EP0871442A1 - Antagonistes benzimidazolyles du recepteur du neuropeptide y - Google Patents

Antagonistes benzimidazolyles du recepteur du neuropeptide y

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Publication number
EP0871442A1
EP0871442A1 EP97905573A EP97905573A EP0871442A1 EP 0871442 A1 EP0871442 A1 EP 0871442A1 EP 97905573 A EP97905573 A EP 97905573A EP 97905573 A EP97905573 A EP 97905573A EP 0871442 A1 EP0871442 A1 EP 0871442A1
Authority
EP
European Patent Office
Prior art keywords
alkylenyl
alkoxy
heterocyclic
preparation
piperidin
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Withdrawn
Application number
EP97905573A
Other languages
German (de)
English (en)
Inventor
Macklin B. Arnold
Thomas C. Britton
Robert F. Bruns, Jr.
Buddy E. Cantrell
Anne M. Happ
Philip A. Hipskind
James J. Howbert
Karen L. Lobb
James A. Nixon
Paul L. Ornstein
Edward C. Smith
Hamideh Zarrinmayeh
Dennis M. Zimmerman
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Eli Lilly and Co
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Eli Lilly and Co
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Filing date
Publication date
Priority claimed from GBGB9600344.7A external-priority patent/GB9600344D0/en
Application filed by Eli Lilly and Co filed Critical Eli Lilly and Co
Publication of EP0871442A1 publication Critical patent/EP0871442A1/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—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 linked by a carbon chain containing only aliphatic 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/12—Radicals substituted by oxygen atoms
    • 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
    • C07D401/12—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 linked by a chain containing hetero atoms as chain links
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • Neuropeptide Y is a peptide present in the central and peripheral nervous systems. The peptide co-exists with noradrenaline in many neurons and acts as a neurotransmitter per se or synergistically together with noradrenaline. Neuropeptide Y- containing fibers are numerous around arteries in the heart, but are also found around the arteries in the respiratory tract, the gastrointestinal tract, and the genitourinary tract. Neuropeptide Y is also present in the cerebrum with effects on blood pressure, feeding, and the release of different hormones. Alterations in central concentrations of neuropeptide Y have been implicated in the etiology of psychiatric disorders. Neuropeptide Y was discovered, isolated and sequenced in
  • Neuropeptide Y is a member of the pancreatic family of peptides and shares significant sequence homology with pancreatic polypeptide and peptide YY.
  • Neuropeptide Y and the other members of its family of peptides all feature a tertiary structure consisting of an N- terminal polyproline helix and an amphiphilic ⁇ -helix, connected with a ⁇ -turn, creating a hairpin-like loop, which is sometimes referred to as the pancreatic polypeptide (PP) fold.
  • the helices are kept together by hydrophobic interactions.
  • the amidated C-terminal end projects away from the hairpin loop.
  • neuropeptide Y was identified as being the most abundant peptide in the central nervous system with widespread distribution including the cortex, brainstem, hippocampus, hypotahlamus, amygdala, and thalamus as well as being present in the peripheral nervous system in sympathetic neurons and adrenal chromaffin cells.
  • Neuropeptide Y seems to fulfill the main criteria for a role as a neurotransmitter, as it is stored in synaptic granules, is released upon electrical nerve stimulation, and acts at specific receptors.
  • neuropeptide Y is an important messenger in its own right, probably in the brain, where neuropeptide Y potently inhibits the activity of adenylate cyclase and induces an increase in the intracellular levels of calcium.
  • Central injection of neuropeptide Y results in blood pressure changes, increased feeding, increased fat storage, elevated blood sugar and insulin, decreased locomotor activity, reduced body temperature, and catalepsy.
  • Neuropeptide Y acts upon membrane receptors that are dependent on guanyl-nucleotide binding proteins, known as G protein-coupled receptors.
  • G proteins are a family of membrane proteins that become activated only after binding guanosine triphosphate. Activated G proteins in turn activate an amplifier enzyme on the inner face of a membrane; the enzyme then converts precursor molecules into second messengers.
  • Neuropeptide Y appears to interact with a family of closely related receptors. These receptors are generally classified into several subtypes based upon the ability of different tissues and receptors to bind different fragments of neuropeptide Y and other members of the PP family of peptides.
  • the Yl receptor subtype appears to be the major vascular neuropeptide Y receptor.
  • the Y2 receptor subtypes can also occur postjunctionally on vascular smooth muscle.
  • the as-yet- unisolated Y3 receptor subtype appears to be neuropeptide Y-spe ⁇ fic, not binding peptide YY. This receptor is likely to be present in the adrenal tissues, medulla, heart, and brain stem, among other areas.
  • neuropeptide Y receptor antagonists In view of the wide number of clinical maladies associated with an excess of neuropeptide Y, the development of neuropeptide Y receptor antagonists will serve to control these clinical conditions.
  • the earliest such receptor antagonists such as Patent Cooperation Treaty Patent Publication WO 91/08223, published June 13, 1991, and Patent Cooperation Treaty Patent Publication WO 94/00486, published January 6, 1994, were peptide derivatives. These antagonists are of limited pharmaceutical utility because of their metabolic instability.
  • This invention provides a class of potent non-peptide neuropeptide Y receptor antagonists.
  • the compounds of the present invention do not suffer from the shortcomings, in terms of metabolic instability, of known peptide-based neuropeptide Y receptor antagonists.
  • This invention encompasses methods for the treatment or prevention of a physiological disorder associated with an excess of neuropeptide Y, which method comprises administering to a mammal in need of said treatment an effective amount of a compound of Formula I
  • R 1 is phenyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, phenyKCi-C ⁇ alkylenyl)-, phenyKCi-C ⁇ alkoxy), phenoxy(C ⁇ -C6 alkylenyl)-, phenyKCi-C ⁇ alkoxy )-(C ⁇ -C ⁇ alkylenyl)-, naphthyl, naphthyKCi-C ⁇ alkylenyl)-, naphthyKCi-C ⁇ alkoxy), naphthyloxy(C ⁇ -C6 alkylenyl)-, or naphthyl(C ⁇ -C ⁇ alkoxy )-(C ⁇ -C6 alkylenyl)-,
  • any one of which phenyl, C 3 -C8 cycloalkyl, phenoxy, naphthyl, or naphthyloxy moieties may be substituted with one or groups selected from the group consisting of halo, trifluoromethyl, Ci-C ⁇ alkyl, C 2 -C7 alkenyl, C2-C7 alkynyl, Ci-C ⁇ alkoxy, Ci-C ⁇ alkylthio, Ci-C ⁇ alkylamino, heterocyclic, unsaturated heterocyclic, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, phenyl, phenoxy, phenyKCi-C ⁇ alkylenyl)-, phenyKCi-C ⁇ alkoxy)-, benzoyl, phenyl(C2-C7 alkanoyl)-, and phenyl(C2-C7 alkanoyloxy)-;
  • R 2 is C 1 -C12 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 2 -C 7 alkanoyl, Ci-C ⁇ alkoxy, heterocyclic(C ⁇ -C6 alkylenyl)-, C3-C8 cycloalkyl, C 3 -C 8 cycloalkenyl, unsaturated heterocyclic(C ⁇ -C6 alkylenyl)-, heterocyclic(C ⁇ -C 6 alkoxy)-, unsaturated heterocyclic(C ⁇ -C6 alkoxy)-, phenyl, phenyKCi-C ⁇ alkylenyl)-, naphthyl, naphthyKCi-C ⁇ alkylenyl)-, phenoxy(C ⁇ -C6 alkylenyl)-, naphthyloxy(C ⁇ -C 6 alkylenyl)-, benzoyKCi-C ⁇ alkylenyl)
  • C 1 -C 12 alkyl, phenyl, naphthyl, phenoxy, naphthyloxy, benzoyl, C 3 -C8 cycloalkyl, C 3 -C 8 cycloalkenyl, heterocyclic(C ⁇ -C6 alkoxy)-, unsaturated heterocyclic(C ⁇ -C ⁇ alkoxy)-, heterocyclic, or unsaturated heterocyclic moieties may be substituted with one or more groups selected from the group consisting of Ci-C ⁇ alkyl, Ci-C ⁇ alkoxy, phenyl, naphthyl, phenyKCi-C ⁇ alkylenyl)-, naphthyKCi-C ⁇ alkylenyl)-, halo, trifluoromethyl, C2-C7 alkenyl, C2-C7 alkynyl, Ci-C ⁇ alkoxy, heterocyclic, unsaturated heterocyclic, heterocyclic(C ⁇ -C6 alkyleny
  • R 2 may also be -(CH 2 ) n -NR 7 R 8 , where, n is 0 to 10, and
  • R 7 and R 8 are independently hydrogen, Ci-C ⁇ alkyl, C 2 -C7 alkanoyl, Ci-C ⁇ alkoxy, heterocyclic(C ⁇ -C6 alkylenyl)-, unsaturated heterocyclic(C ⁇ -C6 alkylenyl)-, phenyl, phenyKCi-C ⁇ alkylenyl)-, naphthyl, naphthyl(C ⁇ -C 6 alkylenyl)-, phenoxy(C ⁇ -C ⁇ alkylenyl)-, naphthyloxy(C ⁇ -C6 alkylenyl)-, benzoyKCi-C ⁇ alkylenyl)-, heterocyclic(C ⁇ -C 6 alkoxy)-, unsaturated heterocyclic(C ⁇ -C6 alkoxy)-, Ci-C ⁇ haloalkyl, C2-C7 alkenyl, C2-C7 alkynyl, C 3 -C8 cycloalken
  • R 3 , R 4 , R 5 , and R 6 are independently hydrogen, halo, C ⁇ -C 6 alkyl, Ci-C ⁇ alkoxy, C2-C7 alkenyl, C2-C7 alkynyl, C2-C7 alkanoyl,
  • This invention also encompasses, in additional embodiments, the novel compounds of Formula I, and the salts and solvates thereof, as well as pharmaceutical formulations comprising a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, in combination with one or more pharmaceutically acceptable carriers, excipients, or diluents therefor.
  • the current invention concerns the discovery that a select group of substituted benzimidazoles, those of Formula I, are useful as neuropeptide Y receptor antagonists.
  • C 1 -C12 alkyl refers to straight or branched, monovalent, saturated aliphatic chains of 1 to 12 carbon atoms and includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, and hexyl.
  • C1-C12 alkyl includes within its definition the terms "Ci-C ⁇ alkyl” and "C1-C4 alkyl”.
  • C2-C7 alkanoyloxy represents a straight or branched alkyl chain having from one to six carbon atoms attached to a carbonyl moiety joined through an oxygen atom.
  • Typical C 2 -C7 alkanoyloxy groups include acetoxy, propanoyloxy, isopropanoyloxy, butanoyloxy, J-butanoyloxy, pentanoyloxy, hexanoyloxy, 3-methylpentanoyloxy and the like.
  • C 3 -C 8 cycloalkyl represents a saturated hydrocarbon ring structure containing from three to eight carbon atoms.
  • Typical C 3 -C8 cycloalkyl groups include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
  • carbamoyl refers to a group of the structure -NH-C(O)-.
  • C2-C7 carbamoyl refers to a group of the structure (Ci-C ⁇ alkyl )-NH-C(O)-
  • Halo represents chloro, fluoro, bromo or iodo.
  • Ci-C ⁇ haloalkyl refers to a straight or branched, monovalent, saturated aliphatic chains of 1 to 6 carbon atoms substituted with one or more halo groups.
  • C1-C10 alkylthio represents a straight or branched alkyl chain having from one to ten carbon atoms attached to a sulfur atom.
  • Typical Ci-Cin alkylthio groups include methylthio, ethylthio, propylthio, isopropylthio, butylthio and the like.
  • the term “C 1 -C1 0 alkylthio” includes within its definition the term “Ci-C ⁇ alkylthio" and "C1-C3 alkylthio".
  • C1-C12 alkylenyl refers to a straight or branched, divalent, saturated aliphatic chains of 1 to 12 carbon atoms and includes, but is not limited to, methylenyl, ethylenyl, propylenyl, isopropylenyl, butylenyl, isobutylenyl, J-butylenyl, pentylenyl, isopentylenyl, hexylenyl, octylenyl, 3-methyloctylenyl, decylenyl.
  • the term "Ci-C ⁇ alkylenyl” is encompassed within the term "C1-C 1 2 alkylenyl”.
  • C1-C 1 0 alkylamino represents a group of the formula
  • C ⁇ -C ⁇ o alkyl wherein a chain having from one to ten carbon atoms is attached to an amino group.
  • Typical C 1 -C4 alkylamino groups include methylamino, ethylamino, propylamino, isopropylamino, butylamino, sec-butylamino and the like.
  • C2-C10 alkenyl as used herein represents a straight or branched, monovalent, unsaturated aliphatic chain having from two to ten carbon atoms.
  • Typical C2-C10 alkenyl groups include ethenyl (also known as vinyl), 1-methylethenyl, 1-methyl- 1-propenyl, 1-butenyl, 1-hexenyl, 2-methyl-2-propenyl, 1-propenyl, 2-propenyl, 2-butenyl, 2-pentenyl, and the like.
  • C2-C10 alkynyl represents a straight or branched, monovalent, unsaturated aliphatic chain having from two to ten carbon atoms with at least one triple bond.
  • Typical C2-C 1 0 alkynyl groups include ethynyl, 1-methylethenyl, 1-propynyl,
  • C 3 -C 8 cycloalkenyl represents a hydrocarbon ring structure containing from three to eight carbon atoms and having at least one double bond within that ring, which is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halo, halo(C ⁇ -C4 alkyl), C 1 -C4 alkyl, C 1 -C4 alkoxy, carboxy, C 1 -C 4 alkoxycarbonyl, carbamoyl, N-(C ⁇ -C4 alkyl )carbamoyl, amino, C 1 -C 4 alkylamino, di(C ⁇ -C 4 alkyDamino or -(CH 2 ) a -R y where a is 1, 2, 3 or 4 and Ry is hydroxy, C1-C 4 alkoxy, carboxy
  • Ci-C ⁇ alkylamino represents a straight or branched alkylamino chain having from one to six carbon atoms attached to an amino group.
  • Typical Ci-C ⁇ alkyl-amino groups include methylamino, ethylamino, propylamino, isopropylamino, butylamino, sec-butylamino and the like.
  • Ci-C ⁇ alkylamino encompasses within this term “C1-C4 alkylamino”.
  • Ci-C ⁇ alkoxy represents a straight or branched alkyl chain having from one to six carbon atoms attached to an oxygen atom.
  • Typical Ci-C ⁇ alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, J-butoxy, pentoxy and the like.
  • the term "Ci-C ⁇ alkoxy” includes within its definition the term “C 1 -C3 alkoxy”.
  • C2-C7 alkanoyl represents a straight or branched alkyl chain having from one to six carbon atoms attached to a carbonyl moiety.
  • Typical C2-C7 alkanoyl groups include ethanoyl, propanoyl, isopropanoyl, butanoyl, £-butanoyl, pentanoyl, hexanoyl, 3-methylpentanoyl and the like.
  • Ci-C ⁇ alkoxycarbonyl represents a straight or branched alkoxy chain having from one to six carbon atoms attached to a carbonyl moiety.
  • Typical alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, i-butoxycarbonyl and the like.
  • C 3 -C 8 cycloalkyl represents a saturated hydrocarbon ring structure containing from three to eight carbon atoms.
  • Typical C 3 -C8 cycloalkyl groups include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
  • heterocycle represents an unsubstituted or substituted stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic ring which is saturated and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized and including a bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the heterocyclic ring may be attached at any heteroatom or carbon atom which affords a stable structure.
  • the hetero-cycle is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halo, halo(C ⁇ -C 4 )-alkyl, C 1 -C 4 alkyl, C1-C 4 alkoxy, carboxy, C 1 -C4 alkoxy ⁇ carbonyl, carbamoyl, N-(C ⁇ -C4)-alkylcarbamoyl, amino, C1-C4 alkylamino, di(C ⁇ -C 4 )alkylamino or -(CH 2 )a-R d where a is 1, 2, 3 or 4; and R d is hydroxy, C1-C4 alkoxy, carboxy, C 1 -C 4 alkoxycarbonyl, amino, carbamoyl, C1-C4 alkylamino or di(C ⁇ -C 4 )alkylamino.
  • the term "unsaturated heterocycle” represents an unsubstituted or substituted stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic ring which has one or more double bonds and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quartemized and including a bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the unsaturated heterocyclic ring may be attached at any heteroatom or carbon atom which affords a stable structure.
  • the unsaturated heterocycle is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halo, Ci-C ⁇ haloalkyl, C1-C4 alkyl, C1-C4 alkoxy, carboxy, C1-C 4 alkoxycarbonyl, carbamoyl, N-(C ⁇ -C4)alkylcarbamoyl, amino, Ci- C4 alkylamino, di(C ⁇ -C 4 )alkylamino or -(CH2) a -R e where a is 1, 2, 3 or 4; and R e is hydroxy, C 1 -C 4 alkoxy, carboxy, C1-C4 alkoxycarbonyl, amino, carbamoyl, C 1 -C4 alkylamino or di(C ⁇ -C4)alkylamino.
  • substituents independently selected from halo, Ci-C ⁇ haloalkyl, C1-C4 alkyl, C1-C4 alkoxy
  • heterocycles and unsaturated heterocycles include piperidinyl, piperazinyl, azepinyl, pyrrolyl, 4- piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoazolyl, furyl, t
  • amino-protecting group refers to substituents of the amino group commonly employed to block or protect the amino functionality while reacting other functional groups on the compound.
  • amino-protecting groups include formyl, trityl, phthalimido, trichloroacetyl, chloroacetyl, bromoacetyl, iodoacetyl, and urethane-type blocking groups such as benzyloxycarbonyl, 4-phenylbenzyloxy carbonyl, 2-methylbenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl, 4-nitrobenzyloxy carbonyl
  • amino-protecting group employed is usually not critical so long as the derivatized amino group is stable to the condition of subsequent reactions on other positions of the intermediate molecule and can be selectively removed at the appropriate point without disrupting the remainder of the molecule including any other amino-protecting groups.
  • Preferred amino-protecting groups are trityl, f-butoxycarbonyl (BoC), allyloxycarbonyl and benzyloxycarbonyl. Further examples of groups referred to by the above terms are described by E. Haslam,
  • carboxy-protecting group refers to substituents of the carboxy group commonly employed to block or protect the carboxy functionality while reacting other functional groups on the compound.
  • carboxy-protecting groups include methyl, jD-nitrobenzyl, p-methylbenzyl, p-methoxy-benzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, 2,4,6-trimethylbenzyl, pentamethylbenzyl, 3,4-methylenedioxybenzyl, benzhydryl,
  • hydroxy-protecting groups refers to substitents of the hydroxy group commonly employed to block or protect the hydroxy functionality while reacting other functional groups on the compound. Examples of such hydroxy-protecting groups include methoxymethyl, benzyloxymethyl, methoxyethoxymethyl,
  • the compounds of the present invention may have one or more asymmetric centers. As a consequence of these chiral centers, those compounds of the present invention occur as racemates, mixtures of enantiomers and as individual enantiomers, as well as diastereomers and mixtures of diastereomers. All asymmetric forms, individual isomers and combinations thereof, are within the scope of the present invention.
  • the terms "R” and “S” are used herein as commonly used in organic chemistry to denote specific configuration of a chiral center.
  • the term “R” (rectus) refers to that configuration of a chiral center with a clockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group.
  • S sinister
  • S refers to that configuration of a chiral center with a counterclockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group.
  • the priority of groups is based upon their atomic number (in order of decreasing atomic number).
  • a partial list of priorities and a discussion of stereochemistry is contained in NOMENCLATURE OF ORGANIC COMPOUNDS: PRINCIPLES AND PRACTICE, (J.H. Fletcher, et al.. eds., 1974) at pages 103-120.
  • the older D-L system may also be used in this document to denote absolute configuration, especially with reference to amino acids.
  • a Fischer projection formula is oriented so that the number 1 carbon of the main chain is at the top.
  • the prefix "D” is used to represent the absolute configuration of the isomer in which the functional (determimng) group is on the right side of the carbon atom at the chiral center and "L", that of the isomer in which it is on the left.
  • the skilled practitioner can proceed by one of two routes.
  • the practitioner may first prepare the mixture of enantiomers and then separate the two enantiomers.
  • a commonly employed method for the resolution of the racemic mixture (or mixture of enantiomers) into the individual enantiomers is to first convert the enantiomers to diastereomers by way of forming a salt with an optically active salt or base. These diastereomers can then be separated using differential solubility, fractional crystallization, chromatography, or like methods. Further details regarding resolution of enantiomeric mixtures can be found in J. Jacques, et al.. ENANTIOMERS, RACEMATES, AND RESOLUTIONS, (1991).
  • the practitioner of this invention may also choose an enantio specific protocol for the preparation of the compounds of Formula I.
  • a protocol employs a synthetic reaction design which maintains the chiral center present in the starting material in a desired orientation.
  • These reaction schemes usually produce compounds in which greater than 95 percent of the title product is the desired enantiomer.
  • this invention includes methods employing the pharmaceutically acceptable salts of the compounds defined by Formula I as well as salts of the compounds of Formula II.
  • a compound of this invention can possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly react with any of a number of organic and inorganic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salt refers to salts of the compounds of the above formula which are substantially non-toxic to living organisms.
  • Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a pharmaceutically acceptable mineral or organic acid or an organic or inorganic base. Such salts are known as acid addition and base addition salts.
  • Acids commonly employed to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like
  • organic acids such as p-toluenesulfonic, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
  • salts examples include the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, hydrochloride, dihydrochloride, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylprop
  • Preferred pharmaceutically acceptable acid addition salts are those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid and methanesulfonic acid.
  • Base addition salts include those derived from inorganic bases, such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and the like.
  • bases useful in preparing the salts of this invention thus include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like.
  • the potassium and sodium salt forms are particularly preferred.
  • any salt of this invention is usually not of a critical nature, so long as the salt as a whole is pharmacologically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole.
  • This invention further encompasses methods employing the pharmaceutically acceptable solvates of the compounds of Formula I.
  • Many of the compounds of Formula I can combine with solvents such as water, methanol, ethanol and acetonitrile to form pharmaceutically acceptable solvates such as the corresponding hydrate, methanolate, ethanolate and acetonitrilate.
  • a prodrug is a drug which has been chemically modified and may be biologically inactive at its site of action, but which may be degraded or modified by one or more enzymatic or other in vivo processes to the parent bioactive form.
  • This prodrug should have a different pharmacokinetic profile than the parent, enabling easier absorption across the mucosal epithelium, better salt formation or solubility, or improved systemic stability (an increase in plasma half-life, for example).
  • ester or amide derivatives which may be cleaved by esterases or lipases; 2) peptides which may be recognized by specific or nonspecific proteases; or
  • the compounds of the present invention are derivatives of benzimidazole which are named and numbered according to the RING INDEX, The American Chemical Society, as follows.
  • R 1 is phenyl, naphthyl, phenyKCi-C ⁇ alkylenyl)-, naphthyKCi-C ⁇ alkylenyl)-, phenyKCi-C ⁇ alkoxy)-, naphthyKCi-C ⁇ alkoxy)-, phenoxy(C ⁇ -C 6 alkylenyl)-, naphthyloxy(C ⁇ -C6 alkylenyl)-, or substituted derivatives thereof; b) R 2 is phenyl, heterocyclic, unsaturated heterocyclic, phenyKCi-C ⁇ alkylenyl)-, naphthyKCi-C ⁇ alkylenyl)-, phenyKCi-C ⁇ alkoxy)-, heterocyclic(Ci-Ce alkylenyl)-, unsaturated heterocyclic(C ⁇ -C6 alkylenyl)-, heterocyclic
  • the preferred compounds of this invention are those compounds which are employed in the preferred methods of this invention.
  • benzimidazole In the scientific literature derivatives of benzimidazole are already known to possess different biological activities, such as analgesic and antiinflammatory activity (Japan Kokai 75,126,682; United States Patent 4,925,853), gastric antisecretory activity (European Patent Publication 246,126), antihistaminic activity (United States Patents
  • the compounds of Formula I can be prepared by processes known in the literature. See f e.g.. G.W.H. Cheeseman and R.F. Cookson, THE CHEMISTRY OF HETEROCYCLIC COMPOUNDS, (A. Weissberger, et al.. eds. 1979).
  • Suitable solvents include ethanol, isopropanol, glacial acetic acid, benzene, toluene, chlorobenzene, glycol, ethylene glycol, dimethyl ether, diethyl ether, dimethylformamide, chloroform, ethyl acetate, and the like.
  • a condensation agent such as phosphorous oxychloride, thionyl chloride, p-toluenesulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid, phosphorous pentoxide, methanesulfonyl hydroxide, methanesulfonyl chloride, and the like.
  • the cyclization reaction may also optionally be performed in the presence of a base such as sodium hydroxide, sodium mesylate, or potassium tert-butylate.
  • R 2 is phenyl a derivative of N- phenyl-o-phenylenediamine was used as the starting material for the cyclization reaction.
  • the examples infra provide sufficient guidance in the preparation of those compounds of Formula I wherein all of R 3 , R 4 , R 5 , and R 6 are hydrogen.
  • R 4 , R 5 , and R 6 is not hydrogen, can be prepared by methods taught in the literature.
  • the compounds of this invention wherein phenyl portion ofthe benzimidazole is substituted with C 2 -C7 alkanoyl can be prepared from the appropriate keto o-phenylenediamine of the formula
  • the keto benzimidazole reactants can be prepared from acetanilide by a Friedel-Crafts acylation with the appropriate derivative of C 2 -C7 alkanoic acid.
  • the resulting 4-keto acetanilide is nitrated to give a 2-nitro-4-ketoacetanilide.
  • the acetanilide is hydrolyzed to give a 2-nitro-4-ketoaniline, which can then be catalytically hydrogenated to yield a 4-keto-o-phenylenediamine which can then be ring closed to provide the 5 or 6-substituted benzimidazole.
  • Those compounds of Formula III wherein phenyl portion of the benzimidazole is substituted with alkyl or alkylenyl may be prepared by means of a Friedel-Crafts alkylation with the appropriate derivative of the substituting moiety using standard procedures, usually employing an alkyl halide or an olefin in the presence of a catalyst such as aluminum chloride, aluminum bromide or another Lewis acid.
  • a catalyst such as aluminum chloride, aluminum bromide or another Lewis acid.
  • An alternative strategy for preparing those compounds of Formula I wherein R 5 is C ⁇ -C 6 alkoxy, R 7 R 8 N-(C ⁇ -C 6 alkoxy)-, or heterocyclic-(C ⁇ -C 6 alkoxy)-, or a substituted derivative thereof involves first reacting a 3-nitro-4-aminophenol with an acyl halide in the presence of a base
  • the ester moiety serving as a hydroxy-protecting group for subsequent reactions.
  • the nitro group is then reduced to an amino group, usually by catalytic hydrogenation.
  • those compounds of Formula I in which R 2 is alkyl or substituted alkyl may be produced by alkylation of an aromatic amine with alkyl halide or tosylate, or the like, in the presence of a suitable base, such as trialkylamine, potassium carbonate, 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), and the like.
  • a suitable base such as trialkylamine, potassium carbonate, 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), and the like.
  • Suitable cyclization catalysts include phosphorous oxychloride, thionyl chloride, phosphorous pentoxide, phosphorous pentachloride, and other like strong dehydrating agents.
  • a preferred method of cleaving this ester is by incubation of the intermediate in a basic solution, such as IN sodium hydroxide, or a weaker base such as potassium carbonate.
  • a basic solution such as IN sodium hydroxide, or a weaker base such as potassium carbonate.
  • the hydroxy group at the 6- position is then substituted using an alkyl or aryl halide, resulting in a compound of Formula I.
  • Those compounds of Formula I wherein R 2 is alkyl or substituted alkyl may alternatively be prepared by the direct alkylation of a benzimidazole wherein the nitrogen at the 1-position is substituted with a hydrogen.
  • This type of alkylation is usually performed by the reaction of the benzimidazole with an alkyl halide in the presence of a strong base, such as sodium hydride.
  • This reaction is usually performed in a polar aprotic solvent, such as N,N-dimethylformamide, dimethyl sulf oxide, dimethylacetamide, hexamethylphosphoric triamide, and the like.
  • Proton nuclear magnetic resonance (*H NMR) spectra were obtained on a GE E-300 spectrometer at 300.15 MHz, a Bruker AM-500 spectrometer at 500 MHz, or a Bruker AC-200P spectrometer at 200 MHz.
  • NMR proton nuclear magnetic resonance
  • Free atom bombardment mass spectroscopy (FAB) was performed on a VG ZAB-2SE instrument.
  • Field desorption mass spectroscopy (FDMS) was performed using either a VG 70SE or a Varian MAT 731 instrument.
  • Optical rotations were measured with a Perkin-Elmer 241 polarimeter. Chromatographic separation on a Waters Prep 500 LC was generally carried out using a linear gradient of the solvents indicated in the text unless otherwise specified. The reactions were generally monitored for completion using thin layer chromatography (TLC). Thin layer chromatography was performed using E. Merck Kieselgel 60 F254 plates, 5 cm x 10 cm,
  • the title compound was prepared essentially as described in Preparation 1 except that an equimolar amount of 4- chlorobenzonitrile was employed instead of the benzyl cyanide employed therein.
  • the title compound was prepared essentially as described in Preparation 1 except that an equimolar amount of 4-chlorobenzyl cyanide was employed instead of the benzyl cyanide employed therein.
  • Ethyl-3-pyridylacetate (lOOg, 0.606 mol) was dissolved in ethanol (1.8 liters), treated with 5% rhodium on alumina (100 g) and hydrogenated at 60°C and 60 psi hydrogen gas overnight. The catalyst was removed by filtration and the solvent evaporated to give a brown liquid (101.4 g, 98%). The brown liquid was dissolved in ethyl acetate (600 ml) and treated with L-(+)-mandelic acid in warm ethyl acetate (600 ml). After cooling in the refrigerator for four hours, the solid was collected and the crystallization fluid reserved for processing to the other enantiomer, infra.
  • the aqueous fraction was extracted with diethyl ether.
  • the organic fractions were combined, washed with water, a saturated sodium bicarbonate solution, and then brine, and then dried over magnesium sulfate.
  • the solvents were removed in vacuo to give the desired title product was a clear liquid. NMR was consistent with proposed title structure.
  • triphenylphosphine (19.95 g, 76 mmol) in anhydrous methylene chloride (110 ml) was added bromine dropwise until the solution turned pale yellow. A few crystals of triphenylphosphine were added to the mixture to bring the color back to white.
  • a suspension of (3'S) 3-[l-(t- butoxycarbonyl)piperidin-3-yl]propanol (13.2 g, 54.4 mmol) and pyridine (8.0 g, 76 mmol) in dry methylene chloride (110 ml). The resulting mixture was stirred for five hours while warming to room temperature. The reaction was stopped by adding water (200 ml).
  • the reaction mixture was poured into water (20 ml).
  • the organic fraction was extracted wtih diethyl ether (3 x 50 ml).
  • the organic fractions were combined, washed with water (2 x 20 ml), and then brine (1 x 20 ml), and then dried over sodium sulfate.
  • the solvents were removed in vacuo to yield a white solid as a crude product. No further purification was performed on this product.
  • n 0, 1, or 2
  • APG is an amino protecting group
  • reaction mixture was then poured into water (10 ml).
  • the organic fraction was extracted with diethyl ether (3 x 15 ml).
  • the organic fractions were combined, washed with water (2 x 10 ml), brine (1 x 10 ml), and then dried over sodium sulfate.
  • the solvents were removed in vacuo, leaving a light brown crude material which was further purified by flash chromatography to yield the desired title product as a white crystalline solid in 70-100% yield.

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Abstract

L'invention concerne une série de benzimidazoles substitués qui sont utiles dans le traitement ou la prévention d'un état associé à un excès de neuropeptides Y. L'invention concerne également des procédés mettant en application ces benzimidazoles substitués, ainsi que des formulations pharmaceutiques comprenant un ou plusieurs de ces composés en tant que principe actif.
EP97905573A 1996-01-09 1997-01-09 Antagonistes benzimidazolyles du recepteur du neuropeptide y Withdrawn EP0871442A1 (fr)

Applications Claiming Priority (5)

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GBGB9600344.7A GB9600344D0 (en) 1996-01-09 1996-01-09 Benzimidzolyl neuropeptide y receptor antagonists
GB9600344 1996-01-09
US2163696P 1996-07-12 1996-07-12
US21636P 1996-07-12
PCT/US1997/000511 WO1997025041A1 (fr) 1996-01-09 1997-01-09 Antagonistes benzimidazolyles du recepteur du neuropeptide y

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Families Citing this family (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU6309698A (en) * 1997-03-12 1998-09-29 Banyu Pharmaceutical Co., Ltd. Drugs containing aminopyridine derivatives as the active ingredient
JP3711238B2 (ja) 1997-08-05 2005-11-02 ファイザー・プロダクツ・インク 神経ペプチドＹ受容体アンタゴニストとしての４−アミノピロ−ル（３，２−ｄ）ピリミジン
SE9703414D0 (sv) * 1997-09-23 1997-09-23 Astra Ab New compounds
DE19801648A1 (de) * 1998-01-17 1999-07-22 Bayer Ag alpha-Substituierte Lactone
US6187777B1 (en) 1998-02-06 2001-02-13 Amgen Inc. Compounds and methods which modulate feeding behavior and related diseases
WO2002046168A1 (fr) * 2000-12-07 2002-06-13 Astrazeneca Ab Composes therapeutiques de benzimidazole
TW593278B (en) * 2001-01-23 2004-06-21 Wyeth Corp 1-aryl-or 1-alkylsulfonylbenzazole derivatives as 5-hydroxytryptamine-6 ligands
WO2003104193A1 (fr) 2002-06-05 2003-12-18 F. Hoffmann-La Roche Ag Derives de 1-sulfonyl-4-aminoalcoxy-indole et leur utilisation comme modulateurs des recepteurs 5-ht6 en traitement de troubles du snc
JP4806628B2 (ja) 2003-05-05 2011-11-02 プロビオドルグ エージー グルタミニルシクラーゼ阻害剤
AU2004290499C1 (en) 2003-11-03 2011-02-24 Probiodrug Ag Combinations useful for the treatment of neuronal disorders
CA2554809C (fr) 2004-02-05 2014-04-29 Probiodrug Ag Nouveaux inhibiteurs de la glutaminyl-cyclase comportant de la n thiouree alkyle et de l'imidazolyl substitue par thioamide
CA2555409A1 (fr) 2004-02-19 2005-09-01 Banyu Pharmaceutical Co., Ltd. Nouveau derive de sulfonamide
US20070049593A1 (en) 2004-02-24 2007-03-01 Japan Tobacco Inc. Tetracyclic fused heterocyclic compound and use thereof as HCV polymerase inhibitor
US7659263B2 (en) 2004-11-12 2010-02-09 Japan Tobacco Inc. Thienopyrrole compound and use thereof as HCV polymerase inhibitor
EP2089383B1 (fr) 2006-11-09 2015-09-16 Probiodrug AG Dérivés 3-hydr0xy-1,5-dihydr0-pyrr0l-2-one utiles en tant qu' inhibiteurs de la glutaminyl-cyclase dans le traitement des ulcères, du cancer et d'autres maladies
DK2091948T3 (da) 2006-11-30 2012-07-23 Probiodrug Ag Nye inhibitorer af glutaminylcyclase
CA2679446C (fr) 2007-03-01 2016-05-17 Probiodrug Ag Nouvelle utilisation d'inhibiteurs de la glutaminyl cyclase
US9656991B2 (en) 2007-04-18 2017-05-23 Probiodrug Ag Inhibitors of glutaminyl cyclase
CA2731184C (fr) 2008-08-22 2017-03-21 Baxter International Inc. Derives de carbonate de benzyle polymeriques
MX2012002993A (es) 2009-09-11 2012-04-19 Probiodrug Ag Derivados heterociclicos como inhibidores de ciclasa glutaminilo.
WO2011107530A2 (fr) 2010-03-03 2011-09-09 Probiodrug Ag Nouveaux inhibiteurs
JP5688745B2 (ja) 2010-03-10 2015-03-25 プロビオドルグ エージー グルタミニルシクラーゼ（ｑｃ、ｅｃ２．３．２．５）の複素環阻害剤
EP2560953B1 (fr) 2010-04-21 2016-01-06 Probiodrug AG Inhibiteurs de glutaminyl cyclase
WO2012047538A1 (fr) 2010-10-06 2012-04-12 Glaxosmithkline Llc Dérivés de benzimidazole utilisés comme inhibiteurs de pi3 kinase
ES2570167T3 (es) 2011-03-16 2016-05-17 Probiodrug Ag Derivados de benzimidazol como inhibidores de glutaminil ciclasa
EP2691375B1 (fr) 2011-03-31 2016-03-16 Bayer Intellectual Property GmbH Benzimidazoles substitués en tant qu'inhibiteurs de kinase mps1
CN103965113A (zh) * 2014-05-06 2014-08-06 四川大学 1-羟乙基-2-取代苯氧甲基苯并咪唑类化合物及其制备方法
ES2812698T3 (es) 2017-09-29 2021-03-18 Probiodrug Ag Inhibidores de glutaminil ciclasa
JP6400869B1 (ja) * 2018-02-23 2018-10-03 日本曹達株式会社 ４，５−ジシアノ−２−（フルオロアルキル）イミダゾールの製造方法

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4772703A (en) * 1986-01-27 1988-09-20 American Home Products Corporation 2-(phenoxymethyl)-quinazolines as antiallergic and antiinflammatory agents

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9725041A1 *

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