated through the formation of diastereomeric salts, for example by salt formation with an enantiomer-pure chiral acid, or by means of chromatography, for example by HPLC, using chromatographic substrates with chiral ligands.
- functional groups of the starting compounds which should not take part in the reaction may be present in unprotected form or may be protected for example by one or more of the protecting groups mentioned below.
- the protecting groups are then wholly or partly removed according to one of the methods described there.
- the protecting groups may already be present in precursors and should protect the functional groups concerned against unwanted secondary reactions. It is a characteristic of protecting groups that they lend themselves readily, i.e. without undesired secondary reactions, to removal, typically by solvolysis, reduction, photolysis or also by enzyme activity, for example under conditions analogous to physiological conditions, and that they are not present in the end-products.
- the specialist knows, or can easily establish, which protecting groups are suitable with the reactions mentioned hereinabove and hereinafter.
- All process steps described here can be carried out under known reaction conditions, preferably under those specifically mentioned, in the absence of or usually in the presence of solvents or diluents, preferably such as are inert to the reagents used and able to dissolve these, in the absence or presence of catalysts, condensing agents or neutralising agents, for example ion exchangers, typically cation exchangers, for example in the H + form, depending on the type of reaction and/or reactants at reduced, normal, or elevated temperature, for example in the range from ⁇ 100° C. to about 190° C., preferably from about ⁇ 80° C. to about 150° C., for example at ⁇ 80 to ⁇ 60° C., at room temperature, at ⁇ 20 to 40° C. or at the boiling point of the solvent used, under atmospheric pressure or in a closed vessel, where appropriate under pressure, and/or in an inert atmosphere, for example under argon or nitrogen.
- solvents or diluents preferably such as are inert
- agents of the invention exhibit valuable pharmacological properties when tested in vitro and in animals, and are therefore useful as pharmaceuticals.
- the agents of the invention are ⁇ 7 nicotinic acetylcholine receptor (nAChR) agonists.
- the agents of the invention display high affinity at the ⁇ 7 nAChR as shown in the following tests:
- the agents of the invention induce significant sensory gating at concentrations of about 10 to about 40 ⁇ M.
- the agents of the invention are therefore useful for the prevention and treatment of psychotic disorders such as schizophrenia, mania, depression and anxiety, and for the prevention and treatment of neurodegenerative disorders such as senile dementia, Alzheimer's disease and other intellectual impairment disorders, such as attention deficit hyperactivity disorders (ADHD); Parkinson's disease, Huntington's chorea, amyotrophic lateral sclerosis, multiple sclerosis, epilepsy, convulsions, Tourette syndrome, OCD (obsessive compulsive disorder), neuropathic, postoperative and inflammatory pain, phantom limb pain, cognition, smoking cessation, memory deficits and dysfunction, learning deficit, panic disorders, narcolepsy, nociception, AIDS dementia, senile dementia, autism, tardive dyskinesia, social phobia, pseudodementia.
- ADHD attention deficit hyperactivity disorders
- Parkinson's disease Huntington's chorea
- amyotrophic lateral sclerosis multiple sclerosis
- epilepsy convulsions
- the appropriate dosage of the agents of the invention will, of course, vary depending upon, for example, the host, the mode of administration and the nature and severity of the condition being treated as well as the relative potency of the particular agent of the invention employed.
- the amount of active agent required may be determined on the basis of known in vitro and in vivo techniques, determining how long a particular active agent concentration in the blood plasma remains at an acceptable level for a therapeutic effect.
- satisfactory results in animals are indicated to be obtained at daily dosages of from about 0.01 to about 20.0 mg/kg p.o.
- an indicated daily dosage is in the range of from about 0.7 to about 1400 mg/day p.o., e.g.
- Oral dosage forms accordingly suitably comprise from about 1.75 or 2.0 to about 700 or 1400 mg of an agent of the invention admixed with an appropriate pharmaceutically acceptable diluent or carrier therefor.
- compositions comprising an agent of the invention include, e.g. a solid dispersion, an aqueous solution, e.g. containing a solubilising agent, a microemulsion and a suspension of, e.g. a hydrochloride salt of a compound of formula I in the range of from 0.1 to 1%, e.g. 0.5%.
- the composition may be buffered to a pH in the range of, e.g. from 3.5 to 9.5, e.g. to pH 4.5, by a suitable buffer.
- the agents of the invention are also useful as research chemicals.
- the agent of the invention may be administered as single active agent or in combination with other active agents commonly employed for the treatment of the disorders mentioned herein, in any usual manner, e.g. orally, for example in the form of tablets or capsules, or parenterally, for example in the form of injection solutions or suspensions.
- compositions for separate administration of the combination partners and for the administration in a fixed combination i.e. a single galenical composition comprising at least two combination partners
- a single galenical composition comprising at least two combination partners
- compositions contain, for example, from about 0.1% to about 99.9%, preferably from about 20% to about 60%, of the active ingredients.
- Pharmaceutical preparations for the combination therapy for enteral or parenteral administration are, for example, those in unit dosage forms, such as sugar-coated tablets, tablets, capsules or suppositories, and furthermore ampoules. If not indicated otherwise, these are prepared in a manner known per se, for example by means of conventional mixing, granulating, sugar-coating, dissolving or lyophilizing processes. It will be appreciated that the unit content of a combination partner contained in an individual dose of each dosage form need not in itself constitute an effective amount since the necessary effective amount can be reached by administration of a plurality of dosage units.
- a therapeutically effective amount of each of the combination partners may be administered simultaneously or sequentially and in any order, and the components may be administered separately or as a fixed combination.
- the method of delay of progression or treatment of a proliferative disease according to the invention may comprise (i) administration of the combination partner (a) in free or pharmaceutically acceptable salt form and (ii) administration of a combination partner (b) in free or pharmaceutically acceptable salt form, simultaneously or sequentially in any order, in jointly therapeutically effective amounts, preferably in synergistically effective amounts, e.g. in daily dosages corresponding to the amounts described herein.
- the individual combination partners can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms.
- administering also encompasses the use of a pro-drug of a combination partner that convert in vivo to the combination partner as such.
- the instant invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment and the term “administering” is to be interpreted accordingly.
- each of the combination partners employed may vary depending on the particular compound or pharmaceutical composition employed, the mode of administration, the condition being treated, the severity of the condition being treated.
- the dosage regimen is selected in accordance with a variety of factors including the route of administration and the renal and hepatic function of the patient.
- a physician, clinician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the single active ingredients required to prevent, counter or arrest the progress of the condition.
- Optimal precision in achieving concentration of the active ingredients within the range that yields efficacy without toxicity requires a regimen based on the kinetics of the active ingredients' availability to target sites.
- the present invention also provides:
- An agent of the invention for use as an alpha-7 receptor agonist for example for use in any of the particular indications hereinbefore set forth.
- composition comprising an agent of the invention as active ingredient together with a pharmaceutically acceptable diluent or carrier therefore.
- a pharmaceutical composition for the treatment or prevention of a disease or condition in which alpha-7 receptor activation plays a role or is implicated comprising an agent of the invention and a carrier.
- a method for the treatment of any of particular indication hereinbefore set forth in a subject in need thereof which comprises administering an effective amount of an agent of the invention.
- a method for treating or preventing a disease or condition in which the alpha-7 receptor activation plays a role or is implicated comprising administering to a mammal in need thereof a therapeutically effective amount of an agent of the invention.
- a method as defined above comprising co-administration, e.g. concomitantly or in sequence, of a therapeutically effective amount of an alpha-7 agonist, e.g. an agent of the invention and a second drug substance, said second drug substance being for example for use in any of the particular indications hereinbefore set forth.
- a combination comprising a therapeutically effective amount of an alpha-7 agonist agonist, e.g. an agent of the invention and a second drug substance, said second drug substance being for example for use in any of the particular indications hereinbefore set forth.
- reaction mixture is evaporated to give an orange semi-solid (2.50 g), which is triturated with AcOEt and filtered to give (rac.)-3-(5-bromo-pyrimidin-2-yloxy)-1-aza-bicyclo[2.2.2]-octane as a white solid.
- the filtrate is purified by FC (silica gel, eluents: AcOEt/MeOH 9:1, then AcOEt/MeOH/NEt 3 70:27:3).
- Example 17 or 18 can be prepared in analogy to Example 17 or 18: stereo- HPLC rt mp. ° C. Ex. chem. X R (min) [a] D rt (salt) M + H + 19 (S) CH 2 phenyl 5.6 ⁇ 31.0° 126-129 282.2 (0.95% (no salt) MeOH) 20 rac. CH 2 2-fluoro-phenyl 5.9 N/A 87-93 300.2 (no salt) 21 rac. CH 2 3-chloro-phenyl 6.6 N/A 163-165 316.2 (no salt) 22 rac. CH 2 3,4-dichloro-phenyl 3.6 N/A 182-184 350.1 (no salt) 23 rac.
- Bromine (18.0 ml, 353.7 mmol) is slowly added to a soln. of 2-amino-5-chloropyridine (15.0 g, 116.7 mmol) in 47% aq. HBr (75.0 ml) at ⁇ 10° C.
- An aq. soln. of NaNO 2 (28.1 g, 407.3 mmol) is slowly added.
- the mixture is stirred for 1 h at ⁇ 10 to ⁇ 5° C., then for 1 h at 5° C.
- the mixture is neutralised with 5M aq. NaOH soln. maintaining the temperature below 25° C.
- the precipitate is filtered and recrystallized from pentane to give 2-bromo-5-chloropyridine.
- reaction mixture is diluted with toluene and washed with 1 M aq. NaOH soln. and brine.
- the aq. layers are re-extracted with toluene (3 ⁇ ).
- the combined organic extracts are dried over MgSO 4 and filtered.
- Step 75.2 Preparation of 3-Chloro-6-(2-fluoro-4-methyl-phenyl)-pyridazine
- Preparation process The pulverized active ingredient is suspended in Lauroglykol® (propylene glycol laurate, Gattefossé S. A., Saint Priest, France) and ground in a wet pulverizer to produce a particle size of about 1 to 3 ⁇ m. 0.419 g portions of the mixture are then introduced into soft gelatin capsules using a capsule-filling machine.
- Lauroglykol® propylene glycol laurate, Gattefossé S. A., Saint Priest, France
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Epidemiology (AREA)
- Pain & Pain Management (AREA)
- Psychiatry (AREA)
- Tropical Medicine & Parasitology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Virology (AREA)
- Physical Education & Sports Medicine (AREA)
- Psychology (AREA)
- Addiction (AREA)
- Hospice & Palliative Care (AREA)
- Rheumatology (AREA)
- Cardiology (AREA)
- Urology & Nephrology (AREA)
- Communicable Diseases (AREA)
- Anesthesiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Vascular Medicine (AREA)
- AIDS & HIV (AREA)
- Oncology (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US11/823,312 US7579362B2 (en) | 2002-09-04 | 2007-06-26 | Aza-bicycloalkyl ethers and their use as alpha7-nAChR agonists |
US12/262,896 US8236803B2 (en) | 2002-09-04 | 2008-10-31 | Aza-bicycloalkyl ethers and their use as alpha7-nAChR agonists |
US13/462,187 US9012451B2 (en) | 2002-09-04 | 2012-05-02 | Aza-bicycloalkyl ethers and their use as ALPHA7-nachr agonists |
US14/643,275 US9567343B2 (en) | 2002-09-04 | 2015-03-10 | Aza-bicyloalkyl ethers and their use as alpha7-nachr agonists |
US15/398,427 US9849117B2 (en) | 2002-09-04 | 2017-01-04 | Aza-bicycloalkyl ethers and their use as alpha7-nachr agonists |
US15/819,535 US20180078536A1 (en) | 2002-09-04 | 2017-11-21 | Aza-bicycloalkyl ethers and their use as alpha7-nachr agonists |
US16/191,693 US20190083474A1 (en) | 2002-09-04 | 2018-11-15 | Aza-bicycloalkyl ethers and their use as alpha7-nachr agonists |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB0220581.3 | 2002-09-04 | ||
GB0220581A GB0220581D0 (en) | 2002-09-04 | 2002-09-04 | Organic Compound |
PCT/EP2003/009772 WO2004022556A1 (en) | 2002-09-04 | 2003-09-03 | Aza-bicycloalkyl ethers and their use as alpha7-nachr agonist |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2003/009772 A-371-Of-International WO2004022556A1 (en) | 2002-09-04 | 2003-09-03 | Aza-bicycloalkyl ethers and their use as alpha7-nachr agonist |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US11/823,312 Continuation US7579362B2 (en) | 2002-09-04 | 2007-06-26 | Aza-bicycloalkyl ethers and their use as alpha7-nAChR agonists |
Publications (1)
Publication Number | Publication Date |
---|---|
US20060167002A1 true US20060167002A1 (en) | 2006-07-27 |
Family
ID=9943515
Family Applications (8)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/526,759 Abandoned US20060167002A1 (en) | 2002-09-04 | 2003-09-03 | Aza-bicycloalkyl ethers and their use as alpha7-nachr agonists |
US11/823,312 Expired - Lifetime US7579362B2 (en) | 2002-09-04 | 2007-06-26 | Aza-bicycloalkyl ethers and their use as alpha7-nAChR agonists |
US12/262,896 Expired - Lifetime US8236803B2 (en) | 2002-09-04 | 2008-10-31 | Aza-bicycloalkyl ethers and their use as alpha7-nAChR agonists |
US13/462,187 Expired - Lifetime US9012451B2 (en) | 2002-09-04 | 2012-05-02 | Aza-bicycloalkyl ethers and their use as ALPHA7-nachr agonists |
US14/643,275 Expired - Lifetime US9567343B2 (en) | 2002-09-04 | 2015-03-10 | Aza-bicyloalkyl ethers and their use as alpha7-nachr agonists |
US15/398,427 Expired - Lifetime US9849117B2 (en) | 2002-09-04 | 2017-01-04 | Aza-bicycloalkyl ethers and their use as alpha7-nachr agonists |
US15/819,535 Abandoned US20180078536A1 (en) | 2002-09-04 | 2017-11-21 | Aza-bicycloalkyl ethers and their use as alpha7-nachr agonists |
US16/191,693 Abandoned US20190083474A1 (en) | 2002-09-04 | 2018-11-15 | Aza-bicycloalkyl ethers and their use as alpha7-nachr agonists |
Family Applications After (7)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US11/823,312 Expired - Lifetime US7579362B2 (en) | 2002-09-04 | 2007-06-26 | Aza-bicycloalkyl ethers and their use as alpha7-nAChR agonists |
US12/262,896 Expired - Lifetime US8236803B2 (en) | 2002-09-04 | 2008-10-31 | Aza-bicycloalkyl ethers and their use as alpha7-nAChR agonists |
US13/462,187 Expired - Lifetime US9012451B2 (en) | 2002-09-04 | 2012-05-02 | Aza-bicycloalkyl ethers and their use as ALPHA7-nachr agonists |
US14/643,275 Expired - Lifetime US9567343B2 (en) | 2002-09-04 | 2015-03-10 | Aza-bicyloalkyl ethers and their use as alpha7-nachr agonists |
US15/398,427 Expired - Lifetime US9849117B2 (en) | 2002-09-04 | 2017-01-04 | Aza-bicycloalkyl ethers and their use as alpha7-nachr agonists |
US15/819,535 Abandoned US20180078536A1 (en) | 2002-09-04 | 2017-11-21 | Aza-bicycloalkyl ethers and their use as alpha7-nachr agonists |
US16/191,693 Abandoned US20190083474A1 (en) | 2002-09-04 | 2018-11-15 | Aza-bicycloalkyl ethers and their use as alpha7-nachr agonists |
Country Status (26)
Country | Link |
---|---|
US (8) | US20060167002A1 (uk) |
EP (3) | EP1537104B1 (uk) |
JP (2) | JP4348422B2 (uk) |
KR (2) | KR100808324B1 (uk) |
CN (1) | CN1325493C (uk) |
AT (1) | ATE448225T1 (uk) |
AU (1) | AU2003260486C1 (uk) |
BR (2) | BR122014026685B1 (uk) |
CA (1) | CA2495685C (uk) |
CY (1) | CY1109765T1 (uk) |
DE (1) | DE60330015D1 (uk) |
DK (1) | DK1537104T3 (uk) |
EC (1) | ECSP055621A (uk) |
ES (1) | ES2336099T3 (uk) |
GB (1) | GB0220581D0 (uk) |
HK (2) | HK1077822A1 (uk) |
IL (2) | IL166918A (uk) |
MX (1) | MXPA05002546A (uk) |
NO (1) | NO331556B1 (uk) |
NZ (1) | NZ538534A (uk) |
PL (1) | PL209425B1 (uk) |
PT (1) | PT1537104E (uk) |
RU (1) | RU2352569C2 (uk) |
SI (1) | SI1537104T1 (uk) |
WO (1) | WO2004022556A1 (uk) |
ZA (1) | ZA200500816B (uk) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20110124631A1 (en) * | 2009-05-11 | 2011-05-26 | Gerhard Koenig | Treatment of cognitive disorders with certain alpha-7 nicotinic acid receptors in combination with acetylcholinesterase inhibitors |
US8569354B2 (en) | 2008-11-19 | 2013-10-29 | Envivo Pharmaceuticals, Inc. | Treatment of cognitive disorders with (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide and pharmaceutically acceptable salts thereof |
US8710227B2 (en) | 2010-05-17 | 2014-04-29 | Envivo Pharmaceuticals, Inc. | Crystalline form of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride monohydrate |
US8884017B2 (en) | 2001-12-27 | 2014-11-11 | Bayer Intellectual Property Gmbh | 2-heteroarylcarboxylic acid amides |
US9585877B2 (en) | 2012-05-08 | 2017-03-07 | Forum Pharmaceuticals, Inc. | Methods of maintaining, treating or improving cognitive function |
US10421755B2 (en) * | 2011-07-15 | 2019-09-24 | Novartis Ag | Salts of aza-bicyclic di-aryl ethers and methods to make them or their precursors |
Families Citing this family (44)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS6262265A (ja) * | 1985-09-13 | 1987-03-18 | Hitachi Ltd | 復水器自動検査補修システム |
GB0220581D0 (en) | 2002-09-04 | 2002-10-09 | Novartis Ag | Organic Compound |
DE602004031124D1 (de) | 2003-08-13 | 2011-03-03 | Neurosearch As | Neue chinuklidinderivative und deren pharmazeutische verwendung |
US7655657B2 (en) | 2003-12-22 | 2010-02-02 | Abbott Laboratories | Fused bicycloheterocycle substituted quinuclidine derivatives |
EP1824848A1 (en) * | 2004-12-10 | 2007-08-29 | Abbott Laboratories | Fused bicycloheterocycle substituted quinuclidine derivatives |
US7160876B2 (en) * | 2003-12-22 | 2007-01-09 | Abbott Laboratories | Fused bicycloheterocycle substituted quinuclidine derivatives |
US7309699B2 (en) | 2003-12-22 | 2007-12-18 | Abbott Laboratories | 3-Quinuclidinyl amino-substituted biaryl derivatives |
US20050245531A1 (en) * | 2003-12-22 | 2005-11-03 | Abbott Laboratories | Fused bicycloheterocycle substituted quinuclidine derivatives |
US20050137203A1 (en) * | 2003-12-22 | 2005-06-23 | Jianguo Ji | 3-quinuclidinyl amino-substituted biaryl derivatives |
US7241773B2 (en) | 2003-12-22 | 2007-07-10 | Abbott Laboratories | 3-quinuclidinyl heteroatom bridged biaryl derivatives |
US20050137217A1 (en) * | 2003-12-22 | 2005-06-23 | Jianguo Ji | Spirocyclic quinuclidinic ether derivatives |
US20050137398A1 (en) * | 2003-12-22 | 2005-06-23 | Jianguo Ji | 3-Quinuclidinyl heteroatom bridged biaryl derivatives |
AR049401A1 (es) | 2004-06-18 | 2006-07-26 | Novartis Ag | Aza-biciclononanos |
GB0415746D0 (en) * | 2004-07-14 | 2004-08-18 | Novartis Ag | Organic compounds |
CA2580856A1 (en) | 2004-09-20 | 2006-03-30 | Xenon Pharmaceuticals Inc. | Heterocyclic derivatives and their use as stearoyl-coa desaturase inhibitors |
BRPI0515482A (pt) | 2004-09-20 | 2008-07-22 | Xenon Pharmaceuticals Inc | derivados heterocìclicos e seus usos como agentes terapêuticos |
JP5149009B2 (ja) * | 2004-09-20 | 2013-02-20 | ゼノン・ファーマシューティカルズ・インコーポレイテッド | ヒトステアロイル−CoAデサチュラーゼを阻害するためのピリダジン誘導体 |
GB0424564D0 (en) | 2004-11-05 | 2004-12-08 | Novartis Ag | Organic compounds |
CA2618646A1 (en) | 2005-06-03 | 2007-11-15 | Xenon Pharmaceuticals Inc. | Aminothiazole derivatives as human stearoyl-coa desaturase inhibitors |
GB0521508D0 (en) * | 2005-10-21 | 2005-11-30 | Novartis Ag | Organic compounds |
GB0525672D0 (en) * | 2005-12-16 | 2006-01-25 | Novartis Ag | Organic compounds |
GB0525673D0 (en) | 2005-12-16 | 2006-01-25 | Novartis Ag | Organic compounds |
US7855208B2 (en) | 2006-02-14 | 2010-12-21 | Neurosearch A/S | 3, 9-diazabicyclo(3.3.1)non-3-yl-aryl methanone derivatives as nicotinic acetylcholine receptor agonists |
DE602007004307D1 (de) * | 2006-02-16 | 2010-03-04 | Neurosearch As | Enantiomerenreine chinuclidinyloxy-pyridazine und ihre verwendung als nikotin-acetylcholin-rezeptorliganden |
AU2007286807B2 (en) | 2006-08-21 | 2013-03-21 | Genentech, Inc. | Aza-benzothiophenyl compounds and methods of use |
RU2476220C2 (ru) * | 2007-08-02 | 2013-02-27 | Таргасепт, Инк. | (2s,3r)-n-(2-((3-пиридинил)метил)-1-азабицикло[2.2.2]окт-3-ил)бензофуран-2-карбоксамид, новые солевые формы и способы их применения |
US8383657B2 (en) | 2007-12-21 | 2013-02-26 | Abbott Laboratories | Thiazolylidine urea and amide derivatives and methods of use thereof |
MX2010014559A (es) | 2008-07-01 | 2011-03-04 | Genentech Inc | Heterociclos bicíclicos sustituidos y metodos de uso. |
AU2009266953A1 (en) | 2008-07-01 | 2010-01-07 | Genentech, Inc. | Isoindolone derivatives as MEK kinase inhibitors and methods of use |
US20120157464A1 (en) * | 2009-07-23 | 2012-06-21 | Novartis Ag | Use of azabicycloalkyl derivatives or pyrrolidine-2-one derivatives for the treatment or prevention of ataxia |
TWI558398B (zh) | 2009-09-22 | 2016-11-21 | 諾華公司 | 菸鹼乙醯膽鹼受體α7活化劑之用途 |
RU2012119488A (ru) | 2009-10-13 | 2013-11-20 | Мсд Осс Б.В. | Конденсированные азиновые производные для лечения заболеваний, связанных с ацетилхолиновым рецептором |
MX2013008704A (es) * | 2011-01-27 | 2013-08-21 | Novartis Ag | Uso de activadores del receptor de acetil-colina nicotinico alfa-7. |
KR20140018286A (ko) | 2011-03-18 | 2014-02-12 | 노파르티스 아게 | 파킨슨병에서의 도파민 유발 이상운동증에서 사용하기 위한 알파 7 니코틴성 아세틸콜린 수용체 활성화제 및 mGluR5 길항제의 조합물 |
JP6162705B2 (ja) * | 2011-10-20 | 2017-07-12 | ノバルティス アーゲー | アルファ7ニコチン性アセチルコリン受容体活性化剤による処置に対する応答性を予測するバイオマーカー |
AU2013356914B2 (en) * | 2012-12-11 | 2017-01-05 | Novartis Ag | Biomarker predictive of responsiveness to alpha 7 nicotinic acetylcholine receptor activator treatment |
EP2742940B1 (en) * | 2012-12-13 | 2017-07-26 | IP Gesellschaft für Management mbH | Fumarate salt of (R)-3-(6-(4-methylphenyl)-pyridin-3-yloxy)-l-aza-bicyclo-[2.2.2]octane for adminstration once daily, twice daily or thrice daily |
KR101879920B1 (ko) * | 2013-01-15 | 2018-07-18 | 노파르티스 아게 | 알파 7 니코틴성 아세틸콜린 수용체 작용물질의 용도 |
US20150313884A1 (en) * | 2013-01-15 | 2015-11-05 | Novartis Ag | Use of alpha 7 nicotinic acetylcholine receptor agonists |
EP2945626B1 (en) * | 2013-01-15 | 2018-09-12 | Novartis AG | Use of alpha 7 nicotinic receptor agonists for the treatment of narcolepsy |
BR112015016992A8 (pt) * | 2013-01-15 | 2018-01-23 | Novartis Ag | uso de agonistas do receptor alfa 7 nicotínico de acetilcolina |
GB201301626D0 (en) | 2013-01-30 | 2013-03-13 | Dignity Sciences Ltd | Composition comprising 15-OHEPA and methods of using the same |
EP4251158A1 (en) | 2020-11-25 | 2023-10-04 | Vanda Pharmaceuticals Inc. | Treatment of public speaking anxiety with an alpha-7 nicotinic acetylcholine receptor agonist |
WO2023213740A1 (en) * | 2022-05-05 | 2023-11-09 | Philip Morris Products S.A. | Nicotinic acetylcholine receptor ligands |
Family Cites Families (96)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB809574A (en) | 1956-01-26 | 1959-02-25 | Gasaccumulator Svenska Ab | Improvements in or relating to electrical signal light systems |
US3539573A (en) | 1967-03-22 | 1970-11-10 | Jean Schmutz | 11-basic substituted dibenzodiazepines and dibenzothiazepines |
BE759371A (fr) | 1969-11-24 | 1971-05-24 | Bristol Myers Co | Azaspirodecanediones heterocycliques et procedes pour leur preparation |
DE2139107A1 (de) | 1971-08-04 | 1973-02-15 | Merck Patent Gmbh | Heterocyclisch substituierte adenosinverbindungen |
ZA848275B (en) | 1983-12-28 | 1985-08-28 | Degussa | New piridine-2-ethers or pyridine-2-thioethers having a nitrogen-containing cycloaliphatic ring |
US4605652A (en) | 1985-02-04 | 1986-08-12 | A. H. Robins Company, Inc. | Method of enhancing memory or correcting memory deficiency with arylamido (and arylthioamido)-azabicycloalkanes |
EP0247266B1 (en) | 1986-01-07 | 1993-03-10 | Beecham Group Plc | Indole derivatives having an azabicyclic side chain, process for their preparation, intermediates, and pharmaceutical compositions |
KR880007433A (ko) | 1986-12-22 | 1988-08-27 | 메리 앤 터커 | 3-아릴옥시-3-치환된 프로판아민 |
ATE133415T1 (de) | 1987-04-15 | 1996-02-15 | Beecham Group Plc | Am brückenkopf substituierte azabicyclenderivate |
GB8718445D0 (en) | 1987-08-04 | 1987-09-09 | Wyeth John & Brother Ltd | Pyridyl-ethers |
CA1307790C (en) | 1987-08-04 | 1992-09-22 | Ian Anthony Cliffe | Ethers |
US5006528A (en) | 1988-10-31 | 1991-04-09 | Otsuka Pharmaceutical Co., Ltd. | Carbostyril derivatives |
DE8817121U1 (de) | 1988-11-22 | 1993-02-04 | Boehringer Ingelheim Kg, 55218 Ingelheim | Neue Quinuclidine |
GB8829079D0 (en) | 1988-12-13 | 1989-01-25 | Beecham Group Plc | Novel compounds |
CA2002182C (en) | 1989-11-03 | 2000-06-13 | Richard J. Wurtman | Compositions for treating the premenstrual or late luteal phase syndrome and methods for their use |
DE4116582A1 (de) | 1990-05-19 | 1991-11-21 | Boehringer Ingelheim Kg | Bicyclische 1-aza-cycloalkane |
YU84791A (sh) | 1990-05-19 | 1994-06-10 | Boehringer Ingelheim Kg. | Biciklicni 1-aza-cikloalkalni |
AU8405991A (en) | 1990-08-31 | 1992-03-30 | Nippon Shinyaku Co. Ltd. | Pyrimidine derivative and medicine |
JP3087763B2 (ja) | 1990-11-30 | 2000-09-11 | 三井化学株式会社 | 新規な複素環式化合物およびそれを含有する医薬組成物 |
US5260303A (en) | 1991-03-07 | 1993-11-09 | G. D. Searle & Co. | Imidazopyridines as serotonergic 5-HT3 antagonists |
AU1752792A (en) | 1991-03-08 | 1992-10-06 | Rhone-Poulenc Rorer International (Holdings) Inc. | Multicyclic tertiary amine polyaromatic squalene synthetase inhibitors |
US5385912A (en) * | 1991-03-08 | 1995-01-31 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Multicyclic tertiary amine polyaromatic squalene synthase inhibitors |
JPH05310732A (ja) | 1992-03-12 | 1993-11-22 | Mitsubishi Kasei Corp | シンノリン−3−カルボン酸誘導体 |
US5612352A (en) * | 1992-04-10 | 1997-03-18 | Zeneca Limited | Heterocyclic compounds |
IL107184A (en) | 1992-10-09 | 1997-08-14 | Abbott Lab | Heterocyclic ether compounds that enhance cognitive function |
AU7394394A (en) | 1992-10-13 | 1995-12-05 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | 3-hydroxyquinuclidin-3-ylphenylquinolines as squalene synthase inhibitors |
WO1994018201A1 (en) | 1993-02-12 | 1994-08-18 | Sankyo Company, Limited | Isoxazoleoxy derivative |
JPH06293768A (ja) | 1993-02-12 | 1994-10-21 | Sankyo Co Ltd | イソオキサゾールオキシ誘導体 |
JP3235913B2 (ja) | 1993-07-30 | 2001-12-04 | エーザイ株式会社 | アミノ安息香酸誘導体 |
JP4208267B2 (ja) | 1993-07-30 | 2009-01-14 | キヤノン株式会社 | 制御装置 |
US5998404A (en) | 1994-10-24 | 1999-12-07 | Eli Lilly And Company | Heterocyclic compounds and their use |
EP0853621A1 (en) | 1995-09-22 | 1998-07-22 | Novo Nordisk A/S | Novel substituted azacyclic or azabicyclic compounds |
SE9600683D0 (sv) | 1996-02-23 | 1996-02-23 | Astra Ab | Azabicyclic esters of carbamic acids useful in therapy |
ZA984637B (en) | 1997-05-30 | 1998-12-21 | Neurosearch As | Spiro-quinuclidine derivatives their preparation and use |
AR013184A1 (es) | 1997-07-18 | 2000-12-13 | Astrazeneca Ab | Aminas heterociclicas espiroazobiciclicas, composicion farmaceutica, uso de dichas aminas para preparar medicamentos y metodo de tratamiento o profilaxis |
US6432975B1 (en) | 1998-12-11 | 2002-08-13 | Targacept, Inc. | Pharmaceutical compositions and methods for use |
US6953855B2 (en) | 1998-12-11 | 2005-10-11 | Targacept, Inc. | 3-substituted-2(arylalkyl)-1-azabicycloalkanes and methods of use thereof |
SE9900100D0 (sv) | 1999-01-15 | 1999-01-15 | Astra Ab | New compounds |
EP1202736B1 (en) | 1999-07-28 | 2008-09-17 | The Board Of Trustees Of The Leland Stanford Junior University | Nicotine in therapeutic angiogenesis and vasculogenesis |
SE9903760D0 (sv) | 1999-10-18 | 1999-10-18 | Astra Ab | New compounds |
SE9904176D0 (sv) | 1999-11-18 | 1999-11-18 | Astra Ab | New use |
SE0000540D0 (sv) * | 2000-02-18 | 2000-02-18 | Astrazeneca Ab | New compounds |
WO2001066546A1 (fr) | 2000-03-09 | 2001-09-13 | Mitsubishi Pharma Corporation | Composes spiro, leur procede de preparation et leur utilisation comme medicaments |
GB0010955D0 (en) | 2000-05-05 | 2000-06-28 | Novartis Ag | Organic compounds |
JP4616971B2 (ja) | 2000-07-18 | 2011-01-19 | 田辺三菱製薬株式会社 | 1−アザビシクロアルカン化合物およびその医薬用途 |
EP1381603A2 (en) | 2000-08-18 | 2004-01-21 | PHARMACIA & UPJOHN COMPANY | Quinuclidine-substituedaryl moieties for treatment of disease ( nicotinic acetylcholine receptor ligands ) |
AU2001284646A1 (en) | 2000-08-21 | 2002-03-04 | Pharmacia And Upjohn Company | Quinuclidine-substituted heteroaryl moieties for treatment of disease |
GB0021885D0 (en) | 2000-09-06 | 2000-10-18 | Fujisawa Pharmaceutical Co | New use |
PE20021019A1 (es) | 2001-04-19 | 2002-11-13 | Upjohn Co | Grupos azabiciclicos sustituidos |
AR036040A1 (es) | 2001-06-12 | 2004-08-04 | Upjohn Co | Compuestos de heteroarilo multiciclicos sustituidos con quinuclidinas y composiciones farmaceuticas que los contienen |
EP1438308A1 (en) | 2001-10-26 | 2004-07-21 | PHARMACIA & UPJOHN COMPANY | N-azabicyclo-substituted hetero-bicyclic carboxamides as nachr agonists |
DE10156719A1 (de) | 2001-11-19 | 2003-05-28 | Bayer Ag | Heteroarylcarbonsäureamide |
DE10162375A1 (de) | 2001-12-19 | 2003-07-10 | Bayer Ag | Bicyclische N-Aryl-amide |
AU2003214936A1 (en) | 2002-02-20 | 2003-09-09 | Pharmacia And Upjohn Company | Azabicyclic compounds with alfa7 nicotinic acetylcholine receptor activity |
DE10211415A1 (de) | 2002-03-15 | 2003-09-25 | Bayer Ag | Bicyclische N-Biarylamide |
DE10211416A1 (de) | 2002-03-15 | 2003-09-25 | Bayer Ag | Essig- und Propionsäureamide |
DE10234424A1 (de) | 2002-07-29 | 2004-02-12 | Bayer Ag | Benzothiophen-, Benzofuran- und Indolharnstoffe |
PL375533A1 (en) * | 2002-08-14 | 2005-11-28 | Neurosearch A/S | Novel quinuclidine derivatives and their use |
GB0220581D0 (en) | 2002-09-04 | 2002-10-09 | Novartis Ag | Organic Compound |
JP4890762B2 (ja) | 2002-09-25 | 2012-03-07 | メモリー・ファーマシューティカルズ・コーポレイション | インダゾール、ベンゾチアゾール、及びベンゾイソチアゾール、並びにそれらの調製及び使用 |
AU2003284898A1 (en) | 2002-10-29 | 2004-05-25 | Micro, Inc. | Combinative nicotinic/d1 agonism therapy for the treatment of alzheimer's disease |
AU2003269413A1 (en) | 2002-11-01 | 2004-05-25 | Pharmacia & Upjohn Company Llc | Nicotinic acetylcholine agonists in the treatment of glaucoma and retinal neuropathy |
EP1562959A2 (en) | 2002-11-01 | 2005-08-17 | Pharmacia & Upjohn Company LLC | Compounds having both alpha7 nachr agonist and 5ht antagonist activity for treatment of cns diseases |
DE60309740T2 (de) | 2002-11-11 | 2007-03-29 | Neurosearch A/S | 1,4-dizabicyclo(3,2,2)nonane derivative, verfahren zu ihrer herstellung und therapeutical verwendung |
MXPA05005666A (es) | 2002-12-11 | 2005-07-26 | Pharmacia & Upjohn Co Llc | Tratamiento de enfermedades con combinaciones de agonistas del receptor nicotinico de acetilcolina alfa-7 y otros compuestos. |
CA2513433A1 (en) | 2003-01-22 | 2004-08-05 | Pharmacia & Upjohn Company Llc | Treatment of diseases with alpha-7 nach receptor full agonists |
WO2005013910A2 (en) | 2003-08-07 | 2005-02-17 | University Of South Florida | Cholinergic modulation of microglial activation via alpha-7 nicotinic receptors |
JP4226981B2 (ja) | 2003-09-24 | 2009-02-18 | 三井金属鉱業株式会社 | プリント配線板の製造方法及びその製造方法で得られたプリント配線板 |
EP1824848A1 (en) | 2004-12-10 | 2007-08-29 | Abbott Laboratories | Fused bicycloheterocycle substituted quinuclidine derivatives |
US20050137203A1 (en) | 2003-12-22 | 2005-06-23 | Jianguo Ji | 3-quinuclidinyl amino-substituted biaryl derivatives |
US7160876B2 (en) | 2003-12-22 | 2007-01-09 | Abbott Laboratories | Fused bicycloheterocycle substituted quinuclidine derivatives |
US20050245531A1 (en) | 2003-12-22 | 2005-11-03 | Abbott Laboratories | Fused bicycloheterocycle substituted quinuclidine derivatives |
US20050137398A1 (en) | 2003-12-22 | 2005-06-23 | Jianguo Ji | 3-Quinuclidinyl heteroatom bridged biaryl derivatives |
US20070060588A1 (en) | 2003-12-22 | 2007-03-15 | Jianguo Ji | Fused bicycloheterocycle substituted quinuclidine derivatives |
US7241773B2 (en) | 2003-12-22 | 2007-07-10 | Abbott Laboratories | 3-quinuclidinyl heteroatom bridged biaryl derivatives |
US7655657B2 (en) | 2003-12-22 | 2010-02-02 | Abbott Laboratories | Fused bicycloheterocycle substituted quinuclidine derivatives |
US20050137204A1 (en) | 2003-12-22 | 2005-06-23 | Abbott Laboratories | Fused bicycloheterocycle substituted quinuclidine derivatives |
JP2007516275A (ja) | 2003-12-23 | 2007-06-21 | ファイザー・プロダクツ・インク | 認知増強および精神病性障害のための治療的組合せ |
US7875624B2 (en) | 2004-02-20 | 2011-01-25 | Novartis Vaccines And Diagnostics, Inc. | Modulating and measuring cellular adhesion |
AU2005233642A1 (en) | 2004-04-13 | 2005-10-27 | Astellas Pharma Inc. | Polycyclic pyridines as potassium ion channel modulators |
JP2007538046A (ja) | 2004-05-19 | 2007-12-27 | ノイロサーチ アクティーゼルスカブ | 新規なアザビシクロアリール誘導体 |
AR049401A1 (es) | 2004-06-18 | 2006-07-26 | Novartis Ag | Aza-biciclononanos |
GB0415746D0 (en) | 2004-07-14 | 2004-08-18 | Novartis Ag | Organic compounds |
DE602005025902D1 (de) | 2004-10-15 | 2011-02-24 | Neurosearch As | Neue azabizyklische arylderivate und medizinische verwendung damit |
GB0424564D0 (en) | 2004-11-05 | 2004-12-08 | Novartis Ag | Organic compounds |
EP1866314B1 (en) | 2005-02-16 | 2010-09-15 | NeuroSearch A/S | Novel diazabicyclic aryl derivatives and their medical use |
EP1863485A2 (en) | 2005-03-18 | 2007-12-12 | Abbott Laboratories | Alpha7 neuronal nicotinic receptor ligand and antipsychotic compositions |
CA2606174A1 (en) | 2005-04-18 | 2006-10-26 | Saeed R. Khan | Design and synthesis of novel tubulin polymerization inhibitors: benzoylphenylurea (bpu) sulfur analogs |
FR2884822B1 (fr) | 2005-04-22 | 2007-06-29 | Aventis Pharma Sa | Derives de triazines, leur preparation et leur application en therapeutique |
GB0508314D0 (en) | 2005-04-25 | 2005-06-01 | Novartis Ag | Organic compounds |
CN101228163A (zh) | 2005-06-14 | 2008-07-23 | 先灵公司 | 天冬氨酰蛋白酶抑制剂 |
GB0521508D0 (en) | 2005-10-21 | 2005-11-30 | Novartis Ag | Organic compounds |
GB0525673D0 (en) | 2005-12-16 | 2006-01-25 | Novartis Ag | Organic compounds |
GB0525672D0 (en) * | 2005-12-16 | 2006-01-25 | Novartis Ag | Organic compounds |
TW200813067A (en) | 2006-05-17 | 2008-03-16 | Astrazeneca Ab | Nicotinic acetylcholine receptor ligands |
JP5310732B2 (ja) | 2008-10-17 | 2013-10-09 | Nokクリューバー株式会社 | 潤滑グリース組成物およびその製造法 |
-
2002
- 2002-09-04 GB GB0220581A patent/GB0220581D0/en not_active Ceased
-
2003
- 2003-09-03 WO PCT/EP2003/009772 patent/WO2004022556A1/en active IP Right Grant
- 2003-09-03 EP EP20030793791 patent/EP1537104B1/en not_active Expired - Lifetime
- 2003-09-03 JP JP2004533455A patent/JP4348422B2/ja not_active Expired - Lifetime
- 2003-09-03 US US10/526,759 patent/US20060167002A1/en not_active Abandoned
- 2003-09-03 DE DE60330015T patent/DE60330015D1/de not_active Expired - Lifetime
- 2003-09-03 SI SI200331746T patent/SI1537104T1/sl unknown
- 2003-09-03 KR KR20057003665A patent/KR100808324B1/ko active IP Right Review Request
- 2003-09-03 BR BR122014026685-5A patent/BR122014026685B1/pt not_active IP Right Cessation
- 2003-09-03 DK DK03793791T patent/DK1537104T3/da active
- 2003-09-03 AT AT03793791T patent/ATE448225T1/de active
- 2003-09-03 AU AU2003260486A patent/AU2003260486C1/en not_active Expired
- 2003-09-03 MX MXPA05002546A patent/MXPA05002546A/es active IP Right Grant
- 2003-09-03 RU RU2005109913A patent/RU2352569C2/ru active
- 2003-09-03 CN CNB038207303A patent/CN1325493C/zh not_active Expired - Lifetime
- 2003-09-03 NZ NZ538534A patent/NZ538534A/en not_active IP Right Cessation
- 2003-09-03 PL PL374013A patent/PL209425B1/pl unknown
- 2003-09-03 KR KR1020077011698A patent/KR20070058027A/ko not_active Application Discontinuation
- 2003-09-03 EP EP20100184187 patent/EP2308876A1/en not_active Withdrawn
- 2003-09-03 ES ES03793791T patent/ES2336099T3/es not_active Expired - Lifetime
- 2003-09-03 BR BRPI0314325A patent/BRPI0314325B8/pt active IP Right Grant
- 2003-09-03 PT PT03793791T patent/PT1537104E/pt unknown
- 2003-09-03 EP EP20090164576 patent/EP2100893A1/en not_active Withdrawn
- 2003-09-03 CA CA 2495685 patent/CA2495685C/en not_active Expired - Lifetime
-
2005
- 2005-01-27 ZA ZA200500816A patent/ZA200500816B/xx unknown
- 2005-02-15 IL IL16691805A patent/IL166918A/en active IP Right Grant
- 2005-02-22 EC ECSP055621 patent/ECSP055621A/es unknown
- 2005-04-01 NO NO20051626A patent/NO331556B1/no not_active IP Right Cessation
- 2005-11-07 HK HK05109896A patent/HK1077822A1/xx not_active IP Right Cessation
- 2005-11-30 HK HK05110918A patent/HK1078868A1/xx not_active IP Right Cessation
-
2007
- 2007-06-26 US US11/823,312 patent/US7579362B2/en not_active Expired - Lifetime
-
2008
- 2008-10-31 US US12/262,896 patent/US8236803B2/en not_active Expired - Lifetime
-
2009
- 2009-02-19 JP JP2009036918A patent/JP5124714B2/ja not_active Expired - Fee Related
-
2010
- 2010-02-10 CY CY101100129T patent/CY1109765T1/el unknown
-
2012
- 2012-05-02 US US13/462,187 patent/US9012451B2/en not_active Expired - Lifetime
-
2013
- 2013-02-28 IL IL225002A patent/IL225002A/en active IP Right Grant
-
2015
- 2015-03-10 US US14/643,275 patent/US9567343B2/en not_active Expired - Lifetime
-
2017
- 2017-01-04 US US15/398,427 patent/US9849117B2/en not_active Expired - Lifetime
- 2017-11-21 US US15/819,535 patent/US20180078536A1/en not_active Abandoned
-
2018
- 2018-11-15 US US16/191,693 patent/US20190083474A1/en not_active Abandoned
Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8884017B2 (en) | 2001-12-27 | 2014-11-11 | Bayer Intellectual Property Gmbh | 2-heteroarylcarboxylic acid amides |
US8569354B2 (en) | 2008-11-19 | 2013-10-29 | Envivo Pharmaceuticals, Inc. | Treatment of cognitive disorders with (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide and pharmaceutically acceptable salts thereof |
US8642638B2 (en) | 2008-11-19 | 2014-02-04 | Envivo Pharmaceuticals, Inc. | Treatment of cognitive disorders with (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide and pharmaceutically acceptable salts thereof |
US8815933B2 (en) | 2008-11-19 | 2014-08-26 | Forum Pharmaceuticals, Inc. | Treatment of cognitive disorders with (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide and pharmaceutically acceptable salts thereof |
US20110124631A1 (en) * | 2009-05-11 | 2011-05-26 | Gerhard Koenig | Treatment of cognitive disorders with certain alpha-7 nicotinic acid receptors in combination with acetylcholinesterase inhibitors |
US8710227B2 (en) | 2010-05-17 | 2014-04-29 | Envivo Pharmaceuticals, Inc. | Crystalline form of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride monohydrate |
US9108961B2 (en) | 2010-05-17 | 2015-08-18 | Forum Pharmaceuticals, Inc. | Crystalline form of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride |
US9273044B2 (en) | 2010-05-17 | 2016-03-01 | Forum Pharmaceuticals, Inc. | Crystalline form of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride monohydrate |
US9550767B2 (en) | 2010-05-17 | 2017-01-24 | Forum Pharmaceuticals, Inc. | Crystalline form of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride monohydrate |
US10421755B2 (en) * | 2011-07-15 | 2019-09-24 | Novartis Ag | Salts of aza-bicyclic di-aryl ethers and methods to make them or their precursors |
US9585877B2 (en) | 2012-05-08 | 2017-03-07 | Forum Pharmaceuticals, Inc. | Methods of maintaining, treating or improving cognitive function |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US9849117B2 (en) | Aza-bicycloalkyl ethers and their use as alpha7-nachr agonists | |
KR101343654B1 (ko) | 1-아자-비시클로〔3.3.1〕노난 | |
US8173667B2 (en) | 1-aza-bicycloalkyl derivatives | |
AU2001262257A1 (en) | Azabicyclic carbamates and their use as alpha-7 nicotinic acetylcholine receptor agonists | |
EP1282620A1 (en) | Azabicyclic carbamates and their use as alpha-7 nicotinic acetylcholine receptor agonists | |
TW201902900A (zh) | 用於誘發軟骨生成之化合物及組合物 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |