EP1305304A1 - Carboxamide compounds and their use as antagonists of a human 11cby receptor - Google Patents
Carboxamide compounds and their use as antagonists of a human 11cby receptorInfo
- Publication number
- EP1305304A1 EP1305304A1 EP01956562A EP01956562A EP1305304A1 EP 1305304 A1 EP1305304 A1 EP 1305304A1 EP 01956562 A EP01956562 A EP 01956562A EP 01956562 A EP01956562 A EP 01956562A EP 1305304 A1 EP1305304 A1 EP 1305304A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- ethoxy
- phenyl
- benzamide
- compound
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- 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
- C07D207/04—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 no double bonds between ring members or between ring members and non-ring members
- C07D207/08—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 no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
-
- 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
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
-
- 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
- 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
- A61P1/04—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
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- 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
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- 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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
-
- 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
- A61P7/10—Antioedematous agents; Diuretics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
- C07C233/67—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
- C07C233/75—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/48—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/84—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
- C07C237/40—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C255/57—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and carboxyl groups, other than cyano groups, bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/62—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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
- C07D211/40—Oxygen atoms
- C07D211/42—Oxygen atoms attached in position 3 or 5
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/54—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
- C07D213/56—Amides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three 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
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/12—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three 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
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
- C07D317/60—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
- 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
- C07D333/24—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
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
Definitions
- This invention relates to a method of treatment using an antagonist of the human 1 ICBy receptor; a new therapeutic use of a class of carboxamide compounds which are antagonists to a human 1 ICBy receptor; also to novel compounds within that class, and to methods for making the compounds.
- WO 98/00401 discloses benzamide derivatives as fibrinogen receptor antagonist prodrugs.
- European Patent EP 0 358 118 (Boehringer Mannheim GmbH) discloses certain bisaryl compounds as inhibitors of erythrocyte aggregation and useful in the treatment of cardiac and circulatory disease.
- EP 0 968 999 discloses certain anilide derivatives useful in the treatment of arrhythmia.
- WO 99/01127 discloses certain N- [(amino alkoxy)phenyl] benzamides that are active as CCR5 receptor ligands, including the compounds N- [4- [2- [bis ( 1 -methylethyl) amino] ethoxy] -2-fluorophenyl] -[1,1 -biphenyl] -4- carboxamide and N-[4-[2-[bis(l-methylethyl)amino]-ethoxy]-phenyl]-[l, -biphenyl]-4- carboxamide.
- WO 99/06146 discloses certain substituted anilides that are antagonists of the CCR5 receptor, including the compounds: biphenyl-4-carboxylic acid [4-(2-dimethylamino-ethoxy)-phenyl]-amide, biphenyl-4-carboxylic acid [4-(2-diisopropylamino-ethoxy)-phenyl] -amide, N-[4-(2-diisopropylamino-ethoxy)-phenyl]-4-phenoxy-benzamide, N-[4-(2-diethylamino-ethoxy)-phenyl]-4-phenoxy-benzamide, N-[4-(2-diisopropylamino-ethoxy)-phenyl]-3-phenoxy-benzamide, N- [4-(2-diethylamino-ethoxy)- ⁇ henyI] -3 -phenoxy-benzamide, 4-cyclohexyl-N-[
- the present invention is based on the finding that a class of carboxamides overlapping with the above-mentioned benzamides and anilides, are, surprisingly, antagonists of a human 1 ICBy receptor disclosed in Nature, 400, 261-265 (1999).
- these compounds are believed to have a role in preventing, ameliorating or correcting dysfunctions or diseases, including, but not limited to, infections such as bacterial, fungal, protozoan and viral infections, particularly infection caused by HIV-1 or HlN-2; pain; cancers; diabetes; obesity; feeding and drinking abnormalities, such as anorexia and bulimia; asthma; Parkinson's disease; both acute and congestive heart failure; hypotension; hypertension; urinary retention; osteoporosis; angina pectoris; myocardial infarction; ulcers; allergies; benign prostatic hypertrophy; psychotic and neurological disorders, including anxiety, schizophrenia, manic depression, delirium, dementia or severe mental retardation; and dyskinesias, such as Huntingdon's disease or Gilles de la Tourette's syndrome, among others, hereinafter referred to as "the Disorders”.
- infections such as bacterial, fungal, protozoan and viral infections, particularly infection caused by HIV-1 or HlN-2
- pain cancers
- diabetes obesity
- a method of treating the Disorders which comprises administering to a mammal suffering from one or more of the Disorders an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, in which:
- each A is independently hydrogen, a C g alkyl optionally substituted by hydroxyl, C g alkoxy, C ⁇ 6 alkenyl or group or a halogen atom or hydroxyl, CN or CF3 group;
- R3 is hydrogen, methyl or ethyl. Preferably R3 is methyl.
- R4 is an optionally substituted aromatic carbocychc or heterocychc ring.
- Z is an O or S atom, or an NH or CH 2 group, or a single bond, at the 3 or 4 position of R4 relative to the carbonyl group.
- Z is a bond.
- Z is a bond at the 4-position of R4 relative to the carbonyl group.
- R5 is an optionally substituted aromatic carbocychc or heterocychc ring, or an optionally substituted, saturated or unsaturated, carbocychc or heterocychc ring.
- R5 is a phenyl ring.
- R1 / and Q is -X-Y-N ⁇ R2 (a) where X is an O or S atom, preferably an O atom;
- Y is a linear or branched C2.4 alkylene group, preferably a C3 alkylene group, optionally
- Rl and R2 are independently a linear or branched C ⁇ . alkyl, preferably ethyl; phenyl C ⁇ .
- Y is a linear or branched C2-4 alkylene group, optionally substituted by a hydroxyl group,
- Rl and R2 are linked to form a 5, 6 or 7-membered ring, preferably a 5-membered ring, optionally containing one or more further heteroatoms selected from O, S or N, where N or C ring atoms are optionally substituted by Ra, -CO-Ra, -CO-NH-Ra, or CO-O-Ra, where Ra is a linear or branched C ⁇ . ⁇ alkyl or aryl group; and the 5, 6 or 7-membered ring is optionally fused to an optionally substituted benzene ring, or a ring atom of the 5, 6 or 7-membered ring is optionally linked by a single bond or methylene group to Y; or (c) where X is an O or S atom, Y is a C2-4 alkylene group, Rl is a C2-4 alkylene group linked to Y to form a 5 or 6 membered ring and R2 is a linear or branched C ⁇ _6 alky
- Y is a C2-4 alkylene group
- Rl is a C2-4 alkylene group linked to X to form a 5 or 6 membered ring and R2 is a linear or branched C ⁇ alkyl group.
- Alkyl groups including alkyl groups that are part of alkoxy, acyl, etc groups, typically contain 1 to 6 carbon atoms, and may be linear or branched, such as methyl, ethyl, i- propyl and t-butyl, and optionally substituted by hydroxyl.
- Aryl groups are typically phenyl, but may include bicyclic groups such as naphthyl. Cycloalkyl groups typically contain from 3 to 7 carbon atoms.
- Heterocychc groups may be monocylic 5 to 7 membered rings containing up to three hetero atoms, such as pyridyl or imidazole, or bicyclic, especially heterocychc rings fused to benzene rings, such as benzoxazole or benzimidazole.
- Aryl, cycloalkyl and heterocychc groups may be optionally subsituted by up to three substituents, which may suitably be selected from aryl, alkyl, alkoxy, halogen, hydroxy and cyano, or by linked substituents such as dioxymethylene.
- Suitable aromatic rings for use as R4 include phenyl, pyridyl, thienyl, furanyl and pyrazolyl.
- Suitable optional substituents for R4 include halogen, CF3, Cj_4 alkyl, C1.4 alkoxy.
- R4 may have 2 or 3 substituents, but preferably has only 1 substituent in addition to Z, or more preferably is unsubstituted apart from Z.
- Particularly suitable substituents for R4 include chloro, fluoro, trifluoromethyl, methyl, methoxy.
- R5 may be monocyclic, for example thienyl, furanyl, imidazolyl, oxadiazolyl, phenyl, pyridinyl, cyclohexyl, piperidinyl, piperazinyl, pyrazinyl, pyrimidinyl; or a fused bicyclic ring system, for example naphthyl, 3,4-dioxymethylene-phenyl, benzofuranyl, indolyl; or a bicyclic system in which a monocyclic ring has a cyclic substituent such as oxadiazolyl, benzyloxy.
- Suitable optional substituents for R5 include halogen, CF3, CF3O, CHF2O,
- R5 may have
- substituents for R5 include chloro, fluoro, trifluoromethyl, cyano, amino, methyl, ethyl, t-butyl, methoxy, acetyl, formyl, methylthio, methanesulphonyl, vinyl, benzyl, benzyloxy, hydrogen.
- all A substituents may be hydrogen, but it is advantageous that no more than 3 are hydrogen.
- Suitable A substituents include halogen, C ⁇ _g alkyl optionally substituted with hydroxy, C ⁇ . alkoxy, acyl and alkenyl.
- Particularly suitable A substituents include Cl-2alkoxy, Cl-2alkyl, Cl-2 acyl.
- Preferable substituents for A include chloro, fluoro, methyl, ethyl, hydroxyethyl, methoxy, formyl, acetyl, vinyl and allyl. More preferable substituents for A include methoxy.
- the A substituent is adjacent to the group Q.
- substituents for Rl and R2 include methyl, ethyl, isopropyl, benzyl, phenethyl.
- Y may especially be -(CH2)2- >
- Y When Y is substituted by hydroxy, it may be for example -CH 2 -CH(OH)-CH 2 -.
- the ring formed by linking Rl and R2 may be pyrrolidinyl, piperidinyl, azepanyl, or imidazolyl.
- Fused rings include indolinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl and benzoazepinyl.
- suitable rings include thiazinyl, oxazinyl and piperazinyl.
- a second N atom may be substituted, for example by phenyl, methyl, ethyl, isopwpyl or acetyl.
- Y is typically -(CH2)2-- The ring may be linked back to Y to form a quinuclidinyl group.
- the ring formed by linking Rl to Y may be a pyrrolidinyl or piperidinyl ring.
- the linkage to Y may be such as to create a ring linked by a single bond from a ring carbon atom directly to X or via a methylene or ethylene linking group.
- R2 is typically methyl so that the N atom of the ring is substituted by methyl.
- the ring formed by linking Rl to N is suitably a 5 or 6- membered ring such as diazinyl or piperazinyl.
- Y is typically -(CH2)2-- R2 is typically methyl so that the second N atom (other than X) of the ring is substituted by methyl.
- R3 H
- X O
- Y CH 2 CH 2
- Z a bond
- R4 Ph
- R5 is either meta or para substituted on R4
- Rl, R2 and R5 are as defined for formula (I).
- A H and OMe
- R3 H
- X N
- R4 phenyl
- Z a para substituted bond
- R5 Ph or cyclohexyl (Cy)
- Y and R2 form a piperazinyl ring between X and N
- Rl is as defined in formula (I).
- a preferred sub-class of compounds for use in the method of treatment of this invention are compounds of formula (I) in which R3 is methyl.
- a particular group of novel compounds is a class of compounds of general formula (VI)
- R5 is phenyl or cyclohexyl optionally substituted by halogen, haloalkyl, alkyl or alkoxy
- Z is O, CH2 or a single bond
- R8 and R9 are independently selected from hydrogen, halogen, alkyl and alkoxy
- Rl and R2 are alkyl or linked together to form a ring
- R3 is ethyl or methyl.
- Another aspect of this invention is a class of novel compounds, or a salt or solvate thereof, which are the compounds of formula (I) excluding the compounds: N-[4-[2-[bis(l-methylethyl)amino]ethoxy]-2-fluorophenyl]-[l,l'-biphenyl]-4- carboxamide,
- a further aspect of this invention is those compounds of the Examples herein which are novel.
- the compounds of formulae (I) to (LX), or their salts or solvates are preferably in pharmaceutically acceptable or substantially pure form.
- pharmaceutically acceptable form is meant, inter alia, of a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and including no material considered toxic at normal dosage levels.
- Suitable salts and solvates include pharmaceutically acceptable salts and pharmaceutically acceptable solvates.
- Suitable pharmaceutically acceptable salts include metal salts, such as for example aluminium, alkali metal salts such as lithium, sodium or potassium, alkaline earth metal salts such as calcium or magnesium and ammonium or substituted ammonium salts, for example those with lower alkylamines such as Methylamine, hydroxy alkylamines such as 2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine or tri-(2-hydroxyethyl)-amine, cycloalkyla ines such as bicyclohexylamine, or with procaine, dibenzylpiperidine, N-benzyl- ⁇ -phenethylamine, dehydroabietylamine, N,N'-bisdehydroabietylamine, glucamine, N-methylglucamine or bases of the pyridine type such as pyridine, colhdine, quinine or quinoline.
- metal salts such as for example aluminium, alkali metal salts such as lithium, sodium or potassium
- Suitable pharmaceutically acceptable salts also includes pharmaceutically acceptable acid addition salts, such as those provided by pharmaceutically acceptable inorganic acids or organic acids.
- Suitable pharmaceutically acceptable acid addition salts provided by pharmaceutically acceptable inorganic acids includes the sulphate, nitrate, phosphate, borate, hydrochloride and hydrobromide and hydroiodide.
- Suitable pharmaceutically acceptable acid addition salts provided by pharmaceutically acceptable organic acids includes the acetate, tartrate, maleate, fumarate, malonate, citrate, succinate, lactate, oxalate, benzoate, ascorbate, methanesulphonate, -keto glutarate and -glycerophosphate.
- Suitable pharmaceutically acceptable solvates include hydrates.
- a substantially pure form will generally contain at least 50% (excluding normal pharmaceutical additives), preferably 75%, more preferably 90% and still more preferably 95% of the compound of formula (I) to (IX) or its salt or solvate.
- One preferred pharmaceutically acceptable form is the crystalline form, including such form in a pharmaceutical composition.
- the additional ionic and solvent moieties must also be non-toxic.
- Examples of pharmaceutically acceptable salts of a compound of formula (I) to (IX) include the acid addition salts with the conventional pharmaceutical acids, for example, maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric, succinic, benzoic, ascorbic and methanesulphonic.
- conventional pharmaceutical acids for example, maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric, succinic, benzoic, ascorbic and methanesulphonic.
- the compounds of formula (I) to (LX) may exist in more than one stereoisomeric form, and the invention extends to all such forms as well as to their mixtures thereof, including racemates.
- the compounds of formula (I) to (JX), or salts or solvates thereof may be prepared by the methods illustrated in the following general reaction schemes, or by modification thereof, using readily available starting materials, reagents and conventional synthetic procedures. If a particular enantiomer of a compound of the present invention is desired, it may be synthesised starting from the desired enantiomer of the starting material and performing reactions not involving racemization processes or it may be prepared by chiral synthesis, or by derivatisation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers.
- diastereomeric salts are formed with an appropriate optically active acid or base, followed by resolution of diastereomeric salts by fractional crystallization and subsequent recovery of the pure enantiomers.
- Compounds of formula (I) to (IX) may prepared by condensing suitably substituted aryl or heteroarylcarboxylic acids and suitably substituted anilines, which are commercially available or synthesized by methods known to the art from commercially available starting materials, using methods known to the art.
- suitably substituted aryl or heteroarylcarboxylic acids are treated with an activating reagent, such as thionyl chloride, at a suitable temperature, such as at reflux, to afford aryl or heteroarylcarbonyl chlorides, and the aryl- or heteroarylcarbonyl chlorides are condensed with suitably substituted anilines in the presence of a suitable base, such as diisopropylethylamine, in a suitable solvent, such as dichloromethane, to give compounds of formula (I).
- an activating reagent such as thionyl chloride
- the compounds of formula (I) may be prepared by reacting a compound of formula (X)
- groups convertible to Rl, R2, R3, R4 and R5 may be present during the coupling, and converted to Rl, R2, R3, R4 and R5 after coupling. Also it may be convenient to convert one Rl, R2, R3, R4 and R5 to another Rl, R2, R3, R4 and R5 group after coupling.
- ring formation between the groups Rl, X,Y, R2 or the addition of suitable cyclic groups embodying Rl, X, Y, R2, may be performed after coupling.
- the compounds of formula (XI) may be prepared in a number of ways, for example when X is O or S coupling an appropriately substituted nitrobenzene compound with a dialkyaminoalcohol or thiol, and converting the NO2 group to NH2 by hydrogenation in the presence of palladium catalyst (or with iron/ammonium chloride) before coupling with an acid chloride, for example as illustrated below:
- Acid chlorides of formula (X) may be prepared from the corresponding acids which are commercially available or described in the literature or may be prepared by methods analogous to those of the literature.
- the acids of fo ⁇ nula (X) may be prepared by combining moieties containing respectively R5 and R4 via Z.
- This may also be achieved conveniently by first coupling a compound of R4-CO-L with the compound of formula (XI) followed by reaction with a compound R5-Z-L (or L-R4- CO-L with R5-Z).
- a compound R5-Z-L or L-R4- CO-L with R5-Z.
- an amine of formula (XI) may be reacted with an appropriately substituted bromobenzoyl chloride which may be then reacted with, for example, an appropriately substituted phenyl moiety with a leaving group, or a cyclic amine, as in the following scheme:
- Novel compounds of formula (I) where the amide nitrogen is alkylated (R3 is methyl or ethyl) may be prepared by alkylating an anilide of formula (XI) before coupling with an acid chloride of formula (X), for example, by utilising the following reductive animation procedure:
- the compounds of formula (I) may be converted into their pharmaceutically acceptable salts by reaction with the appropriate organic or mineral acids.
- Solvates of the compounds of formula (I) may be formed by crystallization or recrystalhzation from the appropriate solvent.
- hydrates may be formed by crystallization or recrystalhzation from aqueous solutions, or solutions in organic solvents containing water.
- salts or solvates of the compounds of formula (I) which are not pharmaceutically acceptable may be useful as intermediates in the production of pharmaceutically acceptable salts or solvates. Accordingly such salts or solvates also form part of this invention.
- the compounds of formula (I) are believed to have a role in preventing, ameliorating or correcting dysfunctions of diseases, including, but not limited to, "the Disorders" previously mentioned.
- the invention also provides a method for the treatment of diabetes, major depression, manic depression, anxiety, schizophrenia and sleep disorders, in human or non-human mammals which method comprises the administration of a therapeutically effective amount of an antagonist to the human 1 ICBy receptor.
- the invention provides a method for the treatment of diabetes in human or non-human mammals which method comprises the administration of a therapeutically effective amount of an antagonist to the human 1 ICBy receptor.
- the invention provides a method for the treatment of major depression, in human or non-human mammals which method comprises the administration of a therapeutically effective amount of an antagonist to the human
- the invention provides a method for the treatment of manic depression, in human or non-human mammals which method comprises the administration of a therapeutically effective amount of an antagonist to the human 1 ICBy receptor.
- the invention provides a method for the treatment of anxiety in human or non-human mammals which method comprises the administration of a therapeutically effective amount of an antagonist to the human HCBy receptor.
- the invention provides a method for the treatment of schizophrenia in human or non-human mammals which method comprises the administration of a therapeutically effective amount of an antagonist to the human 1 ICBy receptor.
- the invention provides a method for the treatment of sleep disorders, in human or non-human mammals which method comprises the administration of a therapeutically effective amount of an antagonist to the human HCBy receptor.
- administration of such compounds to a mammal may be by way of oral (including sub-lingual), parenteral, nasal, rectal or transdermal administration.
- a unit dose will normally contain 1 to 1000 mg, suitably 1 to 500 mg, for example an amount in the range of from 2 to 400 mg such as 2, 5, 10, 20, 30, 40, 50, 100, 200, 300 and 400 mg of the active compound.
- Unit doses will normally be administered once or more than once per day, for example 1, 2, 3, 4, 5 or 6 times a day, more usually 1 to 4 times a day, such that the total daily dose is normally in the range, for a 70 kg adult of 1 to 1000 mg, for example 1 to 500 mg, that is in the range of approximately 0.01 to 15 mg/kg/day, more usually 0.1 to 6 mg/kg/day, for example 1 to 6 mg/kg/day.
- compounds of formula (I) are administered in the form of a unit-dose composition, such as a unit dose oral (including sub-lingual), nasal, rectal, topical or parenteral (especially intravenous) composition.
- compositions are prepared by admixture and are suitably adapted for oral or parenteral administration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable and infusable solutions or suspensions or suppositories.
- Orally administrable compositions are preferred, in particular shaped oral compositions, since they are more convenient for general use.
- Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, diluents, tabletting agents, lubricants, disintegrants, colourants, flavourings, and wetting agents.
- the tablets may be coated according to well known methods in the art.
- Suitable fillers for use include cellulose, mannitol, lactose and other similar agents.
- Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycollate.
- Suitable lubricants include, for example, magnesium stearate.
- Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate.
- solid oral compositions may be prepared by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are, of course, conventional in the art.
- Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
- Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired conventional flavouring or colouring agents.
- suspending agents for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats
- emulsifying agents for example lecithin, sorbitan monooleate
- Oral formulations also include conventional sustained release formulations, such as tablets or granules having an enteric coating.
- fluid unit dose forms are prepared containing the compound and a sterile vehicle.
- the compound depending on the vehicle and the concentration, can be either suspended or dissolved.
- Parenteral solutions are normally prepared by dissolving the compound in a vehicle and filter sterilising before filling into a suitable vial or ampoule and sealing.
- adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle.
- the composition can be frozen after filling into the vial and the water removed under vacuum.
- Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and is sterilised by exposure to ethylene oxide before suspending in the sterile vehicle.
- a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound of the invention.
- compositions will usually be accompanied by written or printed directions for use in the medical treatment concerned.
- Compounds of the present invention may be employed alone or in conjunction with other compounds, such as therapeutic compounds.
- the present invention provides a pharmaceutical composition for use in the treatment and/or prophylaxis of one or more of the Disorders which comprises a compound of this invention, or a pha ⁇ naceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
- the present invention also provides a method of treatment and/or prophylaxis of one or more of the Disorders comprising administering to the sufferer in need thereof an effective or prophylactic amount of a compound of this invention, or a pharmaceutically acceptable salt or solvate thereof.
- the invention provides the use of a compound of this invention, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment and/or prophylaxis of one or more of the Disorders.
- the invention provides the use of a novel compound of this invention, or a pharmaceutically acceptable salt or solvate, thereof as a therapeutic agent, in particular for the treatment and/or prophylaxis of one or more of the Disorders.
- Example A5 Correspondingly Example A7 with 4-(2-pyridy ⁇ )-benzoic acid [J.Chem.Soc; 1940; 355, 356].
- Example A6 Correspondingly Example A7 with 3'-acetyl-biphenyl-4-carboxylic acid [Patent WO- 9743262].
- Example A8 Utilizing the procedure of Example A7 with cyclohexyl-4-benzoic acid [Aldrich], in place of (2'-methyl-biphenyl-4-carboxylic acid).
- Example A9 Correspondingly Example A7 with 4-(2-thienyl)-benzoic acid [J.Chem.Soc.Perkin Trans.1; 17; 1992; 2203].
- Example A10 Correspondingly Example A7 with 4-( 1 -methyl- 1 H-pyrazol-4-yl)-benzoic acid [Paten WO-9906409].
- Example A14 Correspondingly Example A7 with 3 -methanesulfonyl-biphenyl-4-carboxylic acid [Izv.Sib.Otd.Akad.Nauk SSSR Ser.Khim.Nauk; 11; 1966; 62].
- Example A7 with 4-acetyl-4-biphenylcarboxylic acid [Aldrich].
- Example A18
- Example A20 Correspondingly Example A7 with 4-thiophen-3-yl-benzoic acid [J.Chem.Soc.B; 1970; 1595].
- Example A93 Utilizing the procedures of Example A93 with 2-methoxyphenylboronic acid [Aldrich] in place of 4-methylphenylboronic acid, and Example A51 with 2-(diisopropylamino)- ethanol in place of l-(2-hydroxyethyl)-pyrrolidine .
- Example A23 with 2-naphthylboronic acid [Lancaster].
- Example A31 Co ⁇ espondingly Example A23 with 4-carbonylphenylboronic acid [Aldrich].
- Example A37 Utilizing the procedure of Example A35 with 4-cyclohexylbenzoic acid [Aldrich]. in place of 4-biphenylcarboxylic acid.
- Example A47 Correspondingly Example A51 with (S)-(-)-l-methyl-2-py ⁇ olidinemethanol [Aldrich].
- Biphenyl-4-carboxylic acid [3-methoxy-4-(2-pyrroIidin-l-yl-ethoxy)-phenyI amide.
- Example A54 Utilising the procedure of Example A51 with l-dimethylamino-2-propanol [Aldrich] in place of l-(2-hydroxyethyl)-pyrrolidine.
- Example A56 Correspondingly Example A51 with l-(2-hydroxyethyl)-piperidine [Aldrich].
- Example A70 Correspondingly Example A63 with (3,4-methylenedioxyphenyl)boronic acid [Aldrich].
- Example A84 Utilizing the procedures of Example A93 with 4-methoxy-phenylboronic acid [Aldrich] in place of 2-methoxyphenylboronic acid and Example A51 with 2-diethylaminoethanol in place of l-(2-hydroxyethyl)pyrrolidine.
- Example A88 Utilising the procedures of Example A84 with 4-methoxy-3-pyridylboronic acid [Patent WO-9924440] in place of 4-methoxy-phenylboronic acid.
- the amide, 4-bromo-N-[3-methoxy-4(2-pyrrolidin-l-yl-ethoxy)-phenyl]-benzamide (O.lmM 42mg), and 4-methyl-benzene boronic acid [Aldrich] (O.lmM 14mg) were refluxed for 16 hours in a mixture of benzene (8ml), ethanol (2ml) and 2M aqueous sodium carbonate (2ml) in the presence of tetrakis-(triphenylphosphine)-palladium[0] (5mg) under an argon atmosphere.
- Example A103 Utilizing the procedure of Example A93 with 4-(2,6-dimethoxypyrimidinyl)-boronic acid [Frontier] in place of 4-methyl-benzene boronic acid.
- Example A103 Utilizing the procedure of Example A93 with 4-(2,6-dimethoxypyrimidinyl)-boronic acid [Frontier] in place of 4-methyl-benzene boronic acid.
- Example C3 Co ⁇ espondingly Example Cl using 3-methylbiphenyl-4-carboxylic acid [Patent WO- 9534540].
- Example Cl using 5-methyl-l-phenylpyrazole-4-carboxylic acid [Maybridge].
- Example C7
- Example C9 Correspondingly Example Cl using 5-(4-chlorophenyl)-2-trifluoromethyl-furan-3- carboxylic acid [Maybridge].
- the reaction mixture was gently refluxed until t.l.c. analysis showed no starting material.
- the mixture was filtered while hot and the inorganic residues washed with methanol.
- the combined filtrates were partitioned between water (5ml) and ethyl acetate(3 x 10ml), the organic phase dried (MgSO4), filtered, and evaporated.
- the aqueous phase was treated with satd. aq. sodium bicarbonate (lOml), extracted with ethyl acetate (3 x 10ml), dried (MgSO_ ⁇ ), and evaporated. Residues from both extractions were combined and purified by flash chromatography on silica gel using dichloromethane - methanol - aq.
- Example D20 Utilizing the procedure of Example A51 with 3-methyl-4-fluoronitrobenzene [Aldrich] in place of 4-chloro-3-methoxynitrobenzene
- Biphenyl-4-carboxylic acid [4-(2-diisopropylamino-ethoxy)-2-formyl-5-methoxy- phenyl]-amide
- Biphenyl-4-carboxylic acid [4-(2-diisopropylamino-ethoxy)-3-methoxy-phenyl]-amide
- Patent WO-9901127 (223 mg, 0.5 mmol) was treated with glyoxylic acid trihydrate (lml), dichloromethane (5 ml) and methanesulphonic acid (0.5 ml). The mixture was sti ⁇ ed vigorously for 24 hours then treated with satd. aq. sodium bicarbonate (30ml) and extracted with dichloromethane (3 x 20ml). The combined organic phases were dried (MgSO4), filtered and evaporated, then subjected to flash chromatography on silica gel
- Biphenyl-4-carboxylic acid [4-(2-diethylamino-ethoxy)-3-(l-hydroxy-ethyl)-phenyl]- a ide
- To biphenyl-4-carboxylic acid [3-acetyl-4-(2-diethylamino-ethoxy)-phenyl]-amide [Example D24] (20mg, 0.05mmol) dissolved in a 1 :1 mixture of tetrahydrofuran / ethanol (3ml), was added sodium borohydride [Aldrich] (6mg, 0.15mmol). The reaction mixture was sti ⁇ ed at ambient temperature for 16 hours.
- Example D28 [WO9901127] Utilizing the procedure of Example A51 with 4-fluoronitrobenzene [Aldrich] in place of 4-chloro-3-methoxynitrobenzene, and 2-diisopropylaminoethanol in place of l-(2- hydroxyethyl)-pyrrolidine
- Example D30 [WO9901127] Utilizing the procedure of Example D28 with 2-dimethylaminoethanol [Aldrich] in place of 2-diisopropylaminoethanol.
- Example D38 [WO9901127] Utilizing the procedure of Example A22 with 4-fluoronitrobenzene [Aldrich] in place of 4-chloro-3-methoxynitrobenzene, and 4-ethylphenylboronic acid in place of 4- methoxyphenylboronic acid
- Biphenyl-4-carboxylic acid [4-(2-diisopropylamino-ethoxy)-3-methoxy-phenyl] - methyl-amide.
- Example A7 To 4-(2-diisopropylamino-ethoxy)-3-methoxy-phenylamine (lmmol) [Example A7] were added triethylorthoformate (8ml) and trifluoroacetic acid (0.15ml). The resulting solution was heated to 90°C for 4hr. The solution was evaporated then redissolved in ethanol and cooled to approximately -10°C. Sodium borohydride (190mg, 5mmol) was introduced portionwise over 10 minutes then the mixture allowed to warm to room temperature. The solution was sti ⁇ ed at room temperature for 16h, then acidified to pH 1 with 2M hydrochloric acid.
- Biphenyl-4-carboxylic acid [4-(2-diethylamino-ethoxy)-3-methoxy-phenyl]-methyl- amide [Example E9] (45mg, 0.1 mmol), was dissolved in chloroform (1ml) and treated with benzotriazole [Aldrich] (12 mg, 0.1 mmol) and N-chlorosuccinimide (13 mg, 0.1 lmmol). The mixture was sti ⁇ ed at ambient temperature for 16 hours then evaporated and subjected to flash chromatography on silica gel (dichloromethane - methanol - aqueous ammonia) to afford the title compound as an oil.
- Example E9 Utilizing the procedures of Example A93 with [4-(2-diethylamino-ethoxy)-3 -methoxy- phenyl]-methyl-amine [Example E9] in place of 4-(2-diethylamino-ethoxy)-3-methoxy- phenylamine and 2-fluoromethylphenylboronic acid [Aldrich] in place of 4- methoxyphenylboronic acid and of Example 51 with (N-diethyl)ethanolamine in place of 1 -(2-hydroxyethyl)py ⁇ olidine.
- Example E14 Utilizing the procedures of Example A93 with [4-(2-diethylamino-ethoxy)-3 -methoxy- phenyl]-methyl-amine [Example E9] in place of 4-(2-diethylamino-ethoxy)-3-methoxy- phenylamine and 2-fluoromethylphenylboronic acid [Aldrich] in place of 4- methoxypheny
- Example E22 Correspondingly Example E14 with 4-ethylphenylboronic acid [Aldrich] .
- Example E25 Utihsing the procedure of Example El with 4-(2-diisopro ⁇ ylamino-ethoxy)-3-methyl- phenylamine [Example D20] in place of 4-(2-diisopropylamino-ethoxy)-3-methoxy- phenylamine and triethyl orthoacetate in place of triethyl orthoformate.
- Example FI
- Example A7 Utilizing the procedure of Example A7 with 6-phenyl-nicotinic acid (Patent WO- 0006085) in place of 2'-methyl-4-biphenylcarboxylic acid and N-dimethylethanolamine in place of 2-(diisopropylamino)ethanol.
- Biphenyl-4-carboxylic acid [4-((R)-diethylamino-hydroxy-propoxy)-3-methoxy- phenyl]-amide 4- ⁇ itro-2-methoxyphenol [Aldrich] (845mg, 5mmol) was dissolved in DMF (25 ml) and treated with sodium hydride (60% oil dispersion, 200mg). When the effervescence ceased, the mixture was treated with (i?)-p-nitrophenylsulphonyl glycidol [Aldrich] and warmed to 50°C with sti ⁇ ing.
- Example G5 Utilizing the procedure for the preparation of (/?)-diethylamino-(2-methoxy-4-nitro- phenoxy)-propan-2-ol [Example Gl] but replacing dichloromethane with 1,2- dichloroethane and diethylamine with diisopropylamine. In addition, the mixture of amine and epoxide was heated at 80°C for 12h rather than being kept at ambient temperature for 24 hours.
- Example HI 4-Cyclohexyl-iV-[3-methoxy-4-(4-methyl-piperazin-l-yl)-phenyl]-benzamide
- the activity of the compounds used in this invention may be assessed by competitive binding assays to 1 ICBy receptors, as follows:
- Radioligand binding assays were carried out on well washed membranes from HEK293 cells stably expressing HCBy receptors. Membranes (5-15 mg protein) were incubated with [1251] -Melanin Concentrating Hormone (0.22 nM)(obtained from NEN) in the presence and absence of competing test compounds for 45 min at 37°C in a buffer (pH7.4), containing 50mM Tris and 0.2% BSA. Non-specific binding was defined using 0.1 mM Melanin Concentrating Hormone (obtained from Bachem). The test compounds were added at concentrations between 10M and lOpM in 10 concentration steps.
- Bound cpm in the presence of test compound was expressed as a fraction of the bound cpm in the absence of test compound and plotted against the concentration of compound. From this an IC50 was determined from which the pKi was calculated.
- the most potent compounds of the present invention have pKi values in the range of 7.1 to 7.8 For example:
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Cardiology (AREA)
- Diabetes (AREA)
- Epidemiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Psychiatry (AREA)
- Physical Education & Sports Medicine (AREA)
- Hematology (AREA)
- Endocrinology (AREA)
- Pulmonology (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Communicable Diseases (AREA)
- Hospice & Palliative Care (AREA)
- Virology (AREA)
- Oncology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Psychology (AREA)
- Obesity (AREA)
- Reproductive Health (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Anesthesiology (AREA)
Abstract
Description
Claims
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB0018758 | 2000-07-31 | ||
GBGB0018758.3A GB0018758D0 (en) | 2000-07-31 | 2000-07-31 | Novel use and compunds |
GB0112544A GB0112544D0 (en) | 2001-05-23 | 2001-05-23 | Novel use and compounds |
GB0112544 | 2001-05-23 | ||
PCT/EP2001/008637 WO2002010146A1 (en) | 2000-07-31 | 2001-07-26 | Carboxamide compounds and their use as antagonists of a human 11cby receptor |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1305304A1 true EP1305304A1 (en) | 2003-05-02 |
Family
ID=26244767
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP01956562A Withdrawn EP1305304A1 (en) | 2000-07-31 | 2001-07-26 | Carboxamide compounds and their use as antagonists of a human 11cby receptor |
Country Status (20)
Country | Link |
---|---|
EP (1) | EP1305304A1 (en) |
JP (1) | JP2004505070A (en) |
KR (1) | KR20030059084A (en) |
CN (1) | CN1444573A (en) |
AP (1) | AP2003002720A0 (en) |
AU (1) | AU2001278508A1 (en) |
BG (1) | BG107510A (en) |
BR (1) | BR0112856A (en) |
CA (1) | CA2417638A1 (en) |
CZ (1) | CZ2003297A3 (en) |
EA (1) | EA200300064A1 (en) |
HU (1) | HUP0302966A2 (en) |
IL (1) | IL153645A0 (en) |
MA (1) | MA25829A1 (en) |
MX (1) | MXPA03000923A (en) |
NO (1) | NO20030471L (en) |
OA (1) | OA12346A (en) |
PL (1) | PL365183A1 (en) |
SK (1) | SK1142003A3 (en) |
WO (1) | WO2002010146A1 (en) |
Families Citing this family (32)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003097047A1 (en) * | 2002-05-13 | 2003-11-27 | Eli Lilly And Company | Multicyclic compounds for use as melanin concentrating hormone antagonists in the treatment of obesity and diabetes |
DE10233817A1 (en) * | 2002-07-25 | 2004-02-12 | Aventis Pharma Deutschland Gmbh | Substituted diaryl heterocycles, process for their preparation and their use as medicaments |
US7141561B2 (en) | 2002-07-25 | 2006-11-28 | Sanofi-Aventis Deutschland Gmbh | Substituted diaryl heterocycles, process for their preparation and their use as medicaments |
DE10306250A1 (en) * | 2003-02-14 | 2004-09-09 | Aventis Pharma Deutschland Gmbh | Substituted N-aryl heterocycles, processes for their preparation and their use as pharmaceuticals |
US7223788B2 (en) | 2003-02-14 | 2007-05-29 | Sanofi-Aventis Deutschland Gmbh | Substituted N-aryl heterocycles, process for their preparation and their use as medicaments |
EP1620108B1 (en) * | 2003-05-01 | 2012-06-06 | Bristol-Myers Squibb Company | Pyrazole-amine compounds useful as kinase inhibitors |
PL2256106T3 (en) | 2003-07-22 | 2015-08-31 | Astex Therapeutics Ltd | 3,4-disubstituted 1H-pyrazole compounds and their use as cyclin dependent kinases (CDK) and glycogen synthase kinase-3 (GSK-3) modulators |
US7037927B2 (en) | 2003-10-16 | 2006-05-02 | Abbott Laboratories | Amides that inhibit vanilloid receptor subtype 1 (VR1) receptor |
US7241787B2 (en) | 2004-01-25 | 2007-07-10 | Sanofi-Aventis Deutschland Gmbh | Substituted N-cycloexylimidazolinones, process for their preparation and their use as medicaments |
US7319108B2 (en) | 2004-01-25 | 2008-01-15 | Sanofi-Aventis Deutschland Gmbh | Aryl-substituted heterocycles, process for their preparation and their use as medicaments |
CN1950332A (en) * | 2004-03-02 | 2007-04-18 | 神经能质公司 | Heteroalkyl-substituted biphenyl-4-carboxylic acid arylamide analogues |
US7605176B2 (en) | 2004-03-06 | 2009-10-20 | Boehringer Ingelheim International Gmbh | β-ketoamide compounds with MCH antagonistic activity |
DE102004010893A1 (en) * | 2004-03-06 | 2005-09-22 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | New β-ketoamide compounds having MCH antagonist activity and medicaments containing these compounds |
TW200613272A (en) | 2004-08-13 | 2006-05-01 | Astrazeneca Ab | Isoindolone compounds and their use as metabotropic glutamate receptor potentiators |
DE102004039789A1 (en) | 2004-08-16 | 2006-03-02 | Sanofi-Aventis Deutschland Gmbh | Aryl-substituted polycyclic amines, process for their preparation and their use as pharmaceuticals |
AR054425A1 (en) | 2005-01-21 | 2007-06-27 | Astex Therapeutics Ltd | PIPERIDIN ADDITION SALTS 4-IL-ACID AMID 4- (2,6-DICLORO-BENZOILAMINO) 1H-PIRAZOL-3-CARBOXILICO. |
US8404718B2 (en) | 2005-01-21 | 2013-03-26 | Astex Therapeutics Limited | Combinations of pyrazole kinase inhibitors |
US7807706B2 (en) | 2005-08-12 | 2010-10-05 | Astrazeneca Ab | Metabotropic glutamate-receptor-potentiating isoindolones |
AR056155A1 (en) | 2005-10-26 | 2007-09-19 | Bristol Myers Squibb Co | ANTAGONISTS OF NON-BASIC MELANINE CONCENTRATION HORMONE RECEIVER 1 |
US7553836B2 (en) | 2006-02-06 | 2009-06-30 | Bristol-Myers Squibb Company | Melanin concentrating hormone receptor-1 antagonists |
CA2636617A1 (en) | 2006-02-15 | 2007-08-23 | Lothar Schwink | Novel aminoalcohol-substituted aryldihydroisoquinolinones, process for their preparation and their use as medicaments |
GB0625523D0 (en) * | 2006-12-21 | 2007-01-31 | Ge Healthcare Ltd | In vivo imaging agents |
TWI417100B (en) | 2007-06-07 | 2013-12-01 | Astrazeneca Ab | Oxadiazole derivatives and their use as metabotropic glutamate receptor potentiators-842 |
EP2025674A1 (en) | 2007-08-15 | 2009-02-18 | sanofi-aventis | Substituted tetra hydro naphthalines, method for their manufacture and their use as drugs |
PE20091928A1 (en) | 2008-05-29 | 2009-12-31 | Bristol Myers Squibb Co | HAVE HYDROXYSUSTITUTED PYRIMIDINES AS NON-BASIC MELANIN-CONCENTRATING HORMONE RECEPTOR-1 ANTAGONISTS |
SA109300358B1 (en) | 2008-06-06 | 2012-11-03 | استرازينيكا ايه بي | Isoindolone Metabotropic Glutamate receptor Potentiators |
AR072297A1 (en) | 2008-06-27 | 2010-08-18 | Novartis Ag | DERIVATIVES OF INDOL-2-IL-PIRIDIN-3-ILO, PHARMACEUTICAL COMPOSITION THAT INCLUDES THEM AND ITS USE IN MEDICINES FOR THE TREATMENT OF DISEASES MEDIATED BY THE SYNTHESIS ALDOSTERONE. |
JP2012505892A (en) | 2008-10-15 | 2012-03-08 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Condensed heteroaryl diamide compounds useful as MMP-13 inhibitors |
WO2010045188A1 (en) | 2008-10-17 | 2010-04-22 | Boehringer Ingelheim International Gmbh | Heteroaryl substituted indole compounds useful as mmp-13 inhibitors |
UY32442A (en) | 2009-02-13 | 2010-09-30 | Sanofi Aventis | NEW SUBSTITUTED INDANS, PROCESSES FOR THEIR PREPARATION AND USE OF THE SAME AS A MEDICINAL PRODUCT |
TW201040153A (en) | 2009-02-13 | 2010-11-16 | Sanofi Aventis | Novel substituted tetrahydronaphthalenes, process for preparation thereof and use thereof as medicaments |
WO2013130968A1 (en) * | 2012-03-01 | 2013-09-06 | University Of Cincinnati | Ros-activated compounds as selective anti-cancer therapeutics |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ZA985542B (en) * | 1997-07-03 | 1999-04-07 | Smithkline Beecham Corp | Substituted benzanilides as CCR5 receptor ligands antiinflammatory agents and antiviral agents |
TR200100267T2 (en) * | 1998-07-28 | 2001-09-21 | Smithkline Beecham Corporation | Substituted anilide compositions and methods. |
AU2460600A (en) * | 1999-02-10 | 2000-08-29 | Mitsubishi Pharma Corporation | Amide compounds and medicinal use thereof |
-
2001
- 2001-07-26 KR KR10-2003-7001409A patent/KR20030059084A/en not_active Application Discontinuation
- 2001-07-26 CZ CZ2003297A patent/CZ2003297A3/en unknown
- 2001-07-26 MX MXPA03000923A patent/MXPA03000923A/en not_active Application Discontinuation
- 2001-07-26 CA CA002417638A patent/CA2417638A1/en not_active Abandoned
- 2001-07-26 AU AU2001278508A patent/AU2001278508A1/en not_active Abandoned
- 2001-07-26 IL IL15364501A patent/IL153645A0/en unknown
- 2001-07-26 CN CN01813601A patent/CN1444573A/en active Pending
- 2001-07-26 EP EP01956562A patent/EP1305304A1/en not_active Withdrawn
- 2001-07-26 AP APAP/P/2003/002720A patent/AP2003002720A0/en unknown
- 2001-07-26 BR BR0112856-6A patent/BR0112856A/en not_active IP Right Cessation
- 2001-07-26 PL PL01365183A patent/PL365183A1/en unknown
- 2001-07-26 SK SK114-2003A patent/SK1142003A3/en not_active Application Discontinuation
- 2001-07-26 OA OA1200300018A patent/OA12346A/en unknown
- 2001-07-26 WO PCT/EP2001/008637 patent/WO2002010146A1/en not_active Application Discontinuation
- 2001-07-26 JP JP2002515877A patent/JP2004505070A/en active Pending
- 2001-07-26 HU HU0302966A patent/HUP0302966A2/en unknown
- 2001-07-26 EA EA200300064A patent/EA200300064A1/en unknown
-
2003
- 2003-01-24 MA MA27012A patent/MA25829A1/en unknown
- 2003-01-30 BG BG107510A patent/BG107510A/en unknown
- 2003-01-30 NO NO20030471A patent/NO20030471L/en not_active Application Discontinuation
Non-Patent Citations (1)
Title |
---|
See references of WO0210146A1 * |
Also Published As
Publication number | Publication date |
---|---|
BG107510A (en) | 2003-09-30 |
SK1142003A3 (en) | 2003-06-03 |
EA200300064A1 (en) | 2003-06-26 |
WO2002010146A1 (en) | 2002-02-07 |
OA12346A (en) | 2004-04-13 |
MA25829A1 (en) | 2003-07-01 |
IL153645A0 (en) | 2003-07-06 |
AP2003002720A0 (en) | 2003-06-30 |
KR20030059084A (en) | 2003-07-07 |
HUP0302966A2 (en) | 2003-12-29 |
BR0112856A (en) | 2003-07-01 |
CZ2003297A3 (en) | 2003-05-14 |
CN1444573A (en) | 2003-09-24 |
AU2001278508A1 (en) | 2002-02-13 |
NO20030471D0 (en) | 2003-01-30 |
PL365183A1 (en) | 2004-12-27 |
CA2417638A1 (en) | 2002-02-07 |
JP2004505070A (en) | 2004-02-19 |
NO20030471L (en) | 2003-03-28 |
MXPA03000923A (en) | 2003-06-09 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2002010146A1 (en) | Carboxamide compounds and their use as antagonists of a human 11cby receptor | |
KR100752033B1 (en) | Novel Compounds | |
US8183239B2 (en) | Substituted piperazines and piperidines as modulators of the neuropeptide Y2 receptor | |
AU1656600A (en) | Benzamide derivatives and their use as apob-100 secretion inhibitors | |
WO2003087044A2 (en) | Novel carboxamide compounds for use in mch receptor related disorders | |
JP6183451B2 (en) | 2-acylaminothiazole derivatives or salts thereof | |
JP2010520876A (en) | Piperazine and piperidine mGluR5 potentiator | |
TW200530201A (en) | Alkylpiperazine-and alkylhomopiperazine-carboxylate derivatives, their preparation and their application in therapy | |
KR20030068547A (en) | Novel amidoalkyl-piperidine and amidoalkyl-piperazine derivatives useful for the treatment of nervous system disorders | |
BRPI0613987A2 (en) | benzylpiperazine derivatives and their medical use | |
CA2787037C (en) | Arylpiperazine opioid receptor antagonists | |
JP2011500782A (en) | Novel non-peptide derivatives as bradykinin B1 antagonists | |
US20040063686A1 (en) | Carboxamide compounds and their use as antagonists of a human 11cby receptor | |
KR20050119192A (en) | Substituted pyrazole compounds | |
WO2004006922A1 (en) | Aryl piperidine derivatives as inducers of ldl-receptor expression for the treatment of hypercholesterolemia | |
JP4918031B2 (en) | Benzyloxypropylamine derivative | |
KR101473453B1 (en) | New compounds, the preparation thereof and pharmaceutical composition comprising the same | |
JP2003507463A (en) | Substituted piperazine derivatives, their preparation and their use as drugs | |
US20040044037A1 (en) | Amidino-urea serotonin receptor ligands and compositions, their pharmaceutical uses, and methods for their snythesis | |
EP2396334A1 (en) | N-[(2-azabicyclo[2.1.1]hex-1-yl]-aryl-methyl]-benzamide derivatives, preparation thereof, and therapeutic use thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
17P | Request for examination filed |
Effective date: 20030217 |
|
AK | Designated contracting states |
Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR |
|
AX | Request for extension of the european patent |
Extension state: AL LT LV MK RO SI |
|
17Q | First examination report despatched |
Effective date: 20041007 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
|
18D | Application deemed to be withdrawn |
Effective date: 20060210 |
|
REG | Reference to a national code |
Ref country code: HK Ref legal event code: WD Ref document number: 1057541 Country of ref document: HK |