WO2000058303A1 - 4-substituted quinoline derivatives as nk-3 and/or gaba(a) receptor ligands - Google Patents
4-substituted quinoline derivatives as nk-3 and/or gaba(a) receptor ligands Download PDFInfo
- Publication number
- WO2000058303A1 WO2000058303A1 PCT/US2000/008205 US0008205W WO0058303A1 WO 2000058303 A1 WO2000058303 A1 WO 2000058303A1 US 0008205 W US0008205 W US 0008205W WO 0058303 A1 WO0058303 A1 WO 0058303A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- phenylquinolin
- receptor
- phenyl
- imidazoline
- Prior art date
Links
- 0 *c1c(C2=NCC(*=C)(c3ccccc3)N2*)c(cccc2)c2nc1-c1ccccc1 Chemical compound *c1c(C2=NCC(*=C)(c3ccccc3)N2*)c(cccc2)c2nc1-c1ccccc1 0.000 description 4
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/94—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving narcotics or drugs or pharmaceuticals, neurotransmitters or associated receptors
- G01N33/9406—Neurotransmitters
- G01N33/9426—GABA, i.e. gamma-amino-butyrate
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
- G01N2333/70571—Assays involving receptors, cell surface antigens or cell surface determinants for neuromediators, e.g. serotonin receptor, dopamine receptor
Definitions
- This invention relates to quinoline derivatives, pharmaceutical compositions comprising them, and the use of such compounds in the treatment of certain central nervous system and peripheral diseases or disorders.
- This invention also relates to the use of such compounds in combination with one or more other CNS agents to potentiate the effects of the other CNS agents.
- the compounds of this invention are also useful as probes for the localization of cell surface receptors.
- the tachykinins represent a family of structurally related peptides originally isolated based upon their smooth muscle contractile and sialogogic activity. These mammalian peptides include substance P (SP) , neurokinin A (NKA) and neurokinin ⁇ (NKB) . Tachykinins are synthesized in the central nervous system
- Substance P can be produced from three different mRNAs ( ⁇ - , ⁇ - and ⁇ -preprotachykinin mRNAs) that arise from a single gene as a result of alternative RNA splicing, whereas NKA can be generated from either the ⁇ - or the ⁇ -preprotachykinin mRNA through posttranslationally processed precursor polypeptides. These precursors can also be differentially processed so that amino terminally extended forms of NKA (known as neuropeptide K and neuropeptide ⁇ ) are produced.
- NKB is produced from a separate mRNA arising from a second gene known as preprotachykinin B.
- neurokinin- 1 Three receptors for the tachykinin peptides have been moleculary characterized and are referred to as neurokinin- 1
- NK-1 receptor has a natural agonist potency profile of SP>NKA>NKB.
- the NK-2 receptor agonist potency profile is NKA>NKB>SP, and the NK-3 receptor agonist potency profile is NKB>NKA>SP.
- These receptors mediate the variety of tachykinin- stimulated biological effects that generally include 1) modulation of smooth muscle contractile activity, 2) transmission of (generally) excitatory neuronal signals in the CNS and periphery (e.g.
- NK-1 receptors are expressed in a wide variety of peripheral tissues and in the CNS. NK-2 receptors are expressed primarily in the periphery, while NK-3 receptors are primarily (but not exclusively) expressed in the CNS. Recent work confirms the presence of NK-3 receptor binding sites in the human brain.
- NK-3 receptors are located on MCH- containing neurons in the rat lateral hypothalamus and zona incerta.
- administration of NKB into the airways is known to induce mucus secretion and bronchoconstriction, indicating therapeutic utility for NK-3 receptor antagonists in the treatment of patients suffering from airway diseases such as asthma and chronic obstructive pulmonary disease (COPD) .
- COPD chronic obstructive pulmonary disease
- NK-3 receptor antagonists Localization of NK-3 receptors in the gastrointestinal (GI) tract and the bladder indicates therapeutic utility for NK-3 receptor antagonists in the treatment of GI and bladder disorders including inflammatory bowel disease and urinary incontinence.
- Both peptide and nonpeptide antagonists have been developed for each of the tachykinin receptors.
- the first generation of peptide antagonists for the tachykinin receptors had problems with low potency, partial agonism, poor metabolic stability and toxicity, whereas the current generation of non-peptide antagonists display more drug-like properties.
- previous non-peptide NK-3 receptor antagonists suffer from a number of problems such as species selectivity (which limits the potential to evaluate these compounds in many appropriate disease models) .
- New non-peptide NK-3 receptor antagonists are therefore being sought, both as therapeutic agents and as tools to further investigate the anatomical and ultrastructural distribution of NK-3 receptors, as well as the physiologic and pathophysiologic consequences of NK-3 receptor activation.
- the GABA A receptor superfamily represents one of the classes of receptors through which the major inhibitory neurotransmitter, ⁇ -aminobutyric acid, or GABA, acts. Widely, although unequally, distributed through the mammalian brain, GABA mediates many of its actions through a complex of proteins called the GABA A receptor, which causes alteration in chloride conductance and membrane polarization.
- GABA A receptor subunits A number of cDNAs for GABA A receptor subunits have been characterized. To date at least 6 ⁇ , 3 ⁇ , 3 ⁇ , l ⁇ , l ⁇ and 2p subunits have been identified. It is generally accepted that native GABA A receptors are typically composed of 2 ⁇ , 2 ⁇ , and l ⁇ subunits (Pritchett & Seeburg Science 1989; 245:1389-1392 and Knight et . al . , i?ecept. Channels 1998; 6:1-18) .
- Benzodiazepines exert their pharmacological actions by interacting with the benzodiazepine binding sites associated with the GABA A receptor.
- the GABA A receptor contains sites of interaction for several other classes of drugs. These include a steroid binding site, a picrotoxin site, and the barbiturate site.
- the benzodiazepine site of the GABA A receptor is a distinct site on the receptor complex that does not overlap with the site of interaction for
- GABA GABA or for other classes of drugs that bind to the receptor
- GABAergic inhibition Compounds that selectively bind to the benzodiazepine site and enhance the ability of GABA to open GABA A receptor channels are agonists of GABA receptors. Other compounds that interact with the same site but negatively modulate the action of GABA are called inverse agonists. Compounds belonging to a third class bind selectively to the benzodiazepine site and yet have little or no effect on GABA activity, but can block the action of GABA A receptor agonists or inverse agonists that act at this site. These compounds are referred to as antagonists.
- GABA A selective ligands may also act to potentiate the effects of certain other CNS active compounds.
- selective serotonin reuptake inhibitors SSRIs
- SSRIs selective serotonin reuptake inhibitors
- Preferred compounds of the invention bind to neurokinin and/or GABA receptors, in particular these compounds possess affinity for NK-3 receptors and/or GABA A receptors. These compounds are therefore considered to be of potential use in the treatment of a broad array of diseases or disorders in patients which are characterized by modulation of NK-3 and/or GABA A receptors.
- This invention provides compounds of general Formula I : Y—Y 2
- R 1# R 2 , R 3 , R 4 , X, Y and Y 2 are hereinafter defined.
- Preferred compounds of this invention are ligands for neurokinin receptors and GABA receptors, especially NK-3 receptors and GABA A receptors, and are useful in the treatment of a wide range of diseases or disorders including, but not limited to depression, anxiety, sleep disorders, cognitive disorders, low alertness, psychosis, obesity, pain, Parkinson's disease, Alzheimer's disease, neurodegenerative diseases, movement disorders, Down's syndrome, benzodiazepine overdoses, respiratory diseases, inflammatory diseases, neuropathy, immune disorders, migraine, biliary disfunction, and dermatitis.
- diseases or disorders including, but not limited to depression, anxiety, sleep disorders, cognitive disorders, low alertness, psychosis, obesity, pain, Parkinson's disease, Alzheimer's disease, neurodegenerative diseases, movement disorders, Down's syndrome, benzodiazepine overdoses, respiratory diseases, inflammatory diseases, neuropathy, immune disorders, migraine, biliary disfunction, and dermatitis.
- the invention also provides pharmaceutical compositions comprising compounds of Formula I.
- the invention further comprises a method of treating a patient suffering from certain central nervous system and peripheral diseases or disorders with effective concentration of a compound of the invention. Treatment of humans, domesticated companion animals (pets) or livestock animals suffering such conditions with an effective amount of a compound of the invention is contemplated by the invention.
- the invention provides a method of potentiating the actions of other CNS active compounds. This method comprises administering an effective amount of a compound of the invention with another CNS active compound.
- the invention furthermore provides methods of using compounds of this invention as positive controls in assays for receptor activity and using appropriately labeled compounds of the invention as probes for the localization of receptors, particularly NK-3 and/or GABA A receptors, in tissue sections.
- This invention relates to quinoline derivatives, pharmaceutical compositions comprising them, and the use of such compounds in the treatment of certain central nervous system and peripheral diseases or disorders.
- R x is selected from: hydrogen, halogen, hydroxy, C _ 6 alkyl, -0(C ⁇ 6 alkyl), -N0 2/
- alkyl may be straight, branched or cyclic, may contain one or two double or triple bonds, unsubstituted or substituted with one or more substituents selected from: hydroxy, oxo, fluoro, amino, C ⁇ alkoxy;
- R 2 and R 3 are independently selected from the groups consisting of:
- C ⁇ . ⁇ alkyl wherein said C x _ 8 alkyl is be straight, branched or cyclic, may contain one or two double or triple bonds, and is unsubstituted or substituted with one or more of the substituents selected from: ( i ) hydroxy, (ii) oxo,
- Ar x is independently selected at each occurrence from phenyl , naphthyl , thienyl , benzothienyl, pyridyl , quinolyl , pyrazinyl, pyrimidyl, imidazolyl, benzoimidazolyl , furanyl , benzofuranyl , thiazolyl, benzothiazolyl , isothiazolyl , benzisothiazolyl , triazolyl, tetrazolyl, pyrazolyl, and benzopyrazolyl , each of which is unsubstituted or substituted with one or more substituents selected from: hydrogen, halogen, hydroxy, alkyl, -0(C 1 _ 6 alkyl) , - N0 2 , -CN, -S0 2 NH 2 , -S0 2 NH(C 1 6 alkyl) , -S0
- alkyl (C ⁇ alkyl), -NCC ⁇ alkyl) CO (C ⁇ alkyl), -N(C 1 _ 6 alkyl)C0 2 (C ⁇ 6 alkyl), -NHS0 2 (C 1 _ 6 alkyl), -N(C 1 _ 6 alkyl) S0 2 (C 1 _ 6 alkyl), -S0 2 NHCO (C x _ g alkyl), -CONHS0 2 (C 1 e alkyl), -CON(C 1 _ 6 alkyl) (C ⁇ alkyl), -C0 2 (C ⁇ 6 alkyl), - S(C-_ 6 alkyl), -SO(C 1 . s alkyl), or -S0 2 (C ⁇ 6 alkyl), wherein alkyl, is defined as above,
- Ar 2 is independently selected at each occurrence from phenyl, naphthyl , thienyl, benzothienyl , pyridyl, quinolyl , pyrazinyl, pyrimidyl , imidazolyl, benzoimidazolyl , furanyl , benzofuranyl , thiazolyl, benzothiazolyl , isothiazolyl , benzisothiazolyl , triazolyl, tetrazolyl, pyrazolyl, or benzopyrazolyl , and unsubstituted or substituted with one or more substituents selected from: hydrogen, halogen, hydroxy, C 1 _ 8 alkyl, -0(C 1 8 alkyl), - N0 2 , -CN, -S0 2 NH 2 , -S0 2 NH(C 1 _ 8 alkyl), -S0 2 N(C 1.B
- R 4 is selected from:
- X is NH, 0 or N-R 10 , wherein R 10 is C 1 8 alkyl, wherein said C 1 _ B alkyl is defined as above;
- Y ⁇ is -CR ⁇ R ⁇ -, -CR 11 R 12 (CH 2 ) p - , - (CH 2 ) .CR j ⁇ - , or -(CH 2 ) p C0-; where p is 0, 1, or 2; and R 1X and R 12 are independently selected at each occurrence from:
- R 8 and R 9 are as defined above, (5) -C0 2 R 8 , wherein said R 8 is as defined above; and the groups R l and R 12 may be joined together to form a monocyclic, bicyclic, or tricyclic ring;
- Y 2 is -CR 11 R 12 - or -CO- with the proviso that Y 2 is not -CO- when Y 1 is -(CH 2 )pCO- , wherein p, R 1X and R 12 are as defined above ;
- the groups R 10 and R X1 may be joined to form a 5- to 8 -membered ring which may contain one or more double bonds; one or more oxo; one or more 0, S(0)n, N-R 7 wherein n and R 7 are as defined above; one or more groups consisting of hydroxy, halogen, amino, alkyl, -0(C 1 _ 8 alkyl), -N0 2 , -CN, S0 2 NH 2 , -S0 2 NH(C ⁇ 8 alkyl), -S0 2 N(C._ 8 alkyl) ( C ⁇ 8 alkyl), amino, -NH(C 1 _ 8 alkyl), -N(C X _ 8 alkyl) ( C x _ 8 alkyl), -N(C 1 _ 8 alkyl) CO (C ⁇ alkyl), -N(C 1 .
- Preferred compounds include compounds of Formula I, and the pharmaceutically acceptable salts and solvates thereof, wherein X is NH or N-R 10 , where R 10 is as defined as for Formula I.
- R 1; R 2 , R 3 , R 4 , R 10 , R 11# and R 12 are as defined as for
- More preferred compounds of general Formula I include compounds of Formula IB
- R a , R b , and R c and R f , R g , and R h independently represent hydrogen, halogen, hydroxy, ⁇ 6 alkyl, -O C- ⁇ g alkyl), -N0 2 , -CN, S0 2 NH 2 , amino, -NH(C 1 _ 6 alkyl), -N(C 1 . 6 alkyl) (C ⁇ alkyl), N(C 1 6 alkyl)C0(C 1 _ 6 alkyl), -N(C ⁇ 6 alkyl) C0 2 (C x 6 alkyl), - C0N(C 1 . G alkyl) (C ⁇ alkyl), -C0 2 (C, 6 alkyl;
- R d is hydrogen, straight or branched chain alkyl, or straight or branched chain alkoxy
- R 10 is hydrogen, methyl or ethyl.
- R x and R 4 are as defined in Formula I;
- R a , R b , and R c and R f , R g , and R h independently represent hydrogen, halogen, hydroxy, C x _ 6 alkyl, -0(0 ⁇ alkyl), -N0 2 , -CN, -S0 2 NH 2 , amino, -NH(C 1 _ 6 alkyl), -N(C 1 _ 6 alkyl) (C ⁇ alkyl), -N(C 1 _ 6 alkyl) CO (C ⁇ alkyl), -N (C _ 6 alkyl) C0 2 (C. . _ 6 alkyl), -CON(C 1 _ 6 alkyl) (C x 6 alkyl) , -C0 2 (C-_ 6 alkyl) ;
- R d is hydrogen or straight or branched chain alkyl or straight or branched chain alkoxy; R 4 is as defined in Formula I and R 10 is hydrogen, methyl or ethyl.
- Still other preferred compounds of general Formula I include compounds of Formula ID
- R a , R b , and R c independently represent hydrogen, halogen, hydroxy, C ⁇ 6 alkyl, -OfC ⁇ alkyl), -N0 2 , -CN, -S0 2 NH 2 , amino, -NH(C 1 . 6 alkyl), -N(C X _ 6 alkyl) (C ⁇ alkyl), -N(C 1 . 6 alkyl) CO (C ⁇ alkyl), -N(C 1 6 alkyl) C0 2 (C.. ⁇ alkyl), -CON(C 1 . 6 alkyl) (C x 6 alkyl), -C0 2 (C x 6 alkyl), wherein C ⁇ lkyl is as defined above;
- R 4 is as defined for Formula I;
- R 10 is hydrogen, methyl or ethyl; and R lt and R 12 are joined together to form a monocyclic, bicyclic-, or tricyclic ring.
- Still other preferred compounds of general Formula I include compounds of Formula IE
- R a , R b , and R c and R f , R g , and R h independently represent hydrogen, halogen, hydroxy, C ⁇ 6 alkyl, -0(0 ⁇ alkyl), -N0 2 , -CN, -S0 2 NH 2 , amino, -NH(C 1 _ 6 alkyl), -N(C ⁇ 6 alkyl) (C ⁇ 6 alkyl), -N(C 1 _ 6 alkyl )CO(C 1 .
- R 4 is as defined for Formula I;
- R d and R 10 together form an alkylene group of from 3-5 carbon atoms each of which is optionally substituted with methyl or ethyl .
- Another class of preferred compounds of general Formula I includes compounds of Formula IF
- R a , R b , and R c independently represent hydrogen, halogen, hydroxy, Ci- ⁇ alkyl, -Of ⁇ alkyl), -N0 2 , -CN, -S0 2 NH 2 , amino, -NH(C 1 _ 6 alkyl), -N(C 1 _ 6 alkyl) (C . 6 alkyl), -N(C 1 _ 6 alkyl) CO (C x . 6 alkyl), -N(C-_ 6 alkyl) C0 2 (C ⁇ alkyl), -CON(C 1 _ 6 alkyl) (C ⁇ alkyl), -C0 2 is as defined above ;
- R 1# R 2 , and R 4 are as defined in Claim 1;
- R is hydrogen, methyl or ethyl
- R ⁇ l and R 12 are independently from:
- Particularly preferred compounds of Formula IF are compounds of Formula IG
- R a , R b , and R c and R f , R g , and R h independently represent hydrogen, halogen, hydroxy, C _ 6 alkyl, -0(C ⁇ 6 alkyl), -N0 2 , -CN, -S0 2 NH 2 , amino, -NH(C 1 _ 6 alkyl), -Nt .j alkyl) (C ⁇ alkyl), -N(C-_ 6 alkyl) CO (C x _ 6 alkyl), -N(C X . 6 alkyl) C0 2 (C x . 6 alkyl), -CON(C x _g alkyl) (C 1 6 alkyl), -C0 2 (C ⁇ alkyl);
- R d is hydrogen or straight or branched chain alkyl or straight or branched chain alkoxy
- R- L and R 4 are as defined for Formula I;
- R 10 is hydrogen, methyl or ethyl.
- preferred compounds of the invention include compounds of general Formula IA wherein X is oxygen. These compounds will be referred to as compounds of Formula IH.
- More preferred compounds of Formula IH are compounds of Formula Ii
- R 1# R 2 , R 4 , R 11# and R 12 are as defined for Formula I;
- R a , R b , and R c independently represent hydrogen, halogen, hydroxy, C ⁇ e alkyl, alkyl), -N0 2 , -CN, -S0 2 NH 2 , amino, -NH(C 16 alkyl), -N(C 16 alkyl) (C 1 6 alkyl), -N(C ⁇ 6 alkyl ) CO (C 1 6 alkyl), -N(C 1 _ 6 alkyl)C0 2 (C 1 6 alkyl), -CON(C 1 possibly 6 alkyl) (C._ 6 alkyl), -C0 2 (C x g alkyl) .
- Particularly preferred compounds of Formula IH are compounds of Formula IJ
- R 1 and R 4 are as defined for Formula I;
- ⁇ li R a , R b , and R c and R f , R g , and R h independently represent hydrogen, halogen, hydroxy, C x _g alkyl, -0(0 ⁇ alkyl), -N0 2 , -CN, -S0 2 NH 2 , amino, -NH(C 1 _ 6 alkyl), -N(C 1 .
- R d is hydrogen or straight or branched chain alkyl or straight or branched chain alkoxy.
- compounds of the present invention have asymmetric centers and this invention includes all of the optical isomers and mixtures thereof.
- R 12 occurs more than one time in Formula I, its definition on each occurrence is independent of its definition at every other occurrence.
- alkyl includes straight or branched chain alkyl groups and cycloalkyl groups that also may contain double or triple bonds.
- alkyl include methyl, ethyl, propyl , isopropyl, butyl, iso- , sec- and tert- butyl, pentyl , hexyl , heptyl , 3-ethylbutyl , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and the like. Where the number of carbon atoms is designed at the alkyl group includes that number of carbon atoms .
- alkyl which it may contain one or two double or triple bond it is understood that at least two carbons are present in the alkyl for one double or triple bond, and at least four carbons for two double or triple bonds.
- alkoxy represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge, such as methoxy, ethoxy, propoxy and isopropoxy.
- halogen is meant fluorine, chlorine, bromine, and iodine.
- the term "monocyclic” includes, but is not limited to cyclopentyl, cyclohexyl or cycloheptyl; "bicyclic” includes, but is not limited to indanyl , tetrahydronaphthyl , chromanyl benzo [a] [7] annulenyl , bicyclo [4.4.0] decanyl , bicyclo [4 , 3.0] nonanyl, bicyclo [3.3.0] octanyl ; “tricyclic” includes, but is not limited to dibenzoannulenyl , dibenzoxepanyl , dibezothiepanyl .
- patients refers to humans as well as other mammals including pets such as dogs and cats and livestock such as cattle and sheep.
- This invention also includes methods for using compounds of
- Formula I to treat diseases or disorders in patients in which mediation by NK-3 receptors and/or GABA A receptors is of importance .
- Preferred compounds of this invention are ligands for neurokinin and GABA receptors, in particular NK-3 receptors and/or GABA A receptors, and are useful in the treatment of a wide range of diseases or disorders of the central nervous system (CNS) and periphery in mammals in which modulation of NK-3 receptors and/or GABA A receptors is of importance.
- CNS central nervous system
- neurodegenerative disorders such as dementia, Alzheimer's diseases, Parkinson's disease, Huntington' s disease, Down's syndrome, benzodiazepine overdoses, stress related somatic disorders, reflex sympathetic dystrophy, dysthmic disorders, obesity, eating disorders, drug and alcohol addiction, movement disorders, convulsive disorders such as epilepsy, migraine, headache, multiple sclerosis and other demyelinating diseases, AIDS related neuropathy, chemotherapy-induced neuropathy and neuralgia, diabetic or peripheral neuropathy, neurogenic inflammation, inflammatory pain, neuropathic pain, and other types of chronic or acute pain, Reynaud's disease, vasodilation, vasospasm, angina, asthma, chronic obstructive pulmonary diseases, airway hyperreactivity, cough, allergic rhinitis, bronchospasm, bron.chopneumonia
- Non-toxic pharmaceutical salts include salts, include, but not limited to salts with inorganic acids such as hydrochloride, sulfate, phosphate, diphosphate, hydrobromide, and nitrite or salts with an organic acid such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p-toluenesulfonate, 2 -hydroxyethylsulfonate, pamoate, salicylate and stearate.
- pahrmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium and ammonium.
- the present invention also encompasses the prodrugs of the compounds of Formula I .
- Those skilled in the art will recognize various synthetic methodologies (references by N. Bodor, Drugs of the Future, 1981, 6, 165-182, or H. Bundgaard, Advanced Drug Delivery Reviews, 1989, 3, 39-65) which may be employed to prepare non-toxic pharmaceutically acceptable prodrugs of the compounds encompassed by Formula I .
- the compounds of general Formula I may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
- parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
- a pharmaceutical formulation comprising a compound of general Formula I and a pharmaceutically acceptable carrier.
- One or more compounds of general Formula I may be present in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants and if desired other active ingredients.
- compositions containing compounds of general Formula I may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
- compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
- Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
- excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
- the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
- a time delay material such as glyceryl monosterate or glyceryl distearate may be employed.
- Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
- an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
- water or an oil medium for example peanut oil, liquid paraffin or olive oil.
- Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
- excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol , or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monoole
- the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
- preservatives for example ethyl, or n-propyl p-hydroxybenzoate
- coloring agents for example ethyl, or n-propyl p-hydroxybenzoate
- flavoring agents for example ethyl, or n-propyl p-hydroxybenzoate
- sweetening agents such as sucrose or saccharin.
- Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
- the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti- oxidant such as ascorbic acid.
- Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
- a dispersing or wetting agent e.g., glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerin, glycerin, glycerin, glycerin, glycerin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol
- compositions of the invention may also be in the form of oil-in-water emulsions.
- the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
- Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monoleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monoleate.
- the emulsions may also contain sweetening and flavoring agents.
- Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
- the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
- the sterile injectable preparation may also be sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1 , 3-butanediol .
- Suitable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
- sterile, fixed oils are conventionally employed as a solvent or suspending medium.
- any bland fixed oil may be employed including synthetic mono-or diglycerides.
- fatty acids such as oleic acid find use in the preparation of injectables.
- the compounds of general Formula I may also be administered in the form of suppositories for rectal administration of the drug.
- These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
- a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
- Such materials are cocoa butter and polyethylene glycols.
- Compounds of general Formula I may be administered parenterally in a sterile medium.
- the drug depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle.
- adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.
- Dosage levels of the order of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5 mg to about 7 g per patient per day) .
- the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient.
- Frequency of dosage may also vary depending on the compound used and the particular disease treated. However, for treatment of most disorders, a dosage regimen of 4 times daily or less is preferred. For the treatment of schizophrenia, depression, cognitive deficity or anxiety a dosage regimen of 1 or 2 times daily is particularly preferred. For the treatment of sleep disorders a single dose that rapidly reaches effective concentrations is desirable.
- the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
- Preferred compounds of the invention will have certain pharmacological properties. Such properties include, but are not limited to oral bioavailability, low toxicity, low serum protein binding and desirable in vi tro and in vivo half-lifes. Penetration of the blood brain barrier for compounds used to treat CNS disorders is necessary, while low brain levels of compounds used to treat periphereal disorders are often preferred.
- Assays may be used to predict these desirable pharmacological properties. Assays used to predict bioavailability include transport across human intestinal cell monolayers, including Caco-2 cell monolayers. Toxicity to cultured hepatocyctes may be used to predict compound toxicity. Penetration of the blood brain barrier of a compound in humans may be predicted from the brain levels of the compound in laboratory animals given the compound intravenously.
- Serum protein binding may be predicted from albumin binding assays. Such assays are described in a review by Oravcova, et al . (Journal of Chromatography B (1996) volume 677, pages 1-27) . Compound half-life is inversely proportional to the frequency of dosage of a compound. In vi tro half-lifes of compounds may be predicted from assays of microsomal half-life as described by Kuhnz and Gieschen (Drug Metabolism and Disposition, (1998) volume 26, pages 1120-1127) .
- the present invention also pertains to packaged pharmaceutical compositions for treating disorders responsive to NK-3 and/or GABA A receptor modulation, e.g., treatment schizoprenia, depression, or chronic pulmonary obstructive disorder by NK-3 receptor modulation or treatment of sleep disorders, cognitive deficits, anxiety or depression by GABA A receptor modulation.
- the packaged pharmaceutical compositions include a container holding a therapeutically effective amount of at least one NK-3 and/or GABA A receptor modulator as described supra and instructions (e.g., labeling) indicating the the contained NK-3 and/or GABA A receptor ligand is to be used for treating a disorder responsive to NK-3 and/or GABA A receptor modulation in the patient .
- the present invention also pertains to methods of inhibiting the binding of neurokinin to the NK-3 receptor which methods involve contacting a compound of the invention with cells expressing NK-3 receptors, wherein the compound is present at a concentration sufficient to inhibit neurokinin binding to cells expressing a cloned human NK-3 receptor in vitro and to method for altering the signal-tranducing activity of NK-3 receptors, said method comprising exposing cells expressing such receptor to an effective amount of a compound of the invention.
- Preferred compounds of the invention show selectivity for the NK-3 Receptor or the GABA A receptor as measured by standard assays for NK-3 and GABA A Receptor binding (See example 41 for a standard assay of NK-3 receptor binding and example 43 for a standard assay of GABA A receptor binding) .
- Preferred compounds of the invention are those that show selectivity for the NK-3 receptor over the GABA A receptor and exhibit a 10-fold greater affinity for the NK-3 receptor; more preferred compounds exhibit a 100-fold greater affinity for the NK-3 receptor; and most preferred compounds exhibit a 1000 -fold greater affinity for the NK-3 receptor in a standard assay of NK-3 receptor binding than for the GABA A receptor in a standard assay of GABA A receptor binding.
- Preferred compounds of the invention are those that show selectivity for the GABA A receptor over the NK-3 receptor and exhibit a 10-fold greater affinity for the GABA A receptor, more preferred compounds exhibit a 100 -fold greater affinity for the GABA A receptor, and most preferred compounds exhibit a 1000 -fold greater affinity for the GABA A receptor in a standard assay of GABA A receptor binding than for the NK-3 receptor in a standard assay of Nk-3 receptor binding.
- Condition A includes, but is not limited to, heating with or without a solvent such as toluene, ethanol, or xylene at 40- 250 °C; heating with AlMe 3 in a solvent such as toluene at 80-120 °C and, ocassionally, continued heating in the presence of awesson's reagent; or stirring at room temperature in presence of triphenylphosphine, CC1 4 and a base such as triethylamine or diisoprpylethylamine in a solvent such as acetonitrile or a mixture of solvents such as acetonitrile-pyridine .
- a solvent such as toluene, ethanol, or xylene at 40- 250 °C
- AlMe 3 in a solvent such as toluene at 80-120 °C and, ocassionally, continued heating in the presence of awesson's reagent
- R x , R 2 , R 3 , R 4 , R 10 , R 11 , and R 12 are as defined above, W is -COC1 or -C0 2 H.
- Condition C includes, but is not limited to, treatment with sodium methoxide in the presence of methanol as solvent .
- Condition A includes, but is not limited to, heating with or without a solvent such as toluene, ethanol, or xylene at 40- 250 °C; heating with AlMe 3 in a solvent such as toluene at 80-120 °C and, ocassionally, continued heating in the presence of Lawesson's reagent; or stirring at room temperature in presence of triphenylphosphine, CC1 4 and a base such as triethylamine or diisoprpylethylamine in a solvent such as acetonitrile or a mixture of solvents such as acetonitrile-pyridine .
- a solvent such as toluene, ethanol, or xylene at 40- 250 °C
- AlMe 3 in a solvent such as toluene at 80-120 °C and, ocassionally, continued heating in the presence of Lawesson's reagent
- Step 3 N- (2-Amino-2-phenylbutyl) -3-methoxy-2-phenylquinoline-4- carboxamide
- a mixture of 3-methoxy-2-phenylquinoline-4-carboxylic acid (3.0 g) , and the compound of step 2 (3.0 g) , BOP (5.7 g) and TEA (2.0 g) in 25 mL of anhydrous DMF is stirred at ambient temperature overnight.
- the mixture is diluted with water and EtOAc.
- the organic layer is separated, washed with water and concentrated under vacuum.
- the residue is purified on a silica gel column, eluting with EtOAc and Hexane (1:1) to afford the title compound as white foam.
- Step 4. (R,S) -4-Ethyl-4-phenyl-2- (3-methoxy-2-phenylquinolin-4- yl) -imidazoline
- Triphenylphospine (4.3 g) is added once to a mixture of the compound of step 3 (2.3 g) , TEA (1.6 mL) , CC14 (3.1 mL) , pyridine (20 L) and acetonitrile (20 mL) .
- the reaction mixture is stirred at ambient temperature overnight. It is then evaporated and mixed with EtOAc and aqueous Na 2 C0 3 solution. The organic layer is separated, and washed with brine and evaporated. The residue is purified on a silica gel column, eluting with EtOAc and Hexane (from 1: 4 to 1:1) to afford the titled compound as white foam.
- HCl salt is prepared by addition of HCl in ether to a solution of free base in EtOAc and filtration.
- Example 1 The following compounds are prepared by methods analogous to that of Example 1. LC-MS data are given as HPLC retention times and [MH] + . The HPLC retention times of Table 1 are obtained by the method given in Example 1.
- Triphenylphosphine (2.10 g, 8.0 mmol) is added to a mixture of (3 -methoxy-2 -phenylquinolin-4 -yl) carboxylic acid (0.61 g, 2.2 mmol), pyridine (anhydrous, 5 mL) , acetonitrile (anhydrous, 5 mL) , triethylamine (1.4 mL, 10 mmol), 1-amino-2 -phenyl -2- pentanol (0.40 g, 2.2 mmol), and carbon tetrachloride (1.5 mL, 16 mmol) stirred under nitrogen at ambient temperature.
- the following assay is a standard assay for NK-3 receptor binding activity. Assays are performed as described in Krause et al (Proc. Natl. Acad. Sci. USA 94: 310-315, 1997).
- the NK-3 receptor complementary DNA is cloned from human hypothalamic RNA using standard procedures.
- the receptor cDNA is inserted into the expression vector pM 2 to transfect the mammalian Chinese hamster ovary cell line, and a stably expressing clonal cell line is isolated, characterized and used for the current experiments. Cells are grown in minimal essential medium alpha containing 10% fetal bovine serum and 250 ⁇ g/ml G418.
- Cells are liberated from cell culture plates with No-zyme (PBS base, JRH Biosciences), and harvested by low speed centrifugation.
- the cell pellet is homogenized in TBS (0.05 m TrisHCl, 120 mM NaCl, pH 7.4) with a Polytron homogenizer at setting 5 for 20 seconds, and total cellular membranes are isolated by centrifugation at 47,500 x g for 10 minutes.
- the membrane pellet is resuspended by homogenization with the Polytron as above, and the membranes are then isolated by centrifugation at 47,500 x g for 10 minutes. This final membrane pellet is resuspended in TBS at a protein concentration of 350 ⁇ g/ml.
- Receptor binding assays contain a total volume of 200 ⁇ l containing 50 ⁇ g membrane protein, 0.05-0.15 nM 125I-methylPhe7- neurokinin B, drug or blocker in TBS containing 1.0 mg/ml bovine serum albumen, 0.2 mg/ml bacitracin, 20 ⁇ g/ml leupeptin and 20 ⁇ g/ml chymostatin. Incubations are carried out for 2 hours at 4 °C, and the membrane proteins are harvested by passing the incubation mixture by rapid filtration over presoaked GF/B filters to separate bound from free ligand. The filters are presoaked in TBS containing 2% BSA and 0.1% Tween 20.
- Agonist -induced (methylPhe7-neurokinin B) calcium mobilization is monitored using a FLIPR (Molecular Devices) instrument.
- the agonist is added to the cells and fluorescence responses are continuously recorded for up to 5min.
- compounds are preincubated with the cells for up to 30 min. prior to administration of the methylPhe7-neurokinin B agonist usually at a concentration that brings about a 50% maximal activity. Responses are recorded for times up to 5 min.
- Kaleidagraph software Synergy Software, Reading, PA
- y a* (1/ (1+ (b/x) c) ) to determine the EC 50 value or IC 50 value for the response.
- y is the maximum fluorescence signal
- x is the concentration of the agonist or antagonist
- a is the E max
- b corresponds to the EC 50 or IC 50 value
- c is the Hill coefficient.
- the following assay is a standard assay for GABA A receptor binding.
- Rat cortical tissue is dissected and homogenized in 25 volumes (w/v) of Buffer A (0.05 M Tris HCl buffer, pH 7.4 at 4 °C) .
- the tissue homogenate is centrifuged in the cold (4 °C) at 20,000 x g for 20 minutes.
- the supernatant is decanted, the pellet rehomogenized in the same volume of buffer, and centrifuged again at 20,000 x g.
- the supernatant of this centrifugation step is decanted and the pellet stored at -20 °C overnight.
- the pellet is then thawed and resuspended in 25 volumes of Buffer A (original wt/vol) , centrifuged at 20,000 x g and the supernatant decanted. This wash step is repeated once. The pellet is finally resuspended in 50 volumes of Buffer A.
- Buffer A original wt/vol
- Incubations containi 100 ⁇ l of tissue homogenate, 100 ⁇ l of radioligand, (0.5 nM 3 H-Rol5-1788 [ 3 H-Flumazenil] , specific activity 80 Ci/mmol) , and test compound or control (see below) , and are brought to a total volume of 500 ⁇ l with Buffer A. Incubations are carried for 30 min at 4°C and then rapidly filtered through Whatman GFB filters to separate free and bound ligand. Filters are washed twice with fresh Buffer A and counted in a liquid scintillation counter. Nonspecific binding
- control is determined by displacement of 3 H Rol5-1788 with 10 ⁇ M Diazepam (Research Biochemicals International, Natick, MA) .
- Total Specific Binding Total - Nonspecific
- a competition binding curve is obtained with up to 11 points spanning the compound concentration range from 10 "1 M to 10 "S M obtained per curve by the method described above for determining percent inhibition.
- K A values are calculated according the Cheng-Prussof equation. When tested in this assay compounds of the invention exihibit K ⁇ values of less than 1 ⁇ M, preferred compounds of the invention have K values of less than 500 nM and more compounds of the invention have K ⁇ values of less than 100 nM.
- the following assay is used to determine if a compound of the invention act as an agonist, an antagonist, or an inverse agonist at the benzodiazepine site of the GABA A receptor. Assays are carried out as described in White and Gurley
- Electrophysiological recordings are carried out using the two electrode voltage-clamp technique at a membrane holding potential of -70 mV.
- Xenopus Laevis oocytes are enzymatically isolated and injected with non-polyadenylated cRNA mixed in a ratio of 4:1:4 for ⁇ , ⁇ and ⁇ subunits, respectively.
- all of the subunit cRNAs in each combination are human clones or all are rat clones.
- the sequence of each of these cloned subunits is available from GENBANK, e.g., human 1# GENBANK accession no. X14766, human ⁇ 2 , GENBANK accession no. A28100; human ⁇ 3 , GENBANK accession no.
- Compounds are evaluated against a GABA concentration that evokes ⁇ 10% of the maximal evokable GABA current (e.g. 1 ⁇ M - 9 ⁇ M) . Each oocyte is exposed to increasing concentrations of compound in order to evaluate a concentration/effect relationship. Compound efficacy is calculated as a percent- change in current amplitude: 100* ( (Ic/I) -1) , where Ic is the GABA evoked current amplitude observed in the presence of test compound and I is the GABA evoked current amplitude observed in the absence of the test compound.
- Specificity of a compound for the benzodiazepine site is determined following completion of a concentration/effect curve. After washing the oocyte sufficiently to remove previously applied compound, the oocyte is exposed to GABA + 1 ⁇ M R015- 1788, followed by exposure to GABA + 1 ⁇ M R015-1788 + test compound. Percent change due to addition of compound is calculated as described above. Any percent change observed in the presence of R015-1788 is subtracted from the percent changes in current amplitude observed in the absence of 1 ⁇ M R015-1788. These net values are used for the calculation of average efficacy and EC 50 values by standard methods. To evaluate average efficacy and EC 50 values, the concentration/effect data are averaged across cells and fit to the logistic equation.
- radiolabeled probe compounds of the invention are prepared as radiolabeled probes by carrying out their synthesis using precursors comprising at least one atom that is a radioisotope.
- the radioisotope is preferably selected from of at least one of carbon (preferably 1 C) , hydrogen (preferably 3 H) , sulfur (preferably 35 S) , or iodine (preferably 125 I) .
- Such radiolabeled probes are conveniently synthesized by a radioisotope supplier specializing in custom synthesis of radiolabeled probe compounds. Such suppliers include Amersham Corporation, Arlington Heights, IL; Cambridge Isotope Laboratories, Inc. Andover, MA; SRI International, Menlo Park, CA; Wizard Laboratories, West
- Tritium labeled probe compounds are also conveniently prepared catalytically via platinum-catalyzed exchange in tritiated acetic acid, acid-catalyzed exchange in tritiated trifluoroacetic acid, or heterogeneous-catalyzed exchange with tritium gas. Such preparations are also conveniently carried out as a custom radiolabeling by any of the suppliers listed in the preceding paragraph using the compound of the invention as substrate.
- certain precursors may be subjected to tritium-halogen exchange with tritium gas, tritium gas reduction of unsaturated bonds, or reduction using sodium borotritide, as appropriate .
- Receptor autoradiography (receptor mapping) of NK-3 or GABA A receptors in cultured cells or tissue samples is carried out in vitro as described by Kuhar in sections 8.1.1 to 8.1.9 of Current Protocols in Pharmacology (1998) John Wiley & Sons, New York, using radiolabeled compounds of the invention prepared as described in the preceding Example.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Molecular Biology (AREA)
- Immunology (AREA)
- Psychiatry (AREA)
- Urology & Nephrology (AREA)
- Hematology (AREA)
- Biochemistry (AREA)
- Analytical Chemistry (AREA)
- Cell Biology (AREA)
- Pathology (AREA)
- General Physics & Mathematics (AREA)
- Microbiology (AREA)
- Biotechnology (AREA)
- Food Science & Technology (AREA)
- Physics & Mathematics (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Pain & Pain Management (AREA)
- Addiction (AREA)
- Anesthesiology (AREA)
- Hospice & Palliative Care (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Description
Claims
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE60004654T DE60004654T2 (en) | 1999-03-29 | 2000-03-28 | 4-SUBSTITUTED CHINOLINE DERIVATIVES AS NK-3 AND / OR GABA (A) RECEPTOR LIGANDS |
AU40386/00A AU4038600A (en) | 1999-03-29 | 2000-03-28 | 4-substituted quinoline derivatives as nk-3 and/or gaba(a) receptor ligands |
CA002368455A CA2368455A1 (en) | 1999-03-29 | 2000-03-28 | 4-substituted quinoline derivatives as nk-3 and/or gaba(a) receptor ligands |
EP00919753A EP1165542B1 (en) | 1999-03-29 | 2000-03-28 | 4-substituted quinoline derivatives as nk-3 and/or gaba(a) receptor ligands |
AT00919753T ATE247652T1 (en) | 1999-03-29 | 2000-03-28 | 4-SUBSTITUTED QUINOLINE DERIVATIVES AS NK-3 AND/OR GABA(A) RECEPTOR LIGANDS |
JP2000608005A JP2002540203A (en) | 1999-03-29 | 2000-03-28 | 4-Substituted quinoline derivatives as NK-3 and / or GABA (A) receptor ligands |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US12692699P | 1999-03-29 | 1999-03-29 | |
US60/126,926 | 1999-03-29 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2000058303A1 true WO2000058303A1 (en) | 2000-10-05 |
WO2000058303A9 WO2000058303A9 (en) | 2002-12-19 |
Family
ID=22427414
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2000/008205 WO2000058303A1 (en) | 1999-03-29 | 2000-03-28 | 4-substituted quinoline derivatives as nk-3 and/or gaba(a) receptor ligands |
PCT/US2000/008196 WO2000058313A1 (en) | 1999-03-29 | 2000-03-28 | 4-substituted quinoline derivatives as gaba receptor ligands |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2000/008196 WO2000058313A1 (en) | 1999-03-29 | 2000-03-28 | 4-substituted quinoline derivatives as gaba receptor ligands |
Country Status (8)
Country | Link |
---|---|
US (2) | US6413982B1 (en) |
EP (1) | EP1165542B1 (en) |
JP (1) | JP2002540203A (en) |
AT (1) | ATE247652T1 (en) |
AU (2) | AU4038600A (en) |
CA (1) | CA2368455A1 (en) |
DE (1) | DE60004654T2 (en) |
WO (2) | WO2000058303A1 (en) |
Cited By (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001034603A2 (en) * | 1999-11-12 | 2001-05-17 | Neurogen Corporation | Bicyclic and tricyclic heteroaromatic compounds |
WO2004043930A1 (en) * | 2002-11-13 | 2004-05-27 | Merck Sharp & Dohme Limited | Quinoline derivatives which enhance cognition via the gaba-a receptor |
WO2005066137A1 (en) * | 2003-12-19 | 2005-07-21 | Neurogen Corporation | 2,5-diaryl-1h-imidazole-4-carboxamides as neurokinin-3 receptor modulators for the treatment of central nervous system and peripheral diseases |
WO2005116009A1 (en) * | 2004-05-18 | 2005-12-08 | Schering Corporation | Substituted 2-quinolyl-oxazoles useful as pde4 inhibitors |
US7452888B2 (en) | 2002-03-27 | 2008-11-18 | Glaxo Group Limited | Quinoline derivatives and their use as 5-ht6 ligands |
US7879909B2 (en) | 2004-04-12 | 2011-02-01 | United Therapeutics Corporation | Use of Treprostinil to treat neuropathic diabetic foot ulcers |
US9745270B2 (en) | 2008-10-28 | 2017-08-29 | Arena Pharmaceuticals, Inc. | Processes useful for the preparation of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea and crystalline forms related thereto |
US9775829B2 (en) | 2003-07-22 | 2017-10-03 | Arena Pharmaceuticals, Inc. | Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of disorders related thereto |
US9808455B2 (en) | 2007-12-12 | 2017-11-07 | Axovant Sciences Gmbh | Combinations comprising 3-phenylsulfonyl-8-piperazinyl-1yl-quinoline |
US10022355B2 (en) | 2015-06-12 | 2018-07-17 | Axovant Sciences Gmbh | Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of REM sleep behavior disorder |
US10034859B2 (en) | 2015-07-15 | 2018-07-31 | Axovant Sciences Gmbh | Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of hallucinations associated with a neurodegenerative disease |
US10787437B2 (en) | 2008-04-02 | 2020-09-29 | Arena Pharmaceuticals, Inc. | Processes for the preparation of pyrazole derivatives useful as modulators of the 5-HT2A serotonin receptor |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1165542B1 (en) | 1999-03-29 | 2003-08-20 | Neurogen Corporation | 4-substituted quinoline derivatives as nk-3 and/or gaba(a) receptor ligands |
GB0117396D0 (en) | 2001-07-17 | 2001-09-05 | Glaxo Group Ltd | Chemical compounds |
GB0308208D0 (en) | 2003-04-09 | 2003-05-14 | Glaxo Group Ltd | Chemical compounds |
WO2005061462A2 (en) * | 2003-12-19 | 2005-07-07 | Neurogen Corporation | Diaryl pyrazole derivatives and their use as neurokinin-3 receptor modulators |
US20050277639A1 (en) * | 2004-03-02 | 2005-12-15 | Phil Skolnick | 2-Pyridinyl[7-(substituted-pyridin-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl]methanones |
BRPI0812816B8 (en) * | 2007-06-18 | 2021-05-25 | Richter Gedeon Nyrt | compounds derived from sulfonyl-quinoline, ligands with preference for subtype of receptor mglur1 and mglur5, processes for the preparation of said compounds, pharmaceutical formulation comprising said compounds and use thereof |
US7863295B2 (en) * | 2008-02-12 | 2011-01-04 | Children's Medical Center Corporation | Treatments for neuropathy |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1995011885A1 (en) * | 1993-10-27 | 1995-05-04 | Neurogen Corporation | Certain fused pyrrolecarboxanilides; a new class of gaba brain receptor ligands |
WO1996002509A1 (en) * | 1994-07-14 | 1996-02-01 | Smithkline Beecham Farmaceutici S.P.A. | Quinoline derivatives as nk3 antagonists |
US5792766A (en) * | 1996-03-13 | 1998-08-11 | Neurogen Corporation | Imidazo 1,5-c! quinazolines; a new class of GABA brain receptor ligands |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2227769T3 (en) | 1994-05-27 | 2005-04-01 | Glaxosmithkline S.P.A. | DERIVATIVES OF QUINOLINA AS ANTAGONISTS OF THE NK3 TAQUIQUININA RECEPTOR. |
JPH10512855A (en) | 1994-12-23 | 1998-12-08 | スミスクライン・ビーチャム・コーポレイション | Compounds and methods |
AP9801237A0 (en) | 1995-11-24 | 1998-06-30 | Smithkline Beecham Farm S P A | Quinoline derivatives. |
GB9524104D0 (en) | 1995-11-24 | 1996-01-24 | Smithkline Beecham Spa | Novel compounds |
GB9524137D0 (en) | 1995-11-24 | 1996-01-24 | Smithkline Beecham Spa | Novel compounds |
AR004735A1 (en) | 1995-11-24 | 1999-03-10 | Smithkline Beecham Spa | CHINOLEIN 4-AMIDO SUBSTITUTED, A PROCEDURE FOR ITS PREPARATION, A PHARMACEUTICAL COMPOSITION THAT CONTAINS THEM AND THE USE OF THE SAME FOR THE PREPARATION OF A MEDICINAL PRODUCT. |
ATE244711T1 (en) | 1997-05-23 | 2003-07-15 | Glaxosmithkline Spa | QUINOLINE-4-CARBOXAMIDE DERIVATIVES AS NK-2 AND NK-3 RECEPTOR ANTAGONISTS |
AP1201A (en) | 1997-09-17 | 2003-09-01 | Smithkline Beecham Corp | Method for the synthesis of quinoline derivatives. |
US6228868B1 (en) * | 1998-07-27 | 2001-05-08 | Abbott Laboratories | Oxazoline antiproliferative agents |
EP1165542B1 (en) | 1999-03-29 | 2003-08-20 | Neurogen Corporation | 4-substituted quinoline derivatives as nk-3 and/or gaba(a) receptor ligands |
-
2000
- 2000-03-28 EP EP00919753A patent/EP1165542B1/en not_active Expired - Lifetime
- 2000-03-28 AU AU40386/00A patent/AU4038600A/en not_active Abandoned
- 2000-03-28 US US09/536,922 patent/US6413982B1/en not_active Expired - Fee Related
- 2000-03-28 JP JP2000608005A patent/JP2002540203A/en active Pending
- 2000-03-28 AT AT00919753T patent/ATE247652T1/en not_active IP Right Cessation
- 2000-03-28 WO PCT/US2000/008205 patent/WO2000058303A1/en active IP Right Grant
- 2000-03-28 AU AU40380/00A patent/AU4038000A/en not_active Abandoned
- 2000-03-28 WO PCT/US2000/008196 patent/WO2000058313A1/en active Application Filing
- 2000-03-28 DE DE60004654T patent/DE60004654T2/en not_active Expired - Fee Related
- 2000-03-28 CA CA002368455A patent/CA2368455A1/en not_active Abandoned
-
2002
- 2002-05-07 US US10/140,693 patent/US6624175B2/en not_active Expired - Fee Related
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1995011885A1 (en) * | 1993-10-27 | 1995-05-04 | Neurogen Corporation | Certain fused pyrrolecarboxanilides; a new class of gaba brain receptor ligands |
WO1996002509A1 (en) * | 1994-07-14 | 1996-02-01 | Smithkline Beecham Farmaceutici S.P.A. | Quinoline derivatives as nk3 antagonists |
US5792766A (en) * | 1996-03-13 | 1998-08-11 | Neurogen Corporation | Imidazo 1,5-c! quinazolines; a new class of GABA brain receptor ligands |
Non-Patent Citations (1)
Title |
---|
PIERO SAVARINO ET AL.: "Assembled systems ( X-azolopyridine)(quinoline). Bases and Salts.", JOURNAL OF HETEROCYCLIC CHEMISTRY., vol. 29, - 1992, HETEROCORPORATION. PROVO., US, pages 185 - 192, XP002144891, ISSN: 0022-152X * |
Cited By (24)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001034603A3 (en) * | 1999-11-12 | 2002-01-10 | Neurogen Corp | Bicyclic and tricyclic heteroaromatic compounds |
US6511987B1 (en) | 1999-11-12 | 2003-01-28 | Neurogen Corporation | Bicyclic and tricyclic heteroaromatic compounds |
WO2001034603A2 (en) * | 1999-11-12 | 2001-05-17 | Neurogen Corporation | Bicyclic and tricyclic heteroaromatic compounds |
US7326709B2 (en) | 1999-11-12 | 2008-02-05 | Neurogen Corporation | Bicyclic and tricyclic heteroaromatic compounds |
US7799774B2 (en) | 2002-03-27 | 2010-09-21 | Glaxo Group Limited | Quinoline derivatives and their use as 5-HT6 ligands |
US8236947B2 (en) | 2002-03-27 | 2012-08-07 | Glaxo Group Limited | Quinoline derivatives and their use as 5-HT6 ligands |
US7452888B2 (en) | 2002-03-27 | 2008-11-18 | Glaxo Group Limited | Quinoline derivatives and their use as 5-ht6 ligands |
US7977337B2 (en) | 2002-03-27 | 2011-07-12 | Glaxo Group Limited | Quinoline derivatives and their use as 5-HT6 ligands |
US7601837B2 (en) | 2002-03-27 | 2009-10-13 | Glaxo Group Limited | Quinoline derivatives and their use as 5-HT6 ligands |
WO2004043930A1 (en) * | 2002-11-13 | 2004-05-27 | Merck Sharp & Dohme Limited | Quinoline derivatives which enhance cognition via the gaba-a receptor |
US9775829B2 (en) | 2003-07-22 | 2017-10-03 | Arena Pharmaceuticals, Inc. | Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of disorders related thereto |
WO2005066137A1 (en) * | 2003-12-19 | 2005-07-21 | Neurogen Corporation | 2,5-diaryl-1h-imidazole-4-carboxamides as neurokinin-3 receptor modulators for the treatment of central nervous system and peripheral diseases |
US8563614B2 (en) | 2004-04-12 | 2013-10-22 | United Therapeutics Corporation | Use of treprostinil to treat neuropathic diabetic foot ulcers |
US7879909B2 (en) | 2004-04-12 | 2011-02-01 | United Therapeutics Corporation | Use of Treprostinil to treat neuropathic diabetic foot ulcers |
CN1984901B (en) * | 2004-05-18 | 2011-02-09 | 先灵公司 | Substituted 2-quinolyl-oxazoles useful as PDE4 inhibitors. |
US7511062B2 (en) | 2004-05-18 | 2009-03-31 | Schering Corporation | Substituted 2-quinolyl-oxazoles useful as PDE4 inhibitors |
AU2005247906B2 (en) * | 2004-05-18 | 2011-08-25 | Merck Sharp & Dohme Corp. | Substituted 2-quinolyl-oxazoles useful as PDE4 inhibitors |
WO2005116009A1 (en) * | 2004-05-18 | 2005-12-08 | Schering Corporation | Substituted 2-quinolyl-oxazoles useful as pde4 inhibitors |
US9808455B2 (en) | 2007-12-12 | 2017-11-07 | Axovant Sciences Gmbh | Combinations comprising 3-phenylsulfonyl-8-piperazinyl-1yl-quinoline |
US10787437B2 (en) | 2008-04-02 | 2020-09-29 | Arena Pharmaceuticals, Inc. | Processes for the preparation of pyrazole derivatives useful as modulators of the 5-HT2A serotonin receptor |
US9745270B2 (en) | 2008-10-28 | 2017-08-29 | Arena Pharmaceuticals, Inc. | Processes useful for the preparation of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea and crystalline forms related thereto |
US10022355B2 (en) | 2015-06-12 | 2018-07-17 | Axovant Sciences Gmbh | Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of REM sleep behavior disorder |
US10034859B2 (en) | 2015-07-15 | 2018-07-31 | Axovant Sciences Gmbh | Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of hallucinations associated with a neurodegenerative disease |
US11304932B2 (en) | 2015-07-15 | 2022-04-19 | Axovant Sciences Gmbh | Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of hallucinations associated with a neurodegenerative disease |
Also Published As
Publication number | Publication date |
---|---|
ATE247652T1 (en) | 2003-09-15 |
WO2000058303A9 (en) | 2002-12-19 |
JP2002540203A (en) | 2002-11-26 |
EP1165542A1 (en) | 2002-01-02 |
US20020198232A1 (en) | 2002-12-26 |
DE60004654D1 (en) | 2003-09-25 |
DE60004654T2 (en) | 2004-06-24 |
US6413982B1 (en) | 2002-07-02 |
CA2368455A1 (en) | 2000-10-05 |
US6624175B2 (en) | 2003-09-23 |
EP1165542B1 (en) | 2003-08-20 |
AU4038000A (en) | 2000-10-16 |
WO2000058313A1 (en) | 2000-10-05 |
AU4038600A (en) | 2000-10-16 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP1165542B1 (en) | 4-substituted quinoline derivatives as nk-3 and/or gaba(a) receptor ligands | |
EP1177177B1 (en) | Substituted 4-oxo-quinoline-3-carboxamides: gaba brain receptor ligands | |
US6552037B2 (en) | 2-Substituted imidazo[1,2-A]pyridine derivatives | |
US6559163B2 (en) | 2,4-substituted quinoline derivatives | |
US7326709B2 (en) | Bicyclic and tricyclic heteroaromatic compounds | |
US6828329B2 (en) | Aryl fused substituted 4-oxy-pyridines | |
US6297256B1 (en) | Aryl and heteroaryl substituted pyridino derivatives GABA brain receptor ligands | |
US6723332B2 (en) | Oxomidazopyridine-carboxamides | |
US6656941B2 (en) | Aryl substituted tetrahydroindazoles | |
US6310212B1 (en) | 4-substituted quinoline derivatives | |
EP1392692B1 (en) | (oxo-pyrazolo¬1,5a|pyrimidin-2-yl)alkyl-carboxamides | |
US20050059826A1 (en) | Substituted fused pyrroleoximes and fused pyrazoleoximes | |
US20040002608A1 (en) | Substituted imidazole derivatives: GABAA receptor ligands | |
US6528649B2 (en) | Imidazoloisoquinolines | |
US20080032975A1 (en) | Substituted Fused Pyrroleoximes and Fused Pyrazoleoximes |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY CA CH CN CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): GH GM KE LS MW SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
ENP | Entry into the national phase |
Ref document number: 2368455 Country of ref document: CA Ref country code: CA Ref document number: 2368455 Kind code of ref document: A Format of ref document f/p: F |
|
ENP | Entry into the national phase |
Ref country code: JP Ref document number: 2000 608005 Kind code of ref document: A Format of ref document f/p: F |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2000919753 Country of ref document: EP |
|
WWP | Wipo information: published in national office |
Ref document number: 2000919753 Country of ref document: EP |
|
REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
AK | Designated states |
Kind code of ref document: C2 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY CA CH CN CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: C2 Designated state(s): GH GM KE LS MW SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG |
|
COP | Corrected version of pamphlet |
Free format text: PAGES 62-66, CLAIMS, REPLACED BY NEW PAGES 62-66 |
|
WWG | Wipo information: grant in national office |
Ref document number: 2000919753 Country of ref document: EP |