WO2012114285A1 - Heteroaryl derivatives as alpha7 nachr modulators - Google Patents
Heteroaryl derivatives as alpha7 nachr modulators Download PDFInfo
- Publication number
- WO2012114285A1 WO2012114285A1 PCT/IB2012/050806 IB2012050806W WO2012114285A1 WO 2012114285 A1 WO2012114285 A1 WO 2012114285A1 IB 2012050806 W IB2012050806 W IB 2012050806W WO 2012114285 A1 WO2012114285 A1 WO 2012114285A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- optionally substituted
- group
- methyl
- alkynyl
- Prior art date
Links
- BYVJAZOEQHSTMP-UHFFFAOYSA-N Bc1c(C(OC)=O)[s]cc1C Chemical compound Bc1c(C(OC)=O)[s]cc1C BYVJAZOEQHSTMP-UHFFFAOYSA-N 0.000 description 1
- YSTWQCSMRHVGPN-UHFFFAOYSA-N CCC(c([s]c(-c(cc1)ccc1Cl)c1)c1-c(cc1)ccc1S(N)(=O)=O)=O Chemical compound CCC(c([s]c(-c(cc1)ccc1Cl)c1)c1-c(cc1)ccc1S(N)(=O)=O)=O YSTWQCSMRHVGPN-UHFFFAOYSA-N 0.000 description 1
- GNQPIQGQHGUCGA-UHFFFAOYSA-N CCOC(c([s]c(Br)c1N(C)C)c1Br)=O Chemical compound CCOC(c([s]c(Br)c1N(C)C)c1Br)=O GNQPIQGQHGUCGA-UHFFFAOYSA-N 0.000 description 1
- OULCKIOJXFQEFJ-UHFFFAOYSA-N CCOC(c([s]cc1C)c1-c(cc1)ccc1S(N1CCCCC1)(=O)=O)=O Chemical compound CCOC(c([s]cc1C)c1-c(cc1)ccc1S(N1CCCCC1)(=O)=O)=O OULCKIOJXFQEFJ-UHFFFAOYSA-N 0.000 description 1
- 0 Cc1c(*)[s]c(C(O*)=O)c1-c1ccccc1 Chemical compound Cc1c(*)[s]c(C(O*)=O)c1-c1ccccc1 0.000 description 1
- KVUQQNHOEVKYOX-UHFFFAOYSA-N Cc1c(-c(cc2)ccc2Cl)[s]c(C(O)=O)c1-c(cc1C)ccc1S(N)(=O)=O Chemical compound Cc1c(-c(cc2)ccc2Cl)[s]c(C(O)=O)c1-c(cc1C)ccc1S(N)(=O)=O KVUQQNHOEVKYOX-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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
-
- 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
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
-
- 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
- A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
-
- 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
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- 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
- A61P25/14—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
- A61P25/24—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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- 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
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/333—Radicals substituted by oxygen or sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/337—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/22—Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/30—Hetero atoms other than halogen
- C07D333/36—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
Definitions
- the present invention is related to novel compounds of the general formula I,
- Neural nicotinic ACh receptors belong to the class of ligand-gated ion channels (LGIC) comprising of five subunits ( ⁇ 2- ⁇ 10, ⁇ 2- ⁇ 4) arranged in heteropentameric ( ⁇ 4 ⁇ 2) or homopertameric (oc7) configuration (Paterson D et al., Prog. Neurobiol., 2000, 61 , 75- 11 1).
- LGIC ligand-gated ion channels
- ⁇ 4 ⁇ 2 and oc7 nAChR constitute the predominant subtypes expressed in the mammalian brain.
- oc7 nAChR has attained prominence as a therapeutic target due to its abundant expression in the learning and memory centers of brain, hippocampus and the cerebral cortex (Rubboli F et al., Neurochem.
- oc7 nAChR is characterized by a high Ca 2+ ion permeability, which is responsible for neurotransmitter release and consequent modulation of excitatory and inhibitory neurotransmission (Alkondon M et al., Eur. J. Pharmacol., 2000, 393, 59-67; Dajas-Bailador F et al., Trends Pharmacol. Sci., 2004, 25, 317-324).
- high Ca 2+ ion influx also has implications on the long-term potentiation of memory via alterations in gene expression (Bitner RS et al., J. Neurosci., 2007, 27, 10578- 10587; McKay BE et al., Biochem. Pharmacol., 2007, 74, 1120- 1 133).
- pharmacological blockade of a 7 nAChR impairs memory and its activation enhances same in preclinical rodent models implicating oc7 nAChR as target for cognitive enhancement (Hashimoto K et al., Biol. Psychiatry, 2008, 63, 92-97).
- Pathological brain function in sensory-deficit disorders has been associated with nicotinic cholinergic transmission particularly through oc7 receptors (Freedman R et al., Biol. Psychiatry, 1995, 38, 22-33; Tsuang DW et al., Am. J. Med. Genet., 2001 , 105, 662-668; Carson R et al., Neuromolecular, 2008, Med. 10, 377-384; Leonard S et al., Pharmacol. Biochem. Behav., 2001 , 70, 561-570; Freedman R et al., Curr. Psychiatry Rep., 2003, 5, 155-161; Cannon TD et al., Curr. Opin.
- a defective pre-attention processing of sensory information is understood to be the basis of cognitive fragmentation in schizophrenia and related neuropsychiatric disorders (Leiser SC et al., Pharmacol. Ther., 2009, 122, 302-31 1). Genetic linkage studies have traced sharing of the oc7 gene locus for several affective, attention, anxiety and psychotic disorders (Leonard S et al., Pharmacol. Biochem. Behav., 2001 , 70, 561-570; Suemaru K et al., Nippon Yakurigaku Zasshi, 2002, 119, 295-300).
- Nicotinic ACh receptor particularly the interaction of oc7 receptor to ⁇ -42 is implicated as an up-stream pathogenic event in Alzheimer's disease, a major causative factor for dementia (Wang HY et al., J. Neurosci., 2009, 29, 10961- 10973).
- CHRNA7 gene polymorphisms in CHRNA7 have been implicated in dementia with lewy bodies (DLB) and Pick's disease (Feher A et al., Dement. Geriatr. Cogn. Disord., 2009, 28, 56-62).
- nAChRs particularly the oc7 receptor has application for disease-modification of Alzheimer 's disease (AD) and Parkinson's disease (PD) by enhancing neuron survival and preventing neurodegeneration (Wang et al. 2009; Nagele RG et al., Neuroscience, 2002, 1 10, 199-21 1; Jeyarasasingam G et al., Neuroscience, 2002, 109, 275-285). Additionally, oc7 nAChR induced activation of anti-apoptotic (BCL-2) and anti-inflammatory pathways in brain could have neuroprotective effects in neurodegenerative diseases (Marrero MB et al., Brain. Res., 2009, 1256, 1-7).
- Dopamine containing neurons of ventral tegmental area (VTA) and laterodorsal tegmental nucleus (LDT) are known to express nicotinic ACh receptors, particularly oc4, oc3, ⁇ 2, ⁇ 3, ⁇ 4 subunits (Kuzmin A et al., Psychopharmacology (Berl), 2009, 203, 99- 108). Nicotinic ACh receptors, ⁇ 4 ⁇ 2 and ⁇ 3 ⁇ 4 have been identified with candidate-gene approach to have strong mechanistic link for nicotine addiction (Weiss RB et al., PLoS Genet., 2008, 4, el000125).
- oc7 nAChR has particularly been studied for a putative role in cannabis addiction (Solinas M et al., J. Neurosci., 2007, 27, 5615-5620).
- Varenicline a partial agonist at ⁇ 4 ⁇ 2
- nicotinic ACh receptor agonists like epibatidine
- Several new developments have opened the area for use of nicotinic modulators for therapy of pain (Rowbotham MC et al., Pain, 2009, 146, 245-252). Appropriate modulation of the nicotinic ACh receptors could provide for remedial approach to pain related states.
- oc7 nAChR Another key role of the oc7 nAChR is the ability to modulate the production of proinflammatory cytokines, like interleukins (IL), tumor necrosis factor alpha (TNF-a), and high mobility group box (HMGB- 1) in the central nervous system. Consequently, an anti-inflammatory and antinociceptive effect in pain disorders have been demonstrated (Damaj MI et al., Neuropharmacology, 2000, 39, 2785- 2791).
- IL interleukins
- TNF-a tumor necrosis factor alpha
- HMGB-1 high mobility group box
- 'cholinergic anti- inflammatory pathway' is proposed to be a regulatory of local and systemic inflammation and neuro-immune interactions through neural and humoral pathways (Gallowitsch-Puerta M et al., Life Sci., 2007, 80, 2325-2329; Gallowitsch-Puerta and Pavlov 2007; Rosas-Ballina M et al., Mol. Med., 2009, 15, 195-202; Rosas-Ballina M et al., J. Intern. Med., 2009, 265, 663- 679).
- Selective modulators of nicotinic ACh receptors, particularly oc7 type, like GTS-21 attenuate cytokine production and IL- ⁇ after endotoxin exposure.
- oc7 nAChR are understood to have a central role in arthritis pathogenesis and potential therapeutic strategy for treatment of joint inflammation (Westman M et al., Scand. J. Immunol., 2009, 70, 136- 140).
- a putative role for oc7 nAChR has also been implicated in severe sepsis, endotoxemic shock and systemic inflammation (Jin Y et al. (2010) Int. J. Immunogenet. , Liu C et al., Crit. Care. Med., 2009, 37, 634-641).
- Angiogenesis is a critical physiological process for the cell survival and pathologically important for cancer proliferation; several non-neural nicotinic ACh receptors, particularly oc7, oc5, oc3, ⁇ 2, ⁇ 4, are involved (Arias HR et al., Int. J. Biochem. Cell. Biol., 2009, 41 , 1441- 1451; Heeschen C et al., J. Clin. Invest., 2002, 110, 527-536).
- a role of nicotinic ACh receptors in the development of cervical cancer, lung carcinogenesis and paediatric lung disorders in smoking- exposed population has also been studied (Calleja-Macias IE et al., Int. J.
- GTS-21 (DMXB-Anabaseine), an oc7 nAChR agonist, in the P II clinical trials, has shown efficacy in improving cognitive deficits in schizophrenia and inhibition of endotoxin-induced TNF-a release (Olincy A et al., Biol. Psychiatry, 2005, 57(8, Suppl.), Abst 44; Olincy A et al., Arch. Gen. Psychiatry, 2006, 63, 630-638; Goldstein R et al., Acad. Emerg. Med., 2007, 14 (15, Suppl. 1), Abst 474).
- CP-810123 a cc7 nAChR agonist
- SSR-18071 1A also an cc7 nAChR agonist, enhances learning and memory, and protects against MK- 801 /Scopolamine-induced memory loss and prepulse inhibition in preclinical studies (Redrobe JP et al., Eur. J. Pharmacol., 2009, 602, 58-65; Dunlop J et al., J. Pharmacol. Exp.
- ABBF an agonist at oc7 nAChR, improves social recognition memory and working memory in Morris maze task in rats (Boess FG et al., J. Pharmacol. Exp. Ther., 2007, 321, 716-725).
- TC-5619 a selective oc7 nAChR agonist has demonstrated efficacy in animal models of positive and negative symptoms and cognitive dysfunction in schizophrenia (Hauser TA et al., Biochem. Pharmacol., 2009, 78, 803-812).
- XY-4083 an a7 nAChR PAM, normalizes the sensorimotor gating deficits in the DBA/2 mice and memory acquisition in 8-arm radial maze without altering the receptor desensitization kinetics (Ng HJ et al., Proc. Natl. Acad. Sci., U. S. A., 2007, 104, 8059-8064). Yet another PAM, PNU- 120596, profoundly alters a7 nAChR desensitization kinetics and simultaneously protecting against the disruption of prepulse inhibition by MK-801.
- NS- 1738 another PAM, has exhibited efficacy in-vlvo in the animal models of social recognition and spatial memory acquisition in the Morris maze task (Timmermann DB et al., J. Pharmacol. Exp. Ther., 2007, 323, 294-307).
- the present invention further provides a pharmaceutical composition, containing the compounds of the general formula (I) as defined herein, its tautomeric forms, its stereoisomers, its analogues, its prodrugs, its isotopically substituted analogues, its metabolites, its pharmaceutically acceptable salts, its polymorphs, its solvates, its optical isomers, its clathrates and its co-crystals in combination with the usual pharmaceutically employed carriers, diluents and the like are useful for the treatment and/or prophylaxis of diseases or disorder or condition such as Alzheimer's disease (AD), mild cognitive impairment (MCI), senile dementia, vascular dementia, dementia of Parkinson's disease, attention deficit disorder, attention deficit hyperactivity disorder (ADHD), dementia associated with Lewy bodies, AIDS dementia complex (ADC), Pick's disease, dementia associated with Down's syndrome, Huntington's disease, cognitive deficits associated with traumatic brain injury (TBI), cognitive decline associated with stroke, posts troke neuroprotection, cognitive and sensori
- the present invention also provides method of administering a compound of formula I, as defined herein in combination with or as adjunct to medications used in the treatment of attention deficit hyperactivity disorders, schizophrenia, and other cognitive disorders such as Alzheimer's disease, Parkinson's dementia, vascular dementia or dementia associated with Lewy bodies, traumatic brain injury.
- the present invention also provides method of administering a compound of formula I, as defined herein in combination with or as an adjunct to acetylcholinesterase inhibitors, disease modifying drugs or biologies for neurodegenerative disorders, dopaminergic drugs, antidepressants, typical or an atypical antipsychotic.
- the present invention also provides use of a compound of formula I as definded herein in the preparation of a medicament for treating a disease or disorder or condition selected from the group classified or diagnosed as major or minor neurocognitive disorders, or disorders arising due to neurodegeneration.
- the present invention also provides use of a compound of formula I as definded herein in the preparation of a medicament for treating a disease or disorder or condition selected from the group consisting of attention deficit hyperactivity disorders, schizophrenia, cognitive disorders, Alzheimer's disease, Parkinson's dementia, vascular dementia or dementia associated with Lewy bodies, and traumatic brain injury.
- a disease or disorder or condition selected from the group consisting of attention deficit hyperactivity disorders, schizophrenia, cognitive disorders, Alzheimer's disease, Parkinson's dementia, vascular dementia or dementia associated with Lewy bodies, and traumatic brain injury.
- the present invention also provides use of compound of formula I as defined herein in combination with or as an adjunct to acetylcholinesterase inhibitors, disease modifying drugs or biologies for neurodegenerative disorders, dopaminergic drugs, antidepressants, or a typical or atypical antipsychotic.
- the present invention relates to novel compounds of the general formula I, its tautomeric forms, its stereoisomers, its analogues, its prodrugs, its isotopically substituted analogues, its metabolites, its sulfoxides, its N-oxides, its pharmaceutically acceptable salts, its polymorphs, its solvates, its optical isomers, its clathrates, its co-crystals, their combinations with suitable medicament and pharmaceutical compositions containing them.
- Z is selected from the group consisting of -S-, -O- and -N(R a )-;
- R a is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl;
- R 1 is selected from the group consisting of optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl;
- a range of the number of atoms in a structure is indicated (e.g., a Ci i 2 , Ci-8, Ci-6, or Ci-4 alkyl, alkylamino, etc.), it is specifically contemplated that any sub-range or individual number of carbon atoms falling within the indicated range also can be used.
- any chemical group e.g., alkyl, alkylamino, etc.
- any chemical group e.g., alkyl, alkylamino, etc.
- any sub-range thereof e.g., 1-2 carbon atoms, 1-3 carbon atoms, 1-4 carbon atoms, 1-5 carbon atoms, 1-6 carbon atoms, 1-7 carbon atoms, 1-8 carbon atoms, 1-9 carbon atoms, 1- 10 carbon atoms, 1- 1 1 carbon atoms, 1-12
- Another embodiment of the present invention is compound of formula lb;
- R 3 is particularly selected from the group consisting of methyl, ethyl, n-propyl, methoxy, ethoxy, dimethylamino, N- methoxy-N-methyl amino, N-(2-hydroxy ethyl)-N-propyl amino, acetylaminomethyl and piperidinyl.
- R 5 and R 6 are particularly selected independently from the group consisting of hydrogen and methyl, or R 4 and R 5 together with the nitrogen atom to which they are attached form a piperidine ring.
- m is particularly selected from 0, 1 or 2
- R 4 is selected from methyl or two R 4 s together with the carbon atoms to which they are attached forming a six membered carbocycle.
- R a is particularly selected from the group consisting of hydrogen, methyl, ethyl and cyclopropylmethyl.
- the group there by includes the linkages like CH 3 -S-, CH3-CH2-O-, CH3-O-CH2-, CH 3 -S-CH 2 -, CH 3 -N(RTM)-CH 2 -, CH 3 -Si(R m )R n -CH 2 - and the like.
- cycloalkyl also include spiro systems wherein one of the ring is annulated on a single carbon atom such ring systems are exemplified by spiro [2.5] octane, spiro[4.5]decane, spiro [bicyclo [4.1.0]heptane-2, 1 '-cyclopentane] , hexahydro-2'H- spiro [cyclopropane- 1 , 1 '-pentalene] .
- bicyclic heterocycle include, but are not limited to 1 ,3-benzodioxolyl, 1 ,3-benzodithiolyl, 2,3-dihydro- l ,4- benzodioxinyl, 2,3-dihydro- l -benzofuranyl, 2,3-dihydro- l -benzothienyl, 2,3- dihydro- 1 H-indolyl and 1 ,2,3,4-tetrahydroquinolinyl.
- the term heterocycle also include bridged heterocyclic systems such as azabicyclo[3.2. 1 ]octane, azabicyclo[3.3. 1 ]nonane and the like.
- the compounds of general formula I where all the symbols are as defined earlier were prepared by methods described below.
- the invention is not limited to these methods; the compounds may also be prepared by using procedures described for structurally related compounds in the literature.
- Scheme 1 shows a method of preparation of a compound in accordance with an embodiment of the formula la.
- Compound of formula la can be prepared from compound of formula VI, where R 1 , R 2 , R 4 , R 5 , R 6 and m are same as described under generic formula la.
- Compound of formula VI can be converted to its corresponding acid chloride using standard procedures known in synthetic organic chemistry or preferably by reaction with oxalyl chloride in dichloromethane along with DMF followed by reaction with N, O-dimethylhydroxylamine hydrochloride in presence of triethylamine in dichloromethane to provide compound of formula VII.
- the reaction may be carried out in the presence of solvents, for example, DMF, THF, a halogenated hydrocarbon such as chloroform and dichloromethane, an aromatic hydrocarbon such as xylene, benzene, toluene, or mixtures thereof or the like, in the presence of suitable base such as triethylamine, diisopropylethylamine, pyridine or the like at a temperature between 0-50°C using reagents such as l-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (EDCI), 1 ,3-dicyclohexylcarbodiimide (DCC), and auxiliary reagents such as 1- hydroxy-7-azabenzotriazole (HOAT), hydroxybenzotriazole hydrate (HOBT) or the like.
- solvents for example, DMF, THF, a halogenated hydrocarbon such as chloroform and dichloromethane, an aromatic hydrocarbon
- L 1 is halogen or -B(OH)2 in presence of a base or using appropriate conditions given in literature such as Tetrahedron letters 2005, 46(43), 7295-7298, Tetrahedron letters 2003, 44(16), 3385-3386, US2003236413, Synthetic Communications 2009, 39(12), 2082-2092, Tetrahedron letters 2010, 51 (15), 2048- 2051 , Tetrahedron letters 2008, 49(18), 2882-2885, and J. Amer. Chem. Soc. 2005, 127(36), 12640- 12646.
- Scheme 2 shows a method of preparation of compound of formula VI from compound of formula II and an alternative method for compound VI from compound of formula VIII.
- Compound of formula II was in turn prepared by the procedures described in the literature such
- Halogenation can be carried out under a condition generally used in the synthetic organic chemistry using halogenating agents such as bromine, phosphorous tribromide, bromine chloride, aluminium tribromide, hydrogen iodide/iodine, iodine chloride, N-iodosuccinimide, iodine /sulfuric acid and N- chlorosuccinimide.
- halogenating agents such as bromine, phosphorous tribromide, bromine chloride, aluminium tribromide, hydrogen iodide/iodine, iodine chloride, N-iodosuccinimide, iodine /sulfuric acid and N- chlorosuccinimide.
- the inventors have carried out bromination using bromine in the presence of zinc chloride.
- the Suzuki coupling is carried out in a mixture of water, ethanol, methanol and toluene, in presence of base such as potassium phosphate or potassium carbonate or the like, palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) at 50°C or higher temperature.
- base such as potassium phosphate or potassium carbonate or the like
- palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) at 50°C or higher temperature.
- Boronic acid used in this reaction can be prepared by the methods well known in the art by hydro lysing the corresponding boronate. Boronates are generally commercially available.
- a suitable base such as alkalimetal alkoxides or triethylamine or by using an aluminum amide [Tetrahedron 60 (2004) 3439-43] in non-polar organic solvent such as toluene or a polar solvent such as tetrahydrofuran.
- Scheme 4 shows method of preparation of a compound of formula VI, where, R 2 is hydrogen, from dibromo compound of formula XI, where Ak is alkyl group.
- Compound of the formula lb can be prepared starting from compound represented by general formula (ii) wherein R 1 , R 2 , and R a are the same as defined under general formula I or lb and R b is alkyl or -O-alkyl; which in turn can be prepared by adopting the procedures described in literature such as Tetrahedron Letters 2005, 46, 4539-4542, WO2005105789, Tetrahedron Letters 2010, 51 , 1693- 1695; J. Org. Chem. 2009, 74(2), 903-905; Organic Letters 2007, 9(25), 5191-5194; Tetrahedron 2006, 62, 8243-8255 or methods well known in the art. Groups covered under R 2 can be introduced or transformed into a suitable group of choice in any of the succeeding steps of Scheme 7 by general functional group transformation methods known to a person skilled in the relevant art.
- Ester hydrolysis of compound of formula (v), when R b O-alkyl, gave compound of formula (vl) where R 1 , R 2 , R 4 , R 5 , R 6 and m are the same as defined hereinbefore for compounds of formula (iii) and (iv) .
- Ester hydrolysis may be carried out using standard procedures generally used in synthetic organic chemistry or well known in the art with reagents such as sodium hydroxide, potassium hydroxide, lithium hydroxide or the like in solvents such as alcohol, THF, or the like.
- aqueous solution of sodium hydroxide and ethanol are used for this reaction.
- Compound of the formula lb where R 5 and/or R 6 are hydrogen can be converted to compound of formula lb where R 5 and/or R 6 are same as defined in general formula lb excluding hydrogen by reaction with corresponding alkyl halides, alkenyl halides, alkynyl halides, alkanoyl halides or anhydride, aryl halides or boronic acids in presence of a base or by using appropriate conditions given in technical literature literature.
- Salts of compound of formula I can be obtained by dissolving the compound in a suitable solvent, for example in a chlorinated hydrocarbon, such as methyl chloride or chloroform or a low molecular weight aliphatic alcohol, for example, ethanol or isopropanol, which was then treated with the desired acid or base as described in Berge S.M. et al. "Pharmaceutical Salts, a review article in Journal of Pharmaceutical sciences volume 66, page 1- 19 (1977)" and in handbook of pharmaceutical salts properties, selection, and use by P.H.Einrich Stahland Camille G.wermuth, Wiley- VCH (2002).
- a suitable solvent for example in a chlorinated hydrocarbon, such as methyl chloride or chloroform or a low molecular weight aliphatic alcohol, for example, ethanol or isopropanol
- stereoisomers of the compounds of formula I of the present invention may be prepared by stereospecific syntheses or resolution of the achiral compound using an optically active amine, acid or complex forming agent, and separating the diastereomeric salt/complex by fractional crystallization or by column chromatography.
- prodrug denotes a derivative of a compound, which derivative, when administered to warm-blooded animals, e.g. humans, is converted into the compound (drug).
- the enzymatic and/or chemical hydrolytic cleavage of the compounds of the present invention occurs in such a manner that the proven drug form (parent carboxylic acid drug) is released, and the moiety or moieties split off remain nontoxic or are metabolized so that nontoxic metabolic products are produced.
- a carboxylic acid group can be esterified, e.g., with a methyl group or ethyl group to yield an ester.
- an ester When an ester is administered to a subject, the ester is cleaved, enzymatically or non-enzymatically, reductively, oxidatively, or hydrolytically, to reveal the anionic group.
- An anionic group can be esterified with moieties (e.g., acyloxymethyl esters) which are cleaved to reveal an intermediate compound which subsequently decomposes to yield the active compound.
- the prodrugs can be prepared in situ during the isolation and purification of the compounds, or by separately reacting the purified compound with a suitable derivatizing agent.
- hydroxy groups can be converted into esters via treatment with a carboxylic acid in the presence of a catalyst.
- cleavable alcohol prodrug moieties include substituted or unsubstituted, branched or unbranched lower alkyl ester moieties, e.g., ethyl esters, lower alkenyl esters, di- lower alkylamino lower-alkyl esters, e.g., dimethylaminoethyl ester, acylamino lower alkyl esters, acyloxy lower alkyl esters (e.g., pivaloyloxymethyl ester), aryl esters, e.g., phenyl ester, aryl-lower alkyl esters, e.g., benzyl ester, optionally substituted, e.g., with methyl, halo, or methoxy substituents aryl and aryl-lower alkyl esters, amides, lower-alkyl amides, di-lwer alkyl amides, and hydroxy amides.
- Modulation of the nicotinic cholinergic receptors, particularly oc7 may provide for efficacy in a range of cognitive states, right from pre-attention to attention and subsequently working, reference and recognition memory. Accordingly, this invention may find application in the treatment and prophylaxis of multitude of disease conditions including, either one or combinations of, schizophrenia, schizophreniform disorder, cognitive deficits in schizophrenia, brief psychotic disorder, delusional disorder, schizoaffective disorder, shared psychotic disorder, paranoid personality disorder, schizoid personality disorder, schizotypal personality disorder, attention deficit disorder, attention deficit hyperactivity disorder, depression, maniac depression, major depressive disorder, posttraumatic stress disorder, generalized anxiety disorder, tourette's syndrome, cyclothymic disorder, dysthymic disorder, agoraphobia, panic disorder (with or without agoraphobia) , phobias (including social phobia) and bipolar disorders (Thomsen MS et al., Curr.
- this invention may also find application in the treatment of deficits in cholinergic oc7 nAChR following traumatic brain injury (Bennouna M et al., Encephale, 2007, 33, 616-620; Verbois SL et al., Neuropharmacology, 2003, 44, 224-233).
- this invention may find application in the treatment and prophylaxis of multitude of disease conditions including, either one or combinations of, dementia(s) due to Alzheimer's disease, dementia with Lewy bodies, Down's syndrome, head trauma, Stroke, hypoperfusion, Parkinson's disease, Huntington's disease, Prion diseases, progressive supranuclear palsy, radiation therapy, brain tumors, normal-pressure hydrocephalus, subdural hematoma, human immunodeficiency virus (HIV) infection, vitamin deficiency, hypothyroidism, drugs, alcohol, lead, mercury, aluminium, heavy metals, syphilis, Lyme disease, viral encephalitis, fungal infection and cryptococcosis (Zhao X et al., Ann.
- dementia due to Alzheimer's disease
- dementia with Lewy bodies Down's syndrome
- head trauma Stroke
- hypoperfusion Parkinson's disease
- Huntington's disease Huntington's disease
- Prion diseases progressive supranuclear palsy
- this invention may also find application in the prophylaxis and preventive measures immediately after early-stage identification of neurodegenerative disease like Alzheimer's disease and Parkinson's disease.
- Modulation of nicotinic ACh receptors particularly ⁇ 4 ⁇ 2, ⁇ 3 ⁇ 4 and ⁇ 7 may have implications in the development of therapies for nicotine, cannabis addiction and relapse prevention. Accordingly, this invention may find application in the prophylaxis or therapy of nicotine addiction, cannabis addiction, and relapse prevention of nicotine or cannabis addiction. Additionally, this Invention may also provide for an alternative therapy for non-responding addiction patients, patients having Intolerable side-effects with de-addiction therapies or those requiring long- term maintenance therapies.
- This invention may also find application in the treatment and prophylaxis of multitude of pain conditions including, either one or combinations of, pain arising from, peripheral nervous system (PNS), post-diabetic neuralgia (PDN), post-herpetic neuralgia (PHN), multiple sclerosis, Parkinson's disease, low-back pain, fibromyalgia, post-operative pain, acute pain, chronic pain, mononeuropathy, primary lateral sclerosis, pseudobulbar palsy, progressive muscular palsy, progressive bulbar palsy, postpolio syndrome, diabetes induced polyneuropathy, acute demyelinating polyneuropathy (Guillain-Barre syndrome), acute spinal muscular atrophy (Werdnig-Hoffman disease) and secondary neurodegeneration (Donnelly-Roberts DL et al., J.
- PNS peripheral nervous system
- PDN post-diabetic neuralgia
- PPN post-herpetic neuralgia
- multiple sclerosis Parkinson's disease, low-
- the present Invention further provides a pharmaceutical composition, containing the compounds of the general formula (I) as defined above, Its tautomeric forms, Its stereoisomers, Its analogues, Its prodrugs, Its Isotoplcally substituted analogues, Its metabolites, Its pharmaceutically acceptable salts, Its polymorphs, Its solvates, Its optical Isomers, Its clathrates and Its co-crystals In combination with the usual pharmaceutically acceptable carriers, diluents and the like.
- the pharmaceutically acceptable carrier Is preferably one that Is chemically Inert to the compound of the Invention and one that has no detrimental side effects or toxicity under the conditions of use.
- Such pharmaceutically acceptable carriers preferably Include saline (e.g., 0.9% saline), Cremophor EL (which Is a derivative of castor oil and ethylene oxide available from Sigma Chemical Co., St. Louis, MO) (e.g., 5% Cremophor EL/5% ethanol/90% saline, 10% Cremophor EL/90% saline, or 50% Cremophor EL/50% ethanol), propylene glycol (e.g.
- a preferred pharmaceutical carrier Is polyethylene glycol, such as PEG 400, and particularly a composition comprising 40% PEG 400 and 60% water or saline.
- the choice of carrier will be determined In part by the particular compound chosen, as well as by the particular method used to administer the composition. Accordingly, there Is a wide variety of suitable formulations of the pharmaceutical composition of the present Invention.
- the following formulations for oral, aerosol, parenteral, subcutaneous, intravenous, intraarterial, intramuscular, interperitoneal, rectal, and vaginal administration are merely exemplary and are in no way limiting.
- compositions for parenteral administration that comprise a solution of the compound of the invention dissolved or suspended in an acceptable carrier suitable for parenteral administration, including aqueous and non-aqueous, isotonic sterile injection solutions.
- compositions include solutions containing anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
- the compound can be administered in a physiologically acceptable diluent in a pharmaceutical carrier, such as a sterile liquid or mixture of liquids, including water, saline, aqueous dextrose and related sugar solutions, an alcohol, such as ethanol, isopropanol (for example in topical applications), or hexadecyl alcohol, glycols, such as propylene glycol or polyethylene glycol, dime thylsulf oxide, glycerol ketals, such as 2,2- dimethyl- l ,3-dioxolane-4-methanol, ethers, such as poly(ethyleneglycol) 400, an oil, a fatty acid, a fatty acid ester or glyceride, or an acetylated fatty acid glyceride with or without the addition of a pharmaceutically acceptable surfactant, such as a soap or a detergent, suspending agent, such as pectin, carbomers, methylcellulose, hydroxypropyl
- Oils useful in parenteral formulations include petroleum, animal, vegetable, and synthetic oils. Specific examples of oils useful in such formulations include peanut, soybean, sesame, cottonseed, corn, olive, petrolatum, and mineral oil. Suitable fatty acids for use in parenteral formulations include oleic acid, stearic acid, and isostearic acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters.
- Suitable soaps for use in parenteral formulations include fatty alkali metal, ammonium, and triethanolamine salts
- suitable detergents include (a) cationic detergents such as, for example, dimethyl dialkyl ammonium halides, and alkyl pyridinium halides, (b) anionic detergents such as, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates, (c) nonionic detergents such as, for example, fatty amine oxides, fatty acid alkanolamides, and polyoxyethylene polypropylene copolymers, (d) amphoteric detergents such as, for example, alkyl ⁇ -aminopropionates, and 2- alkyl-imidazoline quaternary ammonium salts, and (e) mixtures thereof.
- the parenteral formulations typically will contain from about 0.5% or less to about 25% or more by weight of a compound of the invention in solution. Preservatives and buffers can be used. In order to minimize or eliminate irritation at the site of injection, such compositions can contain one or more nonionic surfactants having a hydrophile-lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulations will typically range from about 5% to about 15% by weight. Suitable surfactants include polyethylene sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
- HLB hydrophile-lipophile balance
- parenteral formulations can be presented in unit-dose or multi-dose sealed containers, such as ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid excipient, for example, water, for injections, immediately prior to use.
- sterile liquid excipient for example, water
- Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets.
- Topical formulations including those that are useful for transdermal drug release, are well known to those of skill in the art and are suitable in the context of the present invention for application to skin.
- Formulations suitable for oral administration can consist of (a) liquid solutions, such as an effective amount of a compound of the invention dissolved in diluents, such as water, saline, or orange juice; (b) capsules, sachets, tablets, lozenges, and troches, each containing a pre-determined amount of the compound of the invention, as solids or granules; (c) powders; (d) suspensions in an appropriate liquid; and (e) suitable emulsions.
- Liquid formulations can include diluents, such as water and alcohols, for example, ethanol, benzyl alcohol, and the polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent.
- diluents such as water and alcohols, for example, ethanol, benzyl alcohol, and the polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent.
- Capsule forms can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers, such as lactose, sucrose, calcium phosphate, and cornstarch.
- Tablet forms can include one or more of lactose, sucrose, mannitol, corn starch, potato starch, alginic acid, micro crystalline cellulose, acacia, gelatin, guar gum, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, disintegrating agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible excipients.
- Lozenge forms can comprise the compound ingredient in a flavor, usually sucrose and acacia or tragacanth, as well as pastilles comprising a compound of the invention in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the compound of the invention, such excipients as are known in the art.
- An compound of the present invention, alone or in combination with other suitable components, can be made into aerosol formulations to be administered via inhalation.
- a compound or epimer of the invention is preferably supplied in finely divided form along with a surfactant and propellant.
- Typical percentages of the compounds of the invention can be about 0.01% to about 20% by weight, preferably about 1% to about 10% by weight.
- the surfactant must, of course, be nontoxic, and preferably soluble in the propellant.
- Representative of such surfactants are the esters or partial esters of fatty acids containing from 6 to 22 carbon atoms, such as caproic, octanoic, lauric, palmitic, stearic, linoleic, linolenic, olesteric and oleic acids with an aliphatic polyhydric alcohol or its cyclic anhydride.
- Mixed esters, such as mixed or natural glycerides can be employed.
- the surfactant can constitute from about 0.1% to about 20% by weight of the composition, preferably from about 0.25% to about 5%.
- the balance of the composition is ordinarily propellant.
- a carrier can also be included as desired, e.g., lecithin, for intranasal delivery.
- These aerosol formulations can be placed into acceptable pressurized propellants, such as dichlorodifluoromethane, propane, nitrogen, and the like. They also can be formulated as pharmaceuticals for non-pressured preparations, such as in a nebulizer or an atomizer. Such spray formulations can be used to spray mucosa.
- the compound of the invention can be made into suppositories by mixing with a variety of bases, such as emulsifying bases or water-soluble bases.
- bases such as emulsifying bases or water-soluble bases.
- Formulations suitable for vaginal administration can be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulas containing, in addition to the compound ingredient, such carriers as are known in the art to be appropriate.
- the concentration of the compound in the pharmaceutical formulations can vary, e.g., from less than about 1% to about 10%, to as much as 20% to 50% or more by weight, and can be selected primarily by fluid volumes, and viscosities, in accordance with the particular mode of administration selected.
- a typical pharmaceutical composition for intravenous infusion could be made up to contain 250 ml of sterile Ringer's solution, and 100 mg of at least one compound of the invention.
- Actual methods for preparing parenterally administrable compounds of the invention will be known or apparent to those skilled in the art and are described in more detail in, for example, Remington's Pharmaceutical Science (17 th ed., Mack Publishing Company, Easton, PA, 1985).
- the compound of the invention can be formulated as inclusion complexes, such as cyclodextrin inclusion complexes, or liposomes.
- Liposomes can serve to target a compound of the invention to a particular tissue, such as lymphoid tissue or cancerous hepatic cells. Liposomes can also be used to increase the half-life of a compound of the invention. Many methods are available for preparing liposomes, as described in, for example, Szoka et al., Ann. Rev. Biophys. Bioeng., 9, 467 (1980) and U.S. Patents 4,235,871 , 4,501 ,728, 4,837,028, and 5,019,369.
- the compounds or pharmaceutical compositions are useful, in an embodiment, for the treatment and/or prophylaxis of diseases or disorder or condition such as Alzheimer's disease (AD), mild cognitive impairment (MCI), senile dementia, vascular dementia, dementia of Parkinson's disease, attention deficit disorder, attention deficit hyperactivity disorder (ADHD), dementia associated with Lewy bodies, AIDS dementia complex (ADC), Pick's disease, dementia associated with Down's syndrome, Huntington's disease, cognitive deficits associated with traumatic brain injury (TBI), cognitive decline associated with stroke, posts troke neuroprotection, cognitive and sensorimotor gating deficits associated with schizophrenia, cognitive deficits associated with bipolar disorder, cognitive impairments associated with depression, acute pain, post-surgical or postoperative pain, chronic pain, inflammation, inflammatory pain, neuropathic pain, smoking cessation, need for new blood vessel growth associated with wound healing, need for new blood vessel growth associated with vascularization of skin grafts, and lack of circulation, arthritis, rheumatoid arthritis, psoriasis, Cr
- compositions are useful for the treatment and/or prophylaxis of diseases or disorder or condition classified or diagnosed as major or minor neurocognitive disorders, or disorders arising due to neurodegeneration.
- the present invention also provide method of administering a compound of formula I, as defined hereinabove in combination with or as adjunct to medications used in the treatment of attention deficit hyperactivity disorders, schizophrenia, and other cognitive disorders such as Alzheimer's disease, Parkinson's dementia, vascular dementia or dementia associated with Lewy bodies, traumatic brain injury.
- the present invention also provide method of administering a compound of formula I, as defined hereinabove in combination with or as an adjunct to acetylcholinesterase inhibitors, disease modifying drugs or biologies for neurodegenerative disorders, dopaminergic drugs, antidepressants, typical or an atypical antipsychotic.
- compound of formula I is useful for preventing or treating a disorder mediated by nicotinic acetylcholine receptors.
- Such compounds can be administered to a subject having such a disorder or susceptible to such disorders in a therapeutically effective amount.
- the compounds are particularly useful for a method of treating a mammal having a condition where modulation of nicotinic acetylcholine receptor activity is of therapeutic benefit, wherein the method is accomplished by administering a therapeutically effective amount of a compound of formula I to a subject having, or susceptible to, such a disorder.
- the present invention also provides a pharmaceutical composition, containing the compounds of the general formula (I) as defined above, its tautomeric forms, its stereoisomers, its analogs, its prodrugs, its isotopes, its metabolites, its pharmaceutically acceptable salts, its polymorphs, its solvates, its optical isomers, its clathrates and its co-crystals in combination with the usual pharmaceutically employed carriers, diluents and the like, and for use in any of the methods described herein.
- the compounds of the invention can be administered in a dose sufficient to treat the disease, condition or disorder.
- doses are known in the art (see, for example, the Physicians' Desk Reference (2004)).
- the compounds can be administered using techniques such as those described in, for example, Wasserman et al., Cancer, 36, pp. 1258- 1268 (1975) and Physicians' Desk Reference, 58th ed., Thomson PDR (2004).
- Suitable doses and dosage regimens can be determined by conventional range- finding techniques known to those of ordinary skill in the art. Generally, treatment is initiated with smaller dosages that are less than the optimum dose of the compound of the present invention. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached.
- the present method can involve the administration of about 0.1 ⁇ g to about 50 mg of at least one compound of the invention per kg body weight of the individual. For a 70 kg patient, dosages of from about 10 ⁇ g to about 200 mg of the compound of the invention would be more commonly used, depending on a patient's physiological response.
- the dose of the pharmaceutically active agent(s) described herein for methods of treating or preventing a disease or condition as described above can be about 0.001 to about 1 mg/kg body weight of the subject per day, for example, about 0.001 mg, 0.002 mg, 0.005 mg, 0.010 mg, 0.015 mg, 0.020 mg, 0.025 mg, 0.050 mg, 0.075 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, 0.5 mg, 0.75 mg, or 1 mg/kg body weight per day.
- the dose of the pharmaceutically active agent(s) described herein for the described methods can be about 1 to about 1000 mg/kg body weight of the subject being treated per day, for example, about 1 mg, 2 mg, 5 mg, 10 mg, 15 mg, 0.020 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 500 mg, 750 mg, or 1000 mg/kg body weight per day.
- the present invention provides methods of treating, preventing, ameliorating, and/or inhibiting a condition modulated by the nicotinic acetylchoine receptor comprising administering a compound of formula (I) or a salt thereof.
- inventive methods can provide any amount of any level of treatment, prevention, amelioration, or inhibition of the disorder in a mammal.
- a disorder, including symptoms or conditions thereof may be reduced by, for example, 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10%.
- the treatment, prevention, amelioration, or inhibition provided by the inventive method can include treatment, prevention, amelioration, or inhibition of one or more conditions or symptoms of the disorder, e.g., cancer.
- treatment,” prevention, “amelioration,” or “inhibition” can encompass delaying the onset of the disorder, or a symptom or condition thereof.
- the term subject includes an "animal” which in turn includes a mammal such as, without limitation, the order Rodentia, such as mice, and the order Lagomorpha, such as rabbits. It is preferred that the mammals are from the order Carnivora, including Felines (cats) and Canines (dogs).
- the mammals are from the order Artiodactyla, including Bovlnes (cows) and Swine (pigs) or of the order Perssodactyla, including Equines (horses). It is most preferred that the mammals are of the order Primates, Ceboids, or Simoids (monkeys) or of the order Anthropoids (humans and apes). An especially preferred mammal is the human.
- ACh Acetylcholine.
- AD Alzheimer 's disease.
- ADC AIDS dementia complex.
- ADHD attention deficit hyperactivity disorder
- ARDS acute respiratory distress syndrome.
- DIPEA diisopropyl ethyl amine
- DLB dementia with Lewy bodies.
- EDCI l-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride.
- FLIPR Fluorometric Imaging Plate Reader.
- HBSS Hank's balanced salt solution.
- HEPES 4-(2-hydroxyethyl)piperazine-l-ethanesulfonic acid.
- HMGB high mobility group box.
- HOAT 1 -hydroxy-7-azabenzotriazole.
- HOBT hydroxybenzotriazole hydrate.
- LGIC ligand-gated ion channels.
- MCI mild cognitive impairment
- NBS N-bromosuccinimide
- NCS N-chlorosuccinimide
- NNRs Neural nicotinic ACh receptors.
- PAM positive allosteric modulation
- PD Parkinson's disease.
- PDN post-diabetic neuralgia.
- PHN post-herpetic neuralgia.
- PNS peripheral nervous system.
- TBI traumatic brain injury
- THF Tetrahydrofuran
- TMS tetramethylsilane.
- TNF-a tumor necrosis factor alpha.
- VTA ventral tegmental area.
- a7 nAChR nicotinic acetylcholine receptor a7 subunit.
- Step 4 5-(4-chlorophenyl)-3-(4-(N-((dimethylamino)methylene)sulfamoyl)phenyl)-iV- methoxy-N,4-dimethylthiophene-2-carboxamide ( 1 d)
- Oxalyl chloride (2.1 g, 1.4 ml, 16.2 mmol) was added dropwise at 0°C to a solution of 5- (4-chlorophenyl)-4-methyl-3- (4-sulfamoylphenyl)thiophene-2- carboxylic acid (compound lc, 2.2g, 5.4 mmol) in a mixture of dichloromethane (40 ml) and DMF (0.8 g, 0.8 ml, 10.8 m mol). The resulting mixture was allowed to warm to room temperature and stirred for 1.5 hr, under a nitrogen atmosphere. The progress of reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure and used directly for further reaction.
- reaction mixture After cooling the reaction mixture to 0°C, the reaction mixture was quenched by adding a solution of saturated ammonium chloride (40 ml) and the resulting mixture was extracted with ethyl acetate (3x50 ml). The combined organic layer was dried over anhydrous Na2S04. The solvent was evaporated from the dried organic layer under reduced pressure to obtain a crude product; which was purified by column chromatography over silica gel (100-200 mesh) using 30- 35% ethyl acetate in hexane as an eluent to obtain the title compound which was further purified by precipitation by dissolving 1.1 g of the compound in dichloromethane (10 ml) and precipitating it by slow addition of diisopropyl ether. (0.89g, 47 %)
- Step 1 Preparation of iV,iV-dimethyl-N'-((4-propionylphenyl)sulfonyl) formimidamide (24a)
- Step 2 Preparation of N'-((4-(2-(l ,3-dithiatan-2-ylidene)propanoyl)phenyl)sulfonyl)- N,N-dimethylformimidamide (24b)
- the resulting reaction mixture was cooled to 0°C and to the cooled reaction mixture was added dibromomethane (1.3g, 0.85 ml, 7.46 mmol) in a dropwise manner at 0°C.
- the resulting reaction mixture was stirred at room temperature for 20 hr. The progress of the reaction was monitored by TLC.
- the reaction mixture was poured into cold water (50 ml) and extracted with ethyl acetate (3x50 ml). The combined organic layer was dried over anhydrous Na2S04.
- Step 3 Preparation of N,N-dimethyl-N'-((4-(2-methyl-3-morpholino-3- thioxopropanoyl)phenyl)sulfonyl)formimidamide (24c)
- reaction mixture was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 2% methanol in dichloromethane as an eluent to obtain the title compound (0.191 g, 32.3%)
- Step 4 Preparation of ethyl-3-(4-(iV-((dimethylamino) methylene) sulfamoyl)phenyl)-4-methyl-5-morpholinothiophene-2-carboxylate (24d)
- the reaction mixture was stirred at reflux temperature for 4 hr. The progress of the reaction was monitored by TLC.
- the reaction mixture was allowed to warm to room temperature and filtered through a celite pad. The celite pad was washed with acetone (2x10 ml). The filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 50-55% ethyl acetate in hexanes as an eluent to obtain the title compound (0.091 g, 43%)
- Step 6 Preparation of 3-(4-(iV-((dimethylamino) methylene) sulfamoyl)phenyl)-iV- methoxy-iV,4-dimethyl-5-morpholinothiophene-2-carboxamide (24f)
- reaction mixture was then slowly added to 150 ml 2N HCl and extracted with ethyl acetate (2 x 150 ml).
- the resulting organic layer was washed with water (1 x 50 ml), brine ( 1 x 50 ml) and dried over sodium sulfate and concentrated under reduced pressure to obtain crude product as semi-solid ( 10. 5 g), which was then purified by column chromatography over silica gel (100-200 mesh) using 7% ethyl acetate in hexanes as an eluent to obtain the title compound (9.0 g, 65.55%).
- Step 3 Methyl 5-bromo-4-methyl-3-(4-sulfamoylphenyl) thiophene-2-carboxylate.
- Step 4 Methyl 5-(4-methoxyphenyl)-4-methyl-3-(4-sulfamoylphenyl) thiophene-2- carboxylate. (7d)
- reaction was monitored by TLC.
- the reaction mixture was cooled to 25°C and filtered through celite, and then washed with ethyl acetate (50ml).
- the filtrate was concentrated under reduced pressure to obtain a crude product, that was then purified by column chromatography over silica gel ( 100-200 mesh) using 50% ethyl acetate in hexanes as an eluent to obtain the title compound (20% ethyl ester as trans esterified product was observed) (2.69 g, 84%).
- Step 5 5-(4-Methoxyphenyl)-4-methyl-3-(4-sulfamoylphenyl)thiophene-2- carboxylic acid. (7e)
- Step 6 3-(4-(N-((dimethylamino)methylene)sulfamoyl)phenyl)-N-methoxy-5-(4- methoxyphenyl)-N,4-dimethylthiophene-2-carboxamide. (71)
- Oxalyl chloride (1.77 g, 1.2 ml, 13.9 mmol) was added drop wise at 0°C to a solution of 5- (4-methoxyphenyl)-4-methyl-3- (4-sulfamoylphenyl)thiophene-2- carboxylic acid (compound 7e, 2.8g, 6.94 mmol) in a mixture of dichlorome thane (75 ml) and DMF ( l .Olg, 1.1 ml, 13.89 mmol). The so obtained mixture was allowed to come at room temperature and stirred for 1.5 hr under a nitrogen atmosphere. The progress of the reaction was monitored by TLC. The reaction mixture was then concentrated under reduced pressure.
- Step 7 4-(5-(4-methoxyphenyl)-4-methyl-2-propionylthiophen-3-yl) benzene sulfonamide (compound 7)
- reaction mixture After cooling the reaction mixture to 0°C, the reaction mixture was quenched by adding a solution of saturated ammonium chloride (50 ml) and the resulting mixture was extracted with ethyl acetate (2 x 100 ml). The combined organic layer was dried over anhydrous Na2S04. The solvent was evaporated from the dried organic layer under reduced pressure to obtain a crude product; which was purified by Preparative HPLC to obtain the title compound (0.84 g, 37%).
- the mixture so obtained was extracted with ethyl acetate (3 x 30 ml).
- the combined organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain a crude product.
- the crude product so obtained was purified by column chromatography over silica gel (100-200 mesh) using 40% ethyl acetate in hexanes as an eluent to obtain first title compound (0.05 g, 9.38%) and second title compound (0.045 g, 8.7%).
- Step 1 Ethyl 4-(bromomethyl)-5-(4-chlorophenyl)-3-(4-sulfamoylphenyl) thiophene-2-carboxylate.
- Step 2 Ethyl 4-(bromomethyl)-5-(4-chlorophenyl)-3-(4-(iV-((dimethylamino) methylene)sulfamoyl)phenyl) thiophene-2-carboxylate.
- the progress of the reaction was monitored by TLC.
- the reaction mixture was concentrated under reduced pressure to obtain 2.9 g of crude product.
- the crude product so obtained was then purified by column chromatography over silica gel ( 100-200 mesh) using 1.5% methanol in DCM as an eluent to obtain the title compound (2.2 g, 73.82 %) .
- Step 3 Ethyl 5-(4-chlorophenyl)-4-((dimethylamino)methyl)-3-(4-(iV- ((dimethylamino)methylene)sulfamoyl)phenyl) thiophene-2-carboxylate.
- the reaction mixture was then concentrated to obtain the crude product as semi-solid (2.38 g).
- the crude product so obtained was purified by column chromatography over silica gel ( 100-200 mesh) using 1.2 % methanol in DCM as an eluent to obtain the title compound ( 1.1 g, 53.39 %).
- Step 4 5-(4-chlorophenyl)-4-((dimethylamino)methyl)-3-(4sulfamoylphenyl) thiophene-2-carboxylic acid (35d).
- Ethyl 5-(4-chlorophenyl)-4-((dimethylamino)methyl)-3-(4-(N-((dimethylamino) methylene)sulfamoyl)phenyl) thiophene-2-carboxylate (compound 35c, 1.0 g, 1.87 mmol) was suspended in ethanol (20ml) and a solution of NaOH (0.37 g, 9.36 mmol) in water (2 ml) was added to it at 25°C. The reaction mixture was heated at 75°C under stirring for 2 hr. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure.
- Step 5 5-(4-chlorophenyl)-4-((dimethylamino)methyl)-3-(4-(iV-((dimethylamino) methylene)sulfamoyl)phenyl)-iV-methoxy-iV-methylthiophene-2-carboxamide.
- Oxalyl chloride (0.39 g, 0.26 ml, 3.1 mmol) was added drop wise at 0°C to a solution of 5-(4-chlorophenyl)-4-((dimethylamino)methyl)-3-(4sulfamoylphenyl) thiophene-2-carboxylic acid (compound 35d, 0.7 g, 1.55 mmol) in a mixture of dichloromethane (25 ml) and DMF (0.27 g, 0.24 ml, 3.10 mmol). The mixture so obtained was allowed to come at room temperature and stirred for 1.5 hr under a nitrogen atmosphere. The progress of the reaction was monitored by TLC. The reaction mixture was then concentrated under reduced pressure.
- Step 1 Ethyl 3-bromo-5-(4-chlorophenyl) thiophene-2-carboxylate.
- reaction mixture was then added tetrakis(triphenylphosphine)palladium(0) (0.37 g, 0.31 mmol) under nitrogen atmosphere and the reaction mixture was heated at about 95 to about 100°C for 3 hr under stirring. The progress of the reaction was monitored by TLC.
- the reaction mixture was then cooled to 25°C and filtered through celite and the celite cake was washed with ethyl acetate (50ml). The filtrate so obtained was concentrated under reduced pressure to obtain a crude product, which was then purified by flash column chromatography using and 6% ethyl acetate in hexanes as an eluent to obtain the title compound (1.5 g, 68.18%).
- Step 2 Ethyl 5-(4-chlorophenyl)-3-(4-sulfamoylphenyl) thiophene-2-carboxylate.
- reaction mixture was then added tetrakis(triphenylphosphine)palladium(0) (0.24 g, 0.20 mmol) under nitrogen atmosphere and the reaction mixture was heated at about 95 to about 100°C for 16 hr under stirring. The progress of the reaction was monitored by TLC.
- the reaction mixture was then cooled to 25°C and filtered through celite, the celite cake was washed with Ethanol (2x25 ml). The filtrate so obtained was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography over silica gel (100-200 mesh) using 50 % ethyl acetate in hexanes as an eluent to obtain the title compound ( 1.35 g, 76.27%).
- Step 3 5-(4-chlorophenyl)-3-(4-sulfamoylphenyl)thiophene-2-carboxylic acid. (33c)
- Step 4 5- (4-chlorophenyl)-3- (4- (N- ((dimethylamino)methylene)sulfamoyl)phenyl)- N-methoxy-N-methylthiophene-2-carboxamide. (33d)
- Oxalyl chloride (0.70 g, 0.48 ml, 5.58 mmol) was added drop wise at 0°C to a solution of 5-(4-chlorophenyl)-3-(4-sulfamoylphenyl)thiophene-2-carboxylic acid (compound 33c, 1.10 g, 2.79 mmol) in a mixture of dichloromethane (30 ml) and DMF (0.40 g, 0.43 ml, 5.58 mmol). The mixture was then allowed to warm to room temperature and stirred for 1.5 hr under a nitrogen atmosphere. The progress of the reaction was monitored by TLC. The reaction mixture was then concentrated under reduced pressure.
- reaction mixture After cooling the reaction mixture to 0°C, the reaction mixture was quenched by addition of a saturated solution of ammonium chloride (10 ml). The mixture so obtained was extracted with ethyl acetate (2x 30 ml), the combined organic layer was dried over anhydrous Na2S04. The solvent was evaporated from the dried organic layer under reduced pressure to obtain a crude product, which was then purified by column chromatography over silica gel (100-200 mesh) using 40% ethyl acetate in hexanes as an eluent to obtain the title compound (0.06 g, 14.6%).
- reaction mixture was then poured onto ice-water ( 150 ml) .
- the mixture so obtained was extracted with ethyl acetate (2 x 100 ml).
- the combined organic layer was dried over sodium sulphate and was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography over silica gel (100-200 mesh) using 2% ethyl acetate in hexanes as an eluent to obtain the title compound (3.40 g, 59.54%).
- reaction mixture was then quenched by addition of cold water (50 ml), the mixture so obtained was then extracted with ethyl acetate (3x 100 ml). The combined organic layer was then dried over sodium sulphate and concentrated under reduced pressure to obtain a crude product, which was then purified by flash column chromatography using 2.5% ethyl acetate in hexanes as an eluent to obtain the title compound (3.2 g, 58.97%).
- Step 4 Ethyl 3-bromo-5-(4-chlorophenyl)-4-(dimethylamino)thiophene-2- carboxylate. (34d)
- reaction mixture was then added tetrakis(triphenylphosphine)palladium(0) (0.48 g, 0.42 mmol) under nitrogen atmosphere and the reaction mixture was heated at about 95 to 100°C for 3 hr under stirring. The progress of the reaction was monitored by TLC.
- the reaction mixture was then cooled to 25°C and filtered through celite, the celite cake was then washed with ethyl acetate (50ml). The filtrate so obtained was then concentrated under reduced pressure to obtain a crude product, which was then purified by flash column chromatography using 12% ethyl acetate in hexanes as an eluent to obtain the title compound (2.5 g, 76.56%).
- Step 5 Ethyl 5-(4-chlorophenyl)-4-(dimethylamino)-3-(4- sulfamoylphenyl)thiophene-2-carboxylate.
- reaction mixture was then added tetrakis(triphenylphosphine)palladium(0) (0.32 g, 0.28 mmol) under nitrogen and the reaction mixture was heated at about 95 to about 100°C for 16 hr under stirring. The progress of the reaction was monitored by TLC.
- the reaction mixture was then cooled to 25°C and filtered through celite. The celite cake was then washed with ethanol (2x25 ml). The combined filtrate was concentrated under reduced pressure to obtain a crude product, which was then purified by flash column chromatography using 55% ethyl acetate in hexanes as an eluent to obtain the title compound (2.0 g, 76.05%).
- Step 6 5- (4-chlorophenyl)-4- (dimethylamino)-3- (4-sulfamoylphenyl)thiophene-2- carboxylic acid. (34 f)
- Step 7 5- (4-chlorophenyl)-4- (dimethylamino)-3- (4-(N- ((dimethylamino)methylene) sulfamoyl)phenyl)-N-methoxy-N-methylthiophene-2-carboxamide.
- Oxalyl chloride (0.58 g, 0.39 ml, 4.57 mmol) was added drop wise to a solution of 5-(4-chlorophenyl)-4-(dimethylamino)-3-(4-sulfamoylphenyl)thiophene-2-carboxylic acid (compound 34f, 1.00 g, 2.28 mmol) in a mixture of dichloromethane (30 ml) and DMF (0.33 g, 0.35 ml, 4.57 mmol) at 0°C. The reaction mixture was then allowed to warm to room temperature and stirred for 1.5 hr under a nitrogen atmosphere. The progress of the reaction was monitored by TLC. The mixture was then concentrated under reduced pressure.
- Step 8 4-(5-(4-chlorophenyl)-4-(dimethylamino)-2-propionylthiophen-3-yl) benzene sulfonamide. (Compound 34)
- the progress of the reaction was monitored by TLC.
- the reaction mixture was then concentrated under reduced pressure.
- the concentrated mass so obtained was diluted with ethyl acetate (30 ml) and washed with saturated sodium bicarbonate solution (2 x 15 ml) and brine (1 x 15ml).
- the organic layer obtained was then dried over anhydrous sodium sulphate, and concentrated under reduced pressure to obtain a crude product, which was then purified by flash column chromatography using 25 % ethyl acetate in hexanes as an eluent to obtain the title compound (0.06 g, 22.50 %).
- Step 1 Methyl-5-(4-chlorophenyl)- l,4-dimethyl- lH-pyrrole-2-carboxylate.
- Step 2 Methyl-3-bromo-5-(4-chlorophenyl)- 1 ,4-dimethyl- lH-pyrrole-2-carboxylate. (49 ⁇ )
- Step 3 Methyl-5-(4-chlorophenyl)- 1 ,4-dimethyl-3-(4-sulfamoylphenyl)- lH-pyrrole- 2-carboxylate. (49 ⁇ )
- reaction mixture was then added tetrakis(triphenylphosphine)palladium(0) (0.349 g, 0.29 mmol) under nitrogen and reaction mixture was heated at about 95 to about 100°C for 15 hr under stirring. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 25°C and filtered through celite. The celite cake was washed with ethanol (100 ml) and ethyl acetate (50 ml).
- Step 4 5-(4-chlorophenyl)- 1 ,4-dimethyl-3-(4-sulfamoylphenyl)- lH-pyrrole-2- carboxylic acid. (49 ⁇ )
- Methyl 5-(4-chlorophenyl)- 1 ,4-dimethyl-3-(4-sulfamoylphenyl)- lH-pyrrole-2- carboxylate (compound 49 ⁇ , 1.6 g, 3.82 mmol) was suspended in ethanol (100 ml) and treated with solution of NaOH (0.76 g 19.13 mmol) in water (20 ml) at 0°C. The reaction mixture was then heated at 80°C under stirring for 15 h. The progress of the reaction was monitored by TLC. The reaction mixture was then concentrated under reduced pressure. The reaction mixture was then treated with dilute HCl to bring pH of the mixture to between 6 and 7.
- Step 5 5-(4-chlorophenyl)-iV-methoxy-iV, l,4-trimethyl-3-(4-sulfamoylphenyl)- lH- pyrrole-2-carboxamide. (49 ⁇ )
- reaction mixture was then cooled to 0°C, and to the cooled reaction mixture was added EDC (0.570g, 2.97 mmol) and triethylamine (0.80g, 1.10 ml, 7.92 mmol).
- EDC 0.570g, 2.97 mmol
- triethylamine 0.80g, 1.10 ml, 7.92 mmol
- the reaction mixture was then stirred at room temperature for 15 hr.
- the progress of the reaction was monitored by TLC.
- the reaction mixture was then concentrated under reduced pressure.
- the residue so obtained was taken in ethyl acetate ( 100 ml) and washed with saturated sodium bicarbonate solution (20 ml) followed by washing with brine (20 ml).
- the organic layer obtained was dried over anhydrous sodium sulphate, and concentrated under reduced pressure to obtain a crude product.
- the crude product was then purified by column chromatography over silica gel (100- 200 mesh) using 50% ethyl acetate in hexanes as an eluent to obtain the title compound (0.680 g, 76.8 %).
- Step 6 5-(4-chlorophenyl)-3-(4-(N-((dimethylamino)methylene)sulfamoyl) phenyl)- iV-methoxy-iV, 1 ,4-trimethyl- lH-pyrrole-2-carboxamide. (49 ⁇ )
- Grignard reagent ethyl magnesium bromide, 0.531 g, 3.98 ml, 1M soln. In THF, 3.98 mmol was added dropwlse under a nitrogen atmosphere to a stirred solution of 5- (4-chlorophenyl)-3- (4-(N- ((dimethylamino)methylene) sulfamoyl)phenyl)-iV- methoxy-iV, l ,4-trimethyl- lH-pyrrole-2-carboxamide (compound 49 ⁇ , 0.400 g, 0.79 mmol) in anhydrous THF (15 ml) at 25°C, and the reaction mixture was then heated to about 70 to about 75°C for 1 hr.
- Step 1 l-(5-(4-chlorophenyl)- l ,4-dimethyl- lH-pyrrol-2-yl)propan- l-one (49a)
- ⁇ , ⁇ -dimethyl propionamide (3.24 g, 3.52 ml, 32.08 mmol) was cooled at 0-5°C and and to this was added POCI3 (4.9 g, 2.9ml, 32.08 mmol) slowly in a dropwise manner. The resulting mixture was then stirred at room temperature (about 25°C) for 20 minutes. The reaction mixture was then diluted with 1 ,2-dichloroethane (60 ml) and cooled to 0°C.
- Step 2 l-(3-Bromo-5-(4-chlorophenyl)- 1 ,4-dimethyl- lH-pyrrol-2-yl)propan- 1-one.
- Step 3 4-(5-(4-chlorophenyl)- l ,4-dimethyl-2-propionyl- lH-pyrrol-3-yl) benzene sulfonamide. (Compound 49)
- reaction mixture was the added tetrakis(triphenylphosphine)palladium(0) (0.51 g, 0.44 mmol) under nitrogen atmosphere and reaction mixture was heated at about 90 to about 95°C for 18 hr under stirring. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 25°C and filtered through celite. The celite cake was washed with 10% methanol in dichloromethane. The combined filtrate so obtained was concentrated under reduced pressure to obtain a crude product, which was then purified by flash column chromatography using 40% ethyl acetate in hexanes as an eluent to obtain the title compound (1.22 g, 33.2%).
- Step 1 l-(5-(4-chlorophenyl)-4-methyl- lH-pyrrol-2-yl)propan- l-one. (53a)
- Step 2 l-(3-Bromo-5-(4-chlorophenyl)-4-methyl- lH-pyrrol-2-yl)propan- 1-one.
- reaction mixture was then added tetrakis(triphenylphosphine)palladium(0) (0.17 g, 0.153 mmol) under nitrogen atmosphere and the reaction mixture was heated at about 90°C to 95°C for 18 hr under stirring. The progress of the reaction was monitored by TLC.
- the reaction mixture was then cooled to 25°C and filtered through celite. The celite cake was washed with 10% methanol in dichlorome thane (3x25ml). The combined filtrate was concentrated under reduced pressure to obtain a crude product, which was then purified by flash column chromatography using 40% ethyl acetate in hexanes as an eluent to obtain the title compound (0.082 g, 6.65%).
- reaction mixture was then stirred at 25°C for 3 hrs. The progress of the reaction was monitored by TLC.
- the reaction mixture was slowly quenched with cold water (30 ml) and the resulting mixture was then extracted with ethyl acetate (2x 30 ml).
- the combined organic layer was then washed with brine (lx 30 ml) and dried over sodium sulfate.
- the dried organic layer was then concentrated under reduced pressure to obtain crude product as semi-solid mass (0. 8 g), which was then purified by flash column chromatography using 5% ethyl acetate in hexanes as an eluent to obtain the title compound (0.6 g, 52.3%).
- Step 2 l-(5-(4-chlorophenyl)- l-ethyl-4-methyl- lH-pyrrol-2-yl)propan- l-one. (51b)
- Step 3 l-(3-bromo-5-(4-chlorophenyl)- 1 -ethyl-4-methyl- lH-pyrrol-2-yl)propan- 1- one. (51c).
- Step 4 4-(5-(4-chlorophenyl)- l-ethyl-4-methyl-2-propionyl- lH-pyrrol-3-yl)benzene sulfonamide. (Compound 51)
- Step 1 Methyl 3-(4-(N-(tert-butyl)sulfamoyl)-3-methylphenyl)-4-methylthiophene- 2-carboxylate (41a)
- reaction mixture was then added tetrakis(triphenylphosphine)palladium(0) (0.09 g, 0.08 mmol) under nitrogen atmosphere and the reaction mixture was heated at a temperature between about 95°C to 100°C for 3 hr under stirring. The progress of the reaction was monitored by TLC.
- the reaction mixture was then cooled to 25°C and filtered through celite. The celite cake was washed with ethyl acetate (20ml). The combined filtrate was then concentrated under reduced pressure to obtain a crude product, which was then purified by flash column chromatography using 30% ethyl acetate in hexanes as an eluent to obtain the title compound (0.53 g, 76.8%).
- reaction mixture was then added tetrakis(triphenylphosphine)palladium(0) (0.86 g, 0.74 mmol) at a temperature of about 25°C and the tube was sealed.
- the reaction mixture was then stirred at 105°C for 15 hours. The progress of the reaction was monitored by TLC.
- the reaction mixture was then filtered and washed with ethyl acetate (2X50 ml).
- the combined organic layer was then concentrated under reduced pressure to obtain crude product, which was then purified by column chromatography over silica gel ( 100-200 mesh) using 45% ethyl acetate in hexanes as an eluent to obtain the title compound (3.5 g, 62.0%).
- Step-3 5- (4-chlorophenyl)-N-methoxy-N,4-dimethyl-3- (4- (plperldln- 1 -ylsulfonyl) phenyl)thiophene-2-carboxamide (48e) .
- Step-4 l-(5-(4-chlorophenyl)-4-methyl-3-(4-(piperidin- 1- ylsulfonyl)phenyl)thlophen-2-yl)propan- l-one (compound 48)
Abstract
Description
Claims
Priority Applications (29)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
MX2013009709A MX343788B (en) | 2011-02-23 | 2012-02-22 | Heteroaryl derivatives as alpha7 nachr modulators. |
NZ615001A NZ615001B2 (en) | 2011-02-23 | 2012-02-22 | Heteroaryl derivatives as alpha7 nachr modulators |
CUP2013000116A CU24177B1 (en) | 2011-02-23 | 2012-02-22 | HETEROARILO DERIVATIVES AS MODULATORS OF NACHR ALFA 7 |
AU2012221800A AU2012221800B2 (en) | 2011-02-23 | 2012-02-22 | Heteroaryl derivatives as alpha7 nAChR modulators |
JP2013554966A JP6118270B2 (en) | 2011-02-23 | 2012-02-22 | Heteroaryl derivatives as alpha 7NACHR modulators |
ES12709965.3T ES2594409T3 (en) | 2011-02-23 | 2012-02-22 | Heteroaryl derivatives as modulators of nAChR á7 |
US14/000,829 US9072731B2 (en) | 2011-02-23 | 2012-02-22 | Heteroaryl derivatives as alpha7 nAChR modulators |
DK12709965.3T DK2678327T3 (en) | 2011-02-23 | 2012-02-22 | Heteroaryl derivatives which ALFA7 nAChR modulators |
GEAP201213238A GEP20156318B (en) | 2011-02-23 | 2012-02-22 | Heteroaryl derivatives as alpha7 nachr modulators |
EA201370184A EA024170B1 (en) | 2011-02-23 | 2012-02-22 | HETEROARYL DERIVATIVES AS ALPHA7 nAChR MODULATORS |
SG2013059431A SG192625A1 (en) | 2011-02-23 | 2012-02-22 | Heteroaryl derivatives as alpha7 nachr modulators |
BR112013021602A BR112013021602A2 (en) | 2011-02-23 | 2012-02-22 | heteroaryl derivatives as nachr alpha7 modulators. |
UAA201311194A UA112076C2 (en) | 2011-02-23 | 2012-02-22 | Heteroaryl derivatives |
CA2826792A CA2826792A1 (en) | 2011-02-23 | 2012-02-22 | Heteroaryl derivatives as alpha7 nachr modulators |
RS20160972A RS55433B1 (en) | 2011-02-23 | 2012-02-22 | Heteroaryl derivatives as alpha7 nachr modulators |
LTEP12709965.3T LT2678327T (en) | 2011-02-23 | 2012-02-22 | Heteroaryl derivatives as alpha7 nachr modulators |
EP12709965.3A EP2678327B9 (en) | 2011-02-23 | 2012-02-22 | Heteroaryl derivatives as alpha7 nachr modulators |
SI201230775A SI2678327T1 (en) | 2011-02-23 | 2012-02-22 | Heteroaryl derivatives as alpha7 nachr modulators |
AP2013007121A AP3649A (en) | 2011-02-23 | 2012-02-22 | Heteroaryl derivatives as alpha7 nachr modulators |
MA36224A MA34957B1 (en) | 2011-02-23 | 2012-02-22 | HETEROARYL DERIVATIVES AS MODULATORS OF NACHR ALPHA 7 |
CN201280010409.0A CN103402994B (en) | 2011-02-23 | 2012-02-22 | As the heteroaryl derivative of the NACHR conditioning agents of α 7 |
KR1020137023970A KR20140026378A (en) | 2011-02-23 | 2012-02-22 | Heteroaryl derivatives as alpha7 nachr modulators |
TNP2013000345A TN2013000345A1 (en) | 2011-02-23 | 2013-08-15 | Heteroaryl derivatives as alpha7 nachr modulators |
ZA2013/06223A ZA201306223B (en) | 2011-02-23 | 2013-08-19 | Heteroaryl derivatives as alpha7 nachir modulators |
IL228052A IL228052A (en) | 2011-02-23 | 2013-08-21 | Heteroaryl derivatives as alpha7 nachr modulators |
US14/705,144 US9393247B2 (en) | 2011-02-23 | 2015-05-06 | Heteroaryl derivatives as alpha7 nAChR modulators |
CY20161101057T CY1118107T1 (en) | 2011-02-23 | 2016-10-19 | ETEROYRUM PRODUCERS AS ALPHA7 NACHR MODELS |
HRP20161481TT HRP20161481T1 (en) | 2011-02-23 | 2016-11-09 | Heteroaryl derivatives as alpha7 nachr modulators |
SM201600409T SMT201600409B (en) | 2011-02-23 | 2016-11-11 |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN242/KOL/2011 | 2011-02-23 | ||
IN242KO2011 | 2011-02-23 | ||
IN1184/KOL/2011 | 2011-09-09 | ||
IN1184KO2011 | 2011-09-09 |
Related Child Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US14/000,829 A-371-Of-International US9072731B2 (en) | 2011-02-23 | 2012-02-22 | Heteroaryl derivatives as alpha7 nAChR modulators |
US14/705,144 Division US9393247B2 (en) | 2011-02-23 | 2015-05-06 | Heteroaryl derivatives as alpha7 nAChR modulators |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2012114285A1 true WO2012114285A1 (en) | 2012-08-30 |
WO2012114285A9 WO2012114285A9 (en) | 2012-10-18 |
Family
ID=45873193
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IB2012/050806 WO2012114285A1 (en) | 2011-02-23 | 2012-02-22 | Heteroaryl derivatives as alpha7 nachr modulators |
Country Status (36)
Country | Link |
---|---|
US (2) | US9072731B2 (en) |
EP (1) | EP2678327B9 (en) |
JP (1) | JP6118270B2 (en) |
KR (1) | KR20140026378A (en) |
CN (1) | CN103402994B (en) |
AP (1) | AP3649A (en) |
AU (1) | AU2012221800B2 (en) |
BR (1) | BR112013021602A2 (en) |
CA (1) | CA2826792A1 (en) |
CL (1) | CL2013002449A1 (en) |
CO (1) | CO6761374A2 (en) |
CR (1) | CR20130415A (en) |
CU (1) | CU24177B1 (en) |
CY (1) | CY1118107T1 (en) |
DK (1) | DK2678327T3 (en) |
DO (1) | DOP2013000191A (en) |
EA (1) | EA024170B1 (en) |
EC (1) | ECSP13012891A (en) |
ES (1) | ES2594409T3 (en) |
GE (1) | GEP20156318B (en) |
GT (1) | GT201300207A (en) |
HR (1) | HRP20161481T1 (en) |
HU (1) | HUE030659T2 (en) |
IL (1) | IL228052A (en) |
LT (1) | LT2678327T (en) |
MA (1) | MA34957B1 (en) |
MX (1) | MX343788B (en) |
NI (1) | NI201300072A (en) |
PE (1) | PE20140703A1 (en) |
PL (1) | PL2678327T3 (en) |
RS (1) | RS55433B1 (en) |
SG (1) | SG192625A1 (en) |
SI (1) | SI2678327T1 (en) |
SM (1) | SMT201600409B (en) |
WO (1) | WO2012114285A1 (en) |
ZA (1) | ZA201306223B (en) |
Cited By (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014072957A1 (en) | 2012-11-12 | 2014-05-15 | Lupin Limited | Thiazole derivatives as alpha 7 nachr modulators |
WO2014111839A1 (en) | 2013-01-16 | 2014-07-24 | Lupin Limited | Pyrrole derivatives as alpha 7 nachr modulators |
WO2014141091A1 (en) | 2013-03-13 | 2014-09-18 | Lupin Limited | Pyrrole derivatives as alpha 7 nachr modulators |
WO2014195848A1 (en) | 2013-06-03 | 2014-12-11 | Lupin Limited | 4-(5-(4-chlorophenyl)-2-(2-cyclopropylacetyl)-1,4-dimethyl-1h-pyrrol-3-yl)benzenesulfonamide as alpha 7 nachr modulator |
WO2014203150A1 (en) | 2013-06-17 | 2014-12-24 | Lupin Limited | Pyrrole derivatives as alpha 7 nachr modulators |
US9388196B2 (en) | 2012-03-06 | 2016-07-12 | Lupin Limited | Thiazole derivatives as alpha 7 nAChR modulators |
US9840481B2 (en) | 2016-03-22 | 2017-12-12 | Merck Sharp & Dohme Corp. | Allosteric modulators of nicotinic acetylcholine receptors |
CN109053766A (en) * | 2012-09-28 | 2018-12-21 | 武田药品工业株式会社 | The preparation method of Thienopyrimidine derivative |
WO2020007905A1 (en) * | 2018-07-05 | 2020-01-09 | Bayer Aktiengesellschaft | Substituted thiophenecarboxamides and analogues as antibacterials agents |
WO2021001331A1 (en) | 2019-07-03 | 2021-01-07 | Bayer Aktiengesellschaft | Substituted thiophene carboxamides and derivatives thereof as microbicides |
CN112533581A (en) * | 2018-06-07 | 2021-03-19 | 密歇根大学董事会 | PRC1 inhibitors and methods of treatment therewith |
WO2021123051A1 (en) | 2019-12-20 | 2021-06-24 | Bayer Aktiengesellschaft | Substituted thiophene carboxamides, thiophene carboxylic acids and derivatives thereof |
RU2797513C2 (en) * | 2018-07-05 | 2023-06-06 | Байер Акциенгезельшафт | Substituted thiophenecarboxamides and analogues as antibacterial agents |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
RS55433B1 (en) | 2011-02-23 | 2017-04-28 | Lupin Ltd | Heteroaryl derivatives as alpha7 nachr modulators |
ES2764660T3 (en) | 2014-12-16 | 2020-06-04 | Axovant Sciences Gmbh | Geminal substituted quinuclidine amide compounds as nicotinic alpha-7 acetylcholine receptor agonists |
AU2016274694A1 (en) | 2015-06-10 | 2018-01-18 | Axovant Sciences Gmbh | Aminobenzisoxazole compounds as agonists of A7-nicotinic acetylcholine receptors |
WO2017027600A1 (en) | 2015-08-12 | 2017-02-16 | Forum Pharmaceuticals, Inc. | GEMINAL SUBSTITUTED AMINOBENZISOXAZOLE COMPOUNDS AS AGONISTS OF α7-NICOTINIC ACETYLCHOLINE RECEPTORS |
Citations (34)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4235871A (en) | 1978-02-24 | 1980-11-25 | Papahadjopoulos Demetrios P | Method of encapsulating biologically active materials in lipid vesicles |
US4501728A (en) | 1983-01-06 | 1985-02-26 | Technology Unlimited, Inc. | Masking of liposomes from RES recognition |
US4837028A (en) | 1986-12-24 | 1989-06-06 | Liposome Technology, Inc. | Liposomes with enhanced circulation time |
US5019369A (en) | 1984-10-22 | 1991-05-28 | Vestar, Inc. | Method of targeting tumors in humans |
US5608082A (en) | 1994-07-28 | 1997-03-04 | Agouron Pharmaceuticals, Inc. | Compounds useful as antiproliferative agents and GARFT inhibitors |
EP1012142A1 (en) | 1997-09-12 | 2000-06-28 | Merck Frosst Canada & Co. | 2,3,5-trisubstituted pyridines as inhibitors of cyclooxygenase-2 |
US20030236413A1 (en) | 2002-05-31 | 2003-12-25 | Cellier Pascal Philippe | Process for arylating or vinylating or alkynating a nucleophilic compound |
WO2004000792A1 (en) | 2002-06-20 | 2003-12-31 | Astrazeneca Ab | A process for the preparation of 3-cyano-1-naphthoic acid and some analogues thereof |
EP1489077A1 (en) | 2002-02-01 | 2004-12-22 | Dainippon Pharmaceutical Co., Ltd. | 2-furancarboxylic acid hydrazides and pharmaceutical compositions containing the same |
WO2005030715A1 (en) | 2003-09-25 | 2005-04-07 | Wyeth | Substituted sulfonamide-indole-2-carboxylic acid derivatives as pai-1 inhibitors |
WO2005105789A2 (en) | 2004-04-28 | 2005-11-10 | Rottapharm S.P.A. | Novel pyrrole derivatives with angiotensin ii antagonist activity |
US20060142349A1 (en) | 2004-12-23 | 2006-06-29 | Pfizer Inc | Methods of modulating the activities of alpha-7 nicotinic acetylcholine receptor |
US20060258670A1 (en) | 2005-05-12 | 2006-11-16 | Patrice Desos | New phenylpyridylpiperazine compounds |
WO2007031440A2 (en) | 2005-09-13 | 2007-03-22 | Janssen Pharmaceutica N.V. | 2-aniline-4-aryl substituted thiazole derivatives |
EP1790640A1 (en) | 2004-09-09 | 2007-05-30 | Chugai Seiyaku Kabushiki Kaisha | Novel imidazolidine derivative and use thereof |
US20070142450A1 (en) | 2004-03-29 | 2007-06-21 | Dahl Bjarne H | Novel urea derivatives and their medical use |
WO2007092751A2 (en) | 2006-02-03 | 2007-08-16 | Eli Lilly And Company | Compounds and methods for modulating fx-receptors |
EP1866314A1 (en) | 2005-02-16 | 2007-12-19 | NeuroSearch A/S | Novel diazabicyclic aryl derivatives and their medical use |
WO2008002974A1 (en) * | 2006-06-27 | 2008-01-03 | Abbott Laboratories | Pyrrole derivatives and their methods of use |
WO2009043784A1 (en) | 2007-10-04 | 2009-04-09 | F. Hoffmann-La Roche Ag | Cyclopropyl aryl amide derivatives and uses thereof |
WO2009043780A1 (en) | 2007-10-04 | 2009-04-09 | F. Hoffmann-La Roche Ag | Tetrazole-substituted aryl amide derivatives and uses thereof |
WO2009115547A1 (en) | 2008-03-19 | 2009-09-24 | Janssen Pharmaceutica Nv | Trisubstituted 1, 2, 4 -triazoiies as nicotinic acetylcholine receptor modulators |
US20090253691A1 (en) | 2006-04-19 | 2009-10-08 | Janssen Pharmaceutica N.V. | Trisubstituted 1,2,4-triazoles |
WO2009127679A1 (en) | 2008-04-17 | 2009-10-22 | Glaxo Group Limited | Indoles as modulators of nicoticic acetylcholine receptor subtype alpha-7 |
WO2009135944A1 (en) | 2008-05-09 | 2009-11-12 | Janssen Pharmaceutica Nv | Trisubstituted pyrazoles as acetylcholine receptor modulators |
WO2009145996A2 (en) | 2008-04-04 | 2009-12-03 | Abbott Laboratories | Amide derivatives as positive allosteric modulators and methods of use thereof |
US7683084B2 (en) | 2006-06-27 | 2010-03-23 | Abbott Laboratories | Thiazoline and oxazoline derivatives and their methods of use |
US20100190819A1 (en) | 2009-01-15 | 2010-07-29 | Richard Kanner | alpha-7 Nicotinic Acetylcholine Receptor Allosteric Modulators, Their Derivatives and Uses Thereof |
US20100222398A1 (en) | 2007-08-08 | 2010-09-02 | Neurosearch A/S | Novel 1,2,3-triazole derivatives useful as modulators of nicotinic acetylcholine receptors |
US20100227869A1 (en) | 2006-02-16 | 2010-09-09 | Dan Peters | Enantiopure quinuclidinyloxy pyridazines and their use as nicotinic acetylcholine receptor ligands |
US20100240707A1 (en) | 2007-10-18 | 2010-09-23 | Janssen Pharmaceutica Nv | 1,3,5-trisubstituted triazole derivative |
WO2010130768A1 (en) | 2009-05-14 | 2010-11-18 | Neurosearch A/S | Novel 1,4-diaza-bicyclo[3.2.1]octane derivatives useful as nicotinic acetylcholine receptor modulators |
WO2011036167A1 (en) | 2009-09-22 | 2011-03-31 | Novartis Ag | Use of nicotinic acetylcholine receptor alpha 7 activators |
WO2011064288A1 (en) | 2009-11-27 | 2011-06-03 | Janssen Pharmaceutica Nv | Morpholinothiazoles as alpha 7 positive allosteric modulators |
Family Cites Families (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3953596A (en) | 1973-06-14 | 1976-04-27 | Ici United States Inc. | 8-Oxa-3-azabicyclo(3.2.1)octane analgesic compositions and method of alleviating pain in animals |
JP2004506734A (en) * | 2000-08-21 | 2004-03-04 | ファルマシア・アンド・アップジョン・カンパニー | Quinuclide-substituted heteroaryl moieties for disease treatment |
DE10244810A1 (en) | 2002-09-26 | 2004-04-08 | Bayer Ag | New morpholine-bridged indazole derivatives |
US7129235B2 (en) | 2003-07-11 | 2006-10-31 | Abbott Laboratories | Amides useful for treating pain |
GB0403038D0 (en) | 2004-02-11 | 2004-03-17 | Novartis Ag | Organic compounds |
JP2008544982A (en) * | 2005-06-29 | 2008-12-11 | アストラゼネカ・アクチエボラーグ | Thiophene-2-carboxamide derivatives as alpha 7 nicotinic receptor modulators |
EP1928848A2 (en) | 2005-08-04 | 2008-06-11 | Apogee Biothechnology Corporation | Sphingosine kinase inhibitors and methods of their use |
EP2086324A2 (en) | 2006-11-02 | 2009-08-12 | Merck & Co., Inc. | Heterocyclyl-substituted anti-hypercholesterolemic compounds |
US20080287479A1 (en) | 2006-12-20 | 2008-11-20 | Pfizer Inc | Inhibitors of serine palmitoyltransferase |
GB0718735D0 (en) | 2007-09-25 | 2007-11-07 | Prolysis Ltd | Antibacterial agents |
WO2010120854A1 (en) | 2009-04-15 | 2010-10-21 | Glaxosmithkline Llc | Chemical compounds |
AU2012213086B2 (en) | 2011-02-03 | 2016-05-05 | Lupin Limited | Pyrrole derivatives used as modulators of alpha7 nAChR |
RS55433B1 (en) | 2011-02-23 | 2017-04-28 | Lupin Ltd | Heteroaryl derivatives as alpha7 nachr modulators |
EP2691368A1 (en) | 2011-03-31 | 2014-02-05 | Lupin Limited | Pyrrole derivatives as nicotinic acetylcholine receptor modulators for use in the treatment of neurodegenerative disorders such as alzheimer's and parkinson's disease |
WO2013005153A1 (en) | 2011-07-05 | 2013-01-10 | Lupin Limited | Biaryl derivatives as nachr modulators |
-
2012
- 2012-02-22 RS RS20160972A patent/RS55433B1/en unknown
- 2012-02-22 SI SI201230775A patent/SI2678327T1/en unknown
- 2012-02-22 EA EA201370184A patent/EA024170B1/en not_active IP Right Cessation
- 2012-02-22 GE GEAP201213238A patent/GEP20156318B/en unknown
- 2012-02-22 JP JP2013554966A patent/JP6118270B2/en active Active
- 2012-02-22 AP AP2013007121A patent/AP3649A/en active
- 2012-02-22 PE PE2013001969A patent/PE20140703A1/en not_active Application Discontinuation
- 2012-02-22 BR BR112013021602A patent/BR112013021602A2/en not_active IP Right Cessation
- 2012-02-22 EP EP12709965.3A patent/EP2678327B9/en active Active
- 2012-02-22 WO PCT/IB2012/050806 patent/WO2012114285A1/en active Application Filing
- 2012-02-22 MA MA36224A patent/MA34957B1/en unknown
- 2012-02-22 CA CA2826792A patent/CA2826792A1/en not_active Abandoned
- 2012-02-22 SG SG2013059431A patent/SG192625A1/en unknown
- 2012-02-22 AU AU2012221800A patent/AU2012221800B2/en not_active Ceased
- 2012-02-22 CN CN201280010409.0A patent/CN103402994B/en not_active Expired - Fee Related
- 2012-02-22 DK DK12709965.3T patent/DK2678327T3/en active
- 2012-02-22 LT LTEP12709965.3T patent/LT2678327T/en unknown
- 2012-02-22 KR KR1020137023970A patent/KR20140026378A/en not_active Application Discontinuation
- 2012-02-22 MX MX2013009709A patent/MX343788B/en active IP Right Grant
- 2012-02-22 PL PL12709965T patent/PL2678327T3/en unknown
- 2012-02-22 CU CUP2013000116A patent/CU24177B1/en active IP Right Grant
- 2012-02-22 US US14/000,829 patent/US9072731B2/en not_active Expired - Fee Related
- 2012-02-22 ES ES12709965.3T patent/ES2594409T3/en active Active
- 2012-02-22 HU HUE12709965A patent/HUE030659T2/en unknown
-
2013
- 2013-08-19 ZA ZA2013/06223A patent/ZA201306223B/en unknown
- 2013-08-21 IL IL228052A patent/IL228052A/en not_active IP Right Cessation
- 2013-08-22 GT GT201300207A patent/GT201300207A/en unknown
- 2013-08-23 DO DO2013000191A patent/DOP2013000191A/en unknown
- 2013-08-23 NI NI201300072A patent/NI201300072A/en unknown
- 2013-08-23 CL CL2013002449A patent/CL2013002449A1/en unknown
- 2013-08-27 CR CR20130415A patent/CR20130415A/en unknown
- 2013-09-13 CO CO13218508A patent/CO6761374A2/en unknown
- 2013-09-20 EC ECSP13012891 patent/ECSP13012891A/en unknown
-
2015
- 2015-05-06 US US14/705,144 patent/US9393247B2/en not_active Expired - Fee Related
-
2016
- 2016-10-19 CY CY20161101057T patent/CY1118107T1/en unknown
- 2016-11-09 HR HRP20161481TT patent/HRP20161481T1/en unknown
- 2016-11-11 SM SM201600409T patent/SMT201600409B/it unknown
Patent Citations (36)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4235871A (en) | 1978-02-24 | 1980-11-25 | Papahadjopoulos Demetrios P | Method of encapsulating biologically active materials in lipid vesicles |
US4501728A (en) | 1983-01-06 | 1985-02-26 | Technology Unlimited, Inc. | Masking of liposomes from RES recognition |
US5019369A (en) | 1984-10-22 | 1991-05-28 | Vestar, Inc. | Method of targeting tumors in humans |
US4837028A (en) | 1986-12-24 | 1989-06-06 | Liposome Technology, Inc. | Liposomes with enhanced circulation time |
US5608082A (en) | 1994-07-28 | 1997-03-04 | Agouron Pharmaceuticals, Inc. | Compounds useful as antiproliferative agents and GARFT inhibitors |
EP1012142A1 (en) | 1997-09-12 | 2000-06-28 | Merck Frosst Canada & Co. | 2,3,5-trisubstituted pyridines as inhibitors of cyclooxygenase-2 |
EP1489077A1 (en) | 2002-02-01 | 2004-12-22 | Dainippon Pharmaceutical Co., Ltd. | 2-furancarboxylic acid hydrazides and pharmaceutical compositions containing the same |
US20030236413A1 (en) | 2002-05-31 | 2003-12-25 | Cellier Pascal Philippe | Process for arylating or vinylating or alkynating a nucleophilic compound |
WO2004000792A1 (en) | 2002-06-20 | 2003-12-31 | Astrazeneca Ab | A process for the preparation of 3-cyano-1-naphthoic acid and some analogues thereof |
WO2005030715A1 (en) | 2003-09-25 | 2005-04-07 | Wyeth | Substituted sulfonamide-indole-2-carboxylic acid derivatives as pai-1 inhibitors |
US20070142450A1 (en) | 2004-03-29 | 2007-06-21 | Dahl Bjarne H | Novel urea derivatives and their medical use |
WO2005105789A2 (en) | 2004-04-28 | 2005-11-10 | Rottapharm S.P.A. | Novel pyrrole derivatives with angiotensin ii antagonist activity |
EP1790640A1 (en) | 2004-09-09 | 2007-05-30 | Chugai Seiyaku Kabushiki Kaisha | Novel imidazolidine derivative and use thereof |
US20060142349A1 (en) | 2004-12-23 | 2006-06-29 | Pfizer Inc | Methods of modulating the activities of alpha-7 nicotinic acetylcholine receptor |
EP1866314A1 (en) | 2005-02-16 | 2007-12-19 | NeuroSearch A/S | Novel diazabicyclic aryl derivatives and their medical use |
US20060258670A1 (en) | 2005-05-12 | 2006-11-16 | Patrice Desos | New phenylpyridylpiperazine compounds |
WO2007031440A2 (en) | 2005-09-13 | 2007-03-22 | Janssen Pharmaceutica N.V. | 2-aniline-4-aryl substituted thiazole derivatives |
WO2007092751A2 (en) | 2006-02-03 | 2007-08-16 | Eli Lilly And Company | Compounds and methods for modulating fx-receptors |
US20100227869A1 (en) | 2006-02-16 | 2010-09-09 | Dan Peters | Enantiopure quinuclidinyloxy pyridazines and their use as nicotinic acetylcholine receptor ligands |
US20090253691A1 (en) | 2006-04-19 | 2009-10-08 | Janssen Pharmaceutica N.V. | Trisubstituted 1,2,4-triazoles |
WO2008002974A1 (en) * | 2006-06-27 | 2008-01-03 | Abbott Laboratories | Pyrrole derivatives and their methods of use |
US7683084B2 (en) | 2006-06-27 | 2010-03-23 | Abbott Laboratories | Thiazoline and oxazoline derivatives and their methods of use |
US7741364B2 (en) | 2006-06-27 | 2010-06-22 | Abbott Laboratories | Pyrrole derivatives and their methods of use |
US20100222398A1 (en) | 2007-08-08 | 2010-09-02 | Neurosearch A/S | Novel 1,2,3-triazole derivatives useful as modulators of nicotinic acetylcholine receptors |
WO2009043780A1 (en) | 2007-10-04 | 2009-04-09 | F. Hoffmann-La Roche Ag | Tetrazole-substituted aryl amide derivatives and uses thereof |
WO2009043784A1 (en) | 2007-10-04 | 2009-04-09 | F. Hoffmann-La Roche Ag | Cyclopropyl aryl amide derivatives and uses thereof |
US20100240707A1 (en) | 2007-10-18 | 2010-09-23 | Janssen Pharmaceutica Nv | 1,3,5-trisubstituted triazole derivative |
WO2009115547A1 (en) | 2008-03-19 | 2009-09-24 | Janssen Pharmaceutica Nv | Trisubstituted 1, 2, 4 -triazoiies as nicotinic acetylcholine receptor modulators |
WO2009145996A2 (en) | 2008-04-04 | 2009-12-03 | Abbott Laboratories | Amide derivatives as positive allosteric modulators and methods of use thereof |
WO2009127678A1 (en) | 2008-04-17 | 2009-10-22 | Glaxo Group Limited | Indoles as modulators of nicotinic acetylcholin receptor subtype alpha-71 |
WO2009127679A1 (en) | 2008-04-17 | 2009-10-22 | Glaxo Group Limited | Indoles as modulators of nicoticic acetylcholine receptor subtype alpha-7 |
WO2009135944A1 (en) | 2008-05-09 | 2009-11-12 | Janssen Pharmaceutica Nv | Trisubstituted pyrazoles as acetylcholine receptor modulators |
US20100190819A1 (en) | 2009-01-15 | 2010-07-29 | Richard Kanner | alpha-7 Nicotinic Acetylcholine Receptor Allosteric Modulators, Their Derivatives and Uses Thereof |
WO2010130768A1 (en) | 2009-05-14 | 2010-11-18 | Neurosearch A/S | Novel 1,4-diaza-bicyclo[3.2.1]octane derivatives useful as nicotinic acetylcholine receptor modulators |
WO2011036167A1 (en) | 2009-09-22 | 2011-03-31 | Novartis Ag | Use of nicotinic acetylcholine receptor alpha 7 activators |
WO2011064288A1 (en) | 2009-11-27 | 2011-06-03 | Janssen Pharmaceutica Nv | Morpholinothiazoles as alpha 7 positive allosteric modulators |
Non-Patent Citations (119)
Title |
---|
"Pharmaceutics and Pharmacy Practice", 1982, J.B. LIPPINCOTT COMPANY, pages: 238 - 250 |
"Remington's Pharmaceutical Science", 1985, MACK PUBLISHING COMPANY |
"Remington's Pharmaceutical Sciences", 1990, MACK PUBLISHING COMPANY, pages: 1445 |
ALBUQUERQUE EX ET AL., ALZHEIMER DIS. ASSOC. DISORD., vol. 15, no. 1, 2001, pages S19 - S25 |
ALKONDON M ET AL., EUR. J. PHARMACOL., vol. 393, 2000, pages 59 - 67 |
ARIAS HR ET AL., INT. J. BIOCHEM. CELL. BIOL., vol. 41, 2009, pages 1441 - 1451 |
BENNOUNA M ET AL., ENCEPHALE, vol. 33, 2007, pages 616 - 620 |
BERGE S.M. ET AL.: "Pharmaceutical Salts", JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 66, 1977, pages 1 - 19, XP002675560, DOI: doi:10.1002/jps.2600660104 |
BIOORGANIC CHEMISTRY, vol. 22, 1994, pages 387 - 394 |
BITNER RS ET AL., J. NEUROSCI., vol. 27, 2007, pages 10578 - 10587 |
BOESS FG ET AL., J. PHARMACOL. EXP. THER., vol. 321, 2007, pages 716 - 725 |
BRUCHFELD A ET AL., J. INTERN. MED., vol. 268, 2010, pages 94 - 101 |
CALLEJA-MACIAS IE ET AL., INT. J. CANCER., vol. 124, 2009, pages 1090 - 1096 |
CANNON TD ET AL., CURR. OPIN. PSYCHIATRY, vol. 18, 2005, pages 135 - 140 |
CARSON R ET AL.: "Neuromolecular", MED., vol. 10, 2008, pages 377 - 384 |
CHAN WK ET AL., NEUROPHARMACOLOGY, vol. 52, 2007, pages 1641 - 1649 |
CURZON P ET AL., NEUROSCI. LETT., vol. 410, 2006, pages 15 - 19 |
DAJAS-BAILADOR F ET AL., TRENDS PHARMACOL. SCI., vol. 25, 2004, pages 317 - 324 |
DAMAJ MI ET AL., NEUROPHARMACOLOGY, vol. 39, 2000, pages 2785 - 2791 |
DECKER MW ET AL., EXPERT. OPIN. INVESTIG. DRUGS, vol. 10, 2001, pages 1819 - 1830 |
DEUTSCH SI ET AL., CLIN. NEUROPHARMACOL., vol. 26, 2003, pages 277 - 283 |
DONNELLY-ROBERTS DL ET AL., J. PHARMACOL. EXP. THER., vol. 285, 1998, pages 777 - 786 |
DUNLOP J ET AL., J. PHARMACOL. EXP. THER., vol. 328, 2009, pages 766 - 776 |
DURIS K ET AL., STROKE, vol. 42, no. 12, 2011, pages 3530 - 6 |
EBBERT JO ET AL., PATIENT. PREFER. ADHERENCE, vol. 4, 2010, pages 355 - 362 |
ENVIVO PHARMACEUTICALS, 12 January 2009 (2009-01-12) |
FAGHIH R ET AL., J. MED. CHEM., vol. 52, 2009, pages 3377 - 3384 |
FAGHIH R. ET AL., J. MED. CHEM., vol. 52, 2009, pages 3377 - 84 |
FEHER A ET AL., DEMENT. GERIATR. COGN. DISORD., vol. 28, 2009, pages 56 - 62 |
FREEDMAN R ET AL., BIOL. PSYCHIATRY, vol. 38, 1995, pages 22 - 33 |
FREEDMAN R ET AL., CURR. PSYCHIATRY REP., vol. 5, 2003, pages 155 - 161 |
GALLOWITSCH-PUERTA M ET AL., LIFE SCI., vol. 80, 2007, pages 2325 - 2329 |
GALLOWITSCH-PUERTA; PAVLOV, LIFE SCI., 2007 |
GIEBELEN IA T ET AL., SHOCK, vol. 27, 2007, pages 443 - 447 |
GOLDSTEIN R ET AL., ACAD. EMERG. MED., vol. 14, no. 15, 2007 |
HARRINGTON CR ET AL., DEMENTIA, vol. 5, 1994, pages 215 - 228 |
HASHIMOTO K ET AL., BIOL. PSYCHIATRY, vol. 63, 2008, pages 92 - 97 |
HAUSER TA ET AL., BIOCHEM. PHARMACOL., vol. 78, 2009, pages 803 - 812 |
HAYDAR SN ET AL., BIOORG. MED. CHEM., vol. 17, 2009, pages 5247 - 5258 |
HEESCHEN C ET AL., J. CLIN. INVEST., vol. 110, 2002, pages 527 - 536 |
J. AMER. CHEM. SOC., vol. 127, no. 36, 2005, pages 12640 - 12646 |
J. CHEM. SOC. PERKIN TRANS.: ORGANIC AND BIOORGANIC CHEMISTRY (1972-1999, 1972, pages 1766 - 1770 |
J. CHEM. SOC. PERKIN TRANS-L:0RGANIC AND BIOORGANIC CHEMISTRY, 1972, pages 1766 - 1770 |
J. MED. CHEM., vol. 52, 2009, pages 3377 |
J. ORG. CHEM., vol. 74, no. 2, 2009, pages 903 - 905 |
J. ORG. CHEM., vol. 75, 2010, pages 3855 - 3858 |
JCS PERKIN TRANS-I:ORGANIC AND BIOORGANIC CHEMISTRY (1972-1999, 1972, pages 1766 - 1770 |
JEYARASASINGAM G ET AL., NEUROSCIENCE, vol. 109, 2002, pages 275 - 285 |
JIN Y ET AL., INT. J. IMMUNOGENET., 2010 |
JOURNAL OF PHARMACEUTICAL SCIENCE, vol. 66, 1977, pages 2 - 19 |
KUZMIN A ET AL., PSYCHOPHARMACOLOGY (BERL, vol. 203, 2009, pages 99 - 108 |
LEISER SC ET AL., PHARMACOL. THER., vol. 122, 2009, pages 302 - 311 |
LEONARD S ET AL., PHARMACOL. BIOCHEM. BEHAV., vol. 70, 2001, pages 561 - 570 |
LIU C ET AL., CRIT. CARE. MED., vol. 37, 2009, pages 634 - 641 |
MANSVELDER HD ET AL., PSYCHOPHARMACOLOGY (BERL, vol. 184, 2006, pages 292 - 305 |
MARRERO MB ET AL., BRAIN. RES., vol. 1256, 2009, pages 1 - 7 |
MARTIN LF ET AL., AM. J. MED. GENET., B NEUROPSYCHIATR. GENET., vol. 144B, 2007, pages 611 - 614 |
MARTIN LF ET AL., PSYCHOPHARMACOLOGY (BERL, vol. 174, 2004, pages 54 - 64 |
MCKAY BE ET AL., BIOCHEM. PHARMACOL., vol. 74, 2007, pages 1120 - 1133 |
N. MIYAURA; A. SUZUKI, CHEM. REV., vol. 95, 1995, pages 2547 |
N.MIYAURA; A. SUZUKI, CHEM. REV., vol. 95, 1995, pages 2547 |
NAGELE RG ET AL., NEUROSCIENCE, vol. 110, 2002, pages 199 - 211 |
NG HJ ET AL., PROC. NATL. ACAD. SCI., U. S. A., vol. 104, 2007, pages 8059 - 8064 |
NIZRI E ET AL., DRUG NEWS PERSPECT., vol. 20, 2007, pages 421 - 429 |
NORDBERG A ET AL., NEUROTOX. RES., vol. 2, 2000, pages 157 - 165 |
O'DONNELL CJ ET AL., J. MED. CHEM., vol. 53, 2010, pages 1222 - 1237 |
OLINCY A ET AL., ARCH. GEN. PSYCHIATRY, vol. 63, 2006, pages 630 - 638 |
OLINCY A ET AL., BIOL. PSYCHIATRY, vol. 57, no. 8, 2005 |
ORG. LETT., vol. 9, no. 25, 2007, pages 5191 - 5194 |
ORGANIC LETTERS, vol. 9, no. 25, 2007, pages 5191 - 5194 |
ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL, vol. 37, no. 5, 2002, pages 545 - 549 |
P.H.EINRICH STAHLAND; CAMILLE G.WERMUTH: "handbook of pharmaceutical salts properties, selection, and use", 2002, WILEY- VCH |
PATERSON D ET AL., PROG. NEUROBIOL., vol. 61, 2000, pages 75 - 111 |
PENA G ET AL., EUR. J. IMMUNOL., vol. 40, 2010, pages 2580 - 2589 |
PENG ZZ ET AL., ZHONGHUA YI XUE YI CHUAN XUE ZA ZHI, vol. 25, 2008, pages 154 - 158 |
PERRY E ET AL., EUR. J. PHARMACOL., vol. 393, 2000, pages 215 - 222 |
PHYSICIANS, DESK REFERENCE, 2004 |
PHYSICIANS: "Desk Reference", 2004, THOMSON PDR |
PICHAT P ET AL., NEUROPSYCHOPHARMACOLOGY, vol. 32, 2007, pages 17 - 34 |
REDROBE JP ET AL., EUR. J. PHARMACOL., vol. 602, 2009, pages 58 - 65 |
RONCARATI R ET AL., J. PHARMACOL. EXP. THER., vol. 329, 2009, pages 459 - 468 |
ROSAS-BALLINA M ET AL., J. INTERN. MED., vol. 265, 2009, pages 663 - 679 |
ROSAS-BALLINA M ET AL., MOL. MED., vol. 15, 2009, pages 195 - 202 |
ROWBOTHAM MC ET AL., PAIN, vol. 146, 2009, pages 245 - 252 |
ROWLEY TJ ET AL., BR. J. ANAESTH., vol. 105, 2010, pages 201 - 207 |
RUBBOLI F ET AL., NEUROCHEM. INT., vol. 25, 1994, pages 69 - 71 |
SANBERG PR ET AL., PHARMACOL. THER., vol. 74, 1997, pages 21 - 25 |
SCHULLER HM ET AL., EUR. J. PHARMACOL., vol. 393, 2000, pages 265 - 277 |
SOLINAS M ET AL., J. NEUROSCI., vol. 27, 2007, pages 5615 - 5620 |
SUEMARU K ET AL., NIPPON YAKURIGAKU ZASSHI, vol. 119, 2002, pages 295 - 300 |
SYNLETT, vol. 7, 2002, pages 1152 - 1154 |
SYNTHETIC COMMUNICATIONS, vol. 39, no. 12, 2009, pages 2082 - 2092 |
SZOKA ET AL., ANN. REV. BIOPHYS. BIOENG., vol. 9, 1980, pages 467 |
TATSUMI ET AL.: "(+)-3-[2-(benzo[b]thiophen-2-yl)-2-oxoethyl]-1-azabicyclo[2.2.2]oct ane as potent agonists for the alpha-7 nicotinic acetylcholine receptor", BIOORG. MED. CHEM. LETT., vol. 14, no. 14, 1 January 2004 (2004-01-01), pages 3781 - 3784, XP002327499, ISSN: 0960-894X, DOI: 10.1016/J.BMCL.2004.04.091 * |
TATSUMI ET AL.: "(R)-3'-(3-Methylbenzo(b)thiophen-5-yl)- spiro(1-azabicyclo(2,2,2)octa ne-3,5'- oxazolidin)-2'-one, a Novel and Potent alpha7 Nicotinic Acetylcholine Receptor Partial Agonist Displays Cognitive Enhancing Properties", J. MED. CHEM., vol. 49, no. 14, 1 January 2006 (2006-01-01), pages 4374 - 4383, XP002538696, ISSN: 0022-2623, [retrieved on 20060616], DOI: 10.1021/JM060249C * |
TETRAHEDRON LETTERS, vol. 44, no. 16, 2003, pages 3385 - 3386 |
TETRAHEDRON LETTERS, vol. 46, 2005, pages 4539 - 4542 |
TETRAHEDRON LETTERS, vol. 46, no. 43, 2005, pages 7295 - 7298 |
TETRAHEDRON LETTERS, vol. 49, no. 18, 2008, pages 2882 - 2885 |
TETRAHEDRON LETTERS, vol. 51, 2010, pages 1693 - 1695 |
TETRAHEDRON LETTERS, vol. 51, no. 15, 2010, pages 2048 - 2051 |
TETRAHEDRON, vol. 60, 2004, pages 3439 - 43 |
TETRAHEDRON, vol. 62, 2006, pages 7902 - 7910 |
TETRAHEDRON, vol. 62, 2006, pages 8243 - 8255 |
THOMSEN MS ET AL., CURR. PHARM. DES., vol. 16, 2010, pages 323 - 343 |
TIMMERMANN DB ET AL., J. PHARMACOL. EXP. THER., vol. 323, 2007, pages 294 - 307 |
TOISSEL: "ASHP Handbook on Injectable Drugs", 1986, pages: 622 - 630 |
TSUANG DW ET AL., AM. J. MED. GENET., vol. 105, 2001, pages 662 - 668 |
VAN KM ET AL., PSYCHOPHARMACOLOGY (BERL, vol. 172, 2004, pages 375 - 383 |
VERBOIS SL ET AL., NEUROPHARMACOLOGY, vol. 44, 2003, pages 224 - 233 |
WANG HY ET AL., J. NEUROSCI., vol. 29, 2009, pages 10961 - 10973 |
WANG J ET AL., J. NEUROSCI. RES., vol. 88, 2010, pages 807 - 815 |
WASSERMAN ET AL., CANCER, vol. 36, 1975, pages 1258 - 1268 |
WEISS RB ET AL., PLOS GENET., vol. 4, 2008, pages EL000125 |
WESTMAN M ET AL., SCAND. J. IMMUNOL., vol. 70, 2009, pages 136 - 140 |
WILENS TE ET AL., BIOCHEM. PHARMACOL., vol. 74, 2007, pages 1212 - 1223 |
YOUNG JW ET AL., EUR. NEUROPSYCHOPHARMACOL., vol. 17, 2007, pages 145 - 155 |
YOUNG JW ET AL., NEUROPSYCHOPHARMACOLOGY, vol. 29, 2004, pages 891 - 900 |
ZHAO X ET AL., ANN. N. Y. ACAD. SCI., vol. 939, 2001, pages 179 - 186 |
Cited By (29)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9388196B2 (en) | 2012-03-06 | 2016-07-12 | Lupin Limited | Thiazole derivatives as alpha 7 nAChR modulators |
CN109053766A (en) * | 2012-09-28 | 2018-12-21 | 武田药品工业株式会社 | The preparation method of Thienopyrimidine derivative |
WO2014072957A1 (en) | 2012-11-12 | 2014-05-15 | Lupin Limited | Thiazole derivatives as alpha 7 nachr modulators |
WO2014111839A1 (en) | 2013-01-16 | 2014-07-24 | Lupin Limited | Pyrrole derivatives as alpha 7 nachr modulators |
US9617211B2 (en) | 2013-01-16 | 2017-04-11 | Lupin Limited | Pyrrole derivatives as alpha 7 nAChR modulators |
JP2016512225A (en) * | 2013-03-13 | 2016-04-25 | ルピン・リミテッドLupin Limited | Pyrrole derivatives as alpha 7NACHR modulators |
CN105051024A (en) * | 2013-03-13 | 2015-11-11 | 鲁平有限公司 | Pyrrole derivatives as alpha 7 nachr modulators |
US9617210B2 (en) | 2013-03-13 | 2017-04-11 | Lupin Limited | Pyrrole derivatives as alpha 7 NACHR modulators |
WO2014141091A1 (en) | 2013-03-13 | 2014-09-18 | Lupin Limited | Pyrrole derivatives as alpha 7 nachr modulators |
US20160107990A1 (en) * | 2013-06-03 | 2016-04-21 | Lupin Limited | 4-(5-(4-chlorophenyl)-2-(2-cyclopropylacetyl)-1,4-dimethyl-1h-pyrrol-3-yl)benzenesulfonamide as alpha 7 nachr modulator |
US9447037B2 (en) | 2013-06-03 | 2016-09-20 | Lupin Limited | 4-(5-(4-chlorophenyl)-2-(2-cyclopropylacetyl)-1,4-dimethyl-1H-pyrrol-3-yl)benzenesulfonamide as alpha 7 nAChR modulator |
AU2014276436B2 (en) * | 2013-06-03 | 2017-03-02 | Lupin Limited | 4-(5-(4-chlorophenyl)-2-(2-cyclopropylacetyl)-1,4-dimethyl-1H-pyrrol-3-yl)benzenesulfonamide as alpha 7 nAChR modulator |
WO2014195848A1 (en) | 2013-06-03 | 2014-12-11 | Lupin Limited | 4-(5-(4-chlorophenyl)-2-(2-cyclopropylacetyl)-1,4-dimethyl-1h-pyrrol-3-yl)benzenesulfonamide as alpha 7 nachr modulator |
US20160137600A1 (en) * | 2013-06-17 | 2016-05-19 | Lupin Limited | Pyrrole Derivatives as Alpha 7 nAChR Modulators |
WO2014203150A1 (en) | 2013-06-17 | 2014-12-24 | Lupin Limited | Pyrrole derivatives as alpha 7 nachr modulators |
US9504680B2 (en) | 2013-06-17 | 2016-11-29 | Lupin Limited | Pyrrole derivatives as alpha 7 nAChR modulators |
US9926285B2 (en) | 2016-03-22 | 2018-03-27 | Merck Sharp & Dohme Corp. | Allosteric modulators of nicotinic acetylcholine receptors |
US9840481B2 (en) | 2016-03-22 | 2017-12-12 | Merck Sharp & Dohme Corp. | Allosteric modulators of nicotinic acetylcholine receptors |
CN112533581A (en) * | 2018-06-07 | 2021-03-19 | 密歇根大学董事会 | PRC1 inhibitors and methods of treatment therewith |
EP3813784A4 (en) * | 2018-06-07 | 2021-12-08 | The Regents Of The University Of Michigan | Prc1 inhibitors and methods of treatment therewith |
WO2020007905A1 (en) * | 2018-07-05 | 2020-01-09 | Bayer Aktiengesellschaft | Substituted thiophenecarboxamides and analogues as antibacterials agents |
US11401254B2 (en) | 2018-07-05 | 2022-08-02 | Bayer Aktiengesellschaft | Substituted thiophenecarboxamides and analogues as antibacterials agents |
RU2797513C2 (en) * | 2018-07-05 | 2023-06-06 | Байер Акциенгезельшафт | Substituted thiophenecarboxamides and analogues as antibacterial agents |
TWI823961B (en) * | 2018-07-05 | 2023-12-01 | 德商拜耳廠股份有限公司 | Thienyloxazolones and analogues |
US11884643B2 (en) | 2018-07-05 | 2024-01-30 | Bayer Aktiengesellschaft | Substituted thiophenecarboxamides and analogues as antibacterials agents |
US11952359B2 (en) | 2018-07-05 | 2024-04-09 | Bayer Aktiengesellschaft | Substituted thiophenecarboxamides and analogues as antibacterials agents |
JP7476118B2 (en) | 2018-07-05 | 2024-04-30 | バイエル・アクチエンゲゼルシヤフト | Substituted thiophene carboxamides and analogues as antibacterial agents. |
WO2021001331A1 (en) | 2019-07-03 | 2021-01-07 | Bayer Aktiengesellschaft | Substituted thiophene carboxamides and derivatives thereof as microbicides |
WO2021123051A1 (en) | 2019-12-20 | 2021-06-24 | Bayer Aktiengesellschaft | Substituted thiophene carboxamides, thiophene carboxylic acids and derivatives thereof |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US9393247B2 (en) | Heteroaryl derivatives as alpha7 nAChR modulators | |
EP2729455B1 (en) | Biaryl derivatives as nachr modulators | |
AU2012235779B2 (en) | Pyrrole derivatives as nicotinic acetylcholine receptor modulators for use in the treatment of neurodegenerative disorders such as Alzheimer's and Parkinson's disease | |
US9388196B2 (en) | Thiazole derivatives as alpha 7 nAChR modulators | |
US9617210B2 (en) | Pyrrole derivatives as alpha 7 NACHR modulators | |
US20130310419A1 (en) | Pyrrole derivatives used as modulators of alpha7 nachr | |
US9617211B2 (en) | Pyrrole derivatives as alpha 7 nAChR modulators | |
NZ615001B2 (en) | Heteroaryl derivatives as alpha7 nachr modulators | |
OA16539A (en) | Heteroaryl derivatives as alpha7 nAChR modulators | |
NZ615583B2 (en) | Pyrrole derivatives as nicotinic acetylcholine receptor modulators for use in the treatment of neurodegenerative disorders such as alzheimer's and parkinson's disease | |
UA112076C2 (en) | Heteroaryl derivatives |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 12709965 Country of ref document: EP Kind code of ref document: A1 |
|
DPE1 | Request for preliminary examination filed after expiration of 19th month from priority date (pct application filed from 20040101) | ||
ENP | Entry into the national phase |
Ref document number: 2826792 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 14000829 Country of ref document: US |
|
WWE | Wipo information: entry into national phase |
Ref document number: 12013501727 Country of ref document: PH Ref document number: MX/A/2013/009709 Country of ref document: MX |
|
ENP | Entry into the national phase |
Ref document number: 2013554966 Country of ref document: JP Kind code of ref document: A |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1301004715 Country of ref document: TH Ref document number: 001969-2013 Country of ref document: PE |
|
WWE | Wipo information: entry into national phase |
Ref document number: CR2013-000415 Country of ref document: CR |
|
ENP | Entry into the national phase |
Ref document number: 20137023970 Country of ref document: KR Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 13218508 Country of ref document: CO |
|
WWE | Wipo information: entry into national phase |
Ref document number: 13238 Country of ref document: GE Ref document number: A201311194 Country of ref document: UA Ref document number: 201370184 Country of ref document: EA |
|
REEP | Request for entry into the european phase |
Ref document number: 2012709965 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2012709965 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: 2012221800 Country of ref document: AU Date of ref document: 20120222 Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: P-2016/0972 Country of ref document: RS |
|
REG | Reference to national code |
Ref country code: BR Ref legal event code: B01A Ref document number: 112013021602 Country of ref document: BR |
|
ENP | Entry into the national phase |
Ref document number: 112013021602 Country of ref document: BR Kind code of ref document: A2 Effective date: 20130823 |