WO1997009308A1 - Antagonistes du recepteur du neuropeptide y indolyle - Google Patents

Antagonistes du recepteur du neuropeptide y indolyle Download PDF

Info

Publication number
WO1997009308A1
WO1997009308A1 PCT/US1996/014163 US9614163W WO9709308A1 WO 1997009308 A1 WO1997009308 A1 WO 1997009308A1 US 9614163 W US9614163 W US 9614163W WO 9709308 A1 WO9709308 A1 WO 9709308A1
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
preparation
consistent
indole
theory
Prior art date
Application number
PCT/US1996/014163
Other languages
English (en)
Inventor
Thomas C. Britton
Robert F. Bruns, Jr.
Donald R. Gehlert
Philip A. Hipskind
Karen L. Lobb
James A. Nixon
Paul L. Ornstein
Edward C. R. Smith
Hamideh Zarrinmayeh
Dennis M. Zimmerman
Original Assignee
Eli Lilly And Company
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from GBGB9523999.2A external-priority patent/GB9523999D0/en
Priority to IL12072496A priority Critical patent/IL120724A0/xx
Priority to EP96930691A priority patent/EP0789688A4/fr
Priority to MX9703186A priority patent/MX9703186A/es
Priority to AU69650/96A priority patent/AU717422B2/en
Priority to JP9511344A priority patent/JPH10508321A/ja
Application filed by Eli Lilly And Company filed Critical Eli Lilly And Company
Priority to NZ318228A priority patent/NZ318228A/xx
Priority to HU9701714A priority patent/HUP9701714A3/hu
Priority to CZ971328A priority patent/CZ132897A3/cs
Priority to BR9606619A priority patent/BR9606619A/pt
Publication of WO1997009308A1 publication Critical patent/WO1997009308A1/fr
Priority to NO972016A priority patent/NO308296B1/no

Links

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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/12—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C07D209/16—Tryptamines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an alkyl or cycloalkyl radical attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • 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
    • C07D403/06—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 carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D417/02—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 two hetero rings
    • C07D417/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems

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-specific, not binding peptide YY. This receptor is likely to be present in the adrenal tissues, medulla, heart, and brain stem, among other areas.
  • 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 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 b is hydrogen, CI-C ⁇ alkyl, Ci-C ⁇ alkoxy, C2-C6 alkanoyl, trifluoromethyl, hydroxy, or halo;
  • R 1 is hydrogen, Ci-C ⁇ alkyl, or -(CH ) V -R la ;
  • R la is phenyl, naphthyl, hexamethyleneiminyl, piperazinyl, heptamethyleneiminyl, imidazolinyl, piperidinyl, tryptolinyl, pyrrolidinyl, quinuclidinyl, or morpholinyl, any one of which phenyl, naphthyl, hexamethyleneiminyl, piperazinyl, heptamethyleneiminyl, imidazolinyl, piperidinyl, tryptolinyl, pyrrolidinyl, quinuclidinyl, or morpholinyl groups may be substituted with one or more moieties selected from the groups consisting of
  • said said said phenyl, benzyl, or C3-C 8 cycloalkyl being optionally substituted with one, two, or three moieties independently selected from the group consisting of Ci-C ⁇ alkyl, halo, or CI-C ⁇ alkoxy,
  • R la may be substituted with -(CH 2 ) W -R lb > where w is 1 to 12 and R lb is piperidinyl, pyrimidyl, pyrrolidinyl, Ci-C ⁇ alkoxy, Ci-C ⁇ alkylthio, di[di(C ⁇ - C ⁇ alkyl)amino(C ⁇ -C6 alkylenyl)]amino, di(C ⁇ -C 6 alkyl)amino ( C ⁇ -C6 alkylenyl )amino, phenyl, C 3 -C 8 cycloalkyl, pyrrolidinyl, and acetamido,
  • said phenyl, or C 3 -C 8 cycloalkyl being optionally substituted with one, two, or three moieties independently selected from the group consisting of Ci-C ⁇ alkyl, halo, or Ci-C ⁇ alkoxy;
  • A is a bond, -(CH 2 ) m or -C(O)-;
  • a 1 is a bond, -NR a -, -0-, -(CH 2 ) m -, or -S(0) n -;
  • q 0 to 6;
  • n 0, 1, or 2;
  • n 0 to 6;
  • s is 0 to 6;
  • R a is hydrogen, Ci-C ⁇ alkyl, or C 2 -C6 alkanoyl
  • D is a bond, C 2 -C 4 alkenylenyl, or -C(X)(Y)-,
  • R c is hydrogen, benzyl, acetyl, benzoyl, or Ci-C ⁇ alkyl
  • one of X 1 and Y 1 is hydroxy and the other is hydrogen, or both X 1 and Y 1 are hydrogen, or X 1 and Y 1 combine to form
  • Rd is hydrogen or Ci-C ⁇ alkyl
  • R 2 is hydroxy, CI-C ⁇ alkyl, Ci-C ⁇ alkoxy, phenoxy, or a group of the formula
  • R 4 and R 5 are independently hydrogen, Ci-C ⁇ alkyl, phenyl, or phenyKCi-C ⁇ alkylenyl)-, or R 2 is a heterocyclic ring selected from the group consisting of hexamethyleneiminyl, piperazinyl, heptamethyleneiminyl, imidazolinyl, piperidinyl, 2 -tryptolinyl, pyrrolidinyl, quinuclidinyl, or morpholinyl;
  • any one of which hexamethyleneiminyl, piperazinyl, heptamethyleneiminyl, imidazolinyl, piperidinyl, 2- tryptolinyl, pyrrolidinyl, quinuclidinyl, or morpholinyl groups may be substituted with one or more moieties selected from the group consisting of Ci-C ⁇ alkyl, halo, trifluoromethyl, benzyl, phenyl, di(C ⁇ -C ⁇ alkyDamino, di(C ⁇ -C6 alkyl)amino(C ⁇ -C 6 alkylenyl)-, Ci-C ⁇ alkylamino(C ⁇ -C 6 alkylenyl)-, C2-C 6 alkanoyl, carboxamido, 2-aminoacetyl, C2-C 6 alkanoyloxy, Ci-C ⁇ alkoxycarbonyl-, Ci-C ⁇ alkylamino, C 3 -C 8 cycl
  • R 2 is a group of the formula
  • R a , R 5a , and R 6a are independently hydrogen, Ci-C ⁇ alkyl, trifluoromethyl, or Ci-C ⁇ alkoxy,
  • R a is hydrogen, Ci-C ⁇ alkyl, trifluoromethyl, or Ci-C ⁇ alkoxy and R a and R 6a combine to form, together with the mtrogen to which they are attached, pyrrolidinyl, piperidinyl, hexamethyleneiminyl, or heptamethyleneiminyl,
  • R a is oxygen, and R 5a and R 6a combine to form, together with the nitrogen to which they are attached, pyrrolidinyl, piperidinyl, hexamethyleneiminyl, or heptamethyleneiminyl;
  • R is phenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, C 3 -C 8 cycloalkyl, pyrazinyl, allyl, thiazolyl, furyl, pyrimidyl, pyridinyl, quinolinyl, isoquinolinyl, oxazolyl, pyridazinyl, imidazolyl, triazolyl, tetrazolyl, hexamethyleneiminyl, heptamethyleneiminyl, piperidinyl, pyrrolidinyl, quinuclidinyl, or morpholinyl,
  • R x and Ry are independently hydrogen, Ci-C ⁇ alkyl, phenyl, benzyl, piperidinyl, pyrrolidinyl, hexamethyleneiminyl, heptamethyleneiminyl, morpholinyl, piperazinyl, or C 3 -C8 cycloalkyl,
  • R x R y N is a ring selected from the group consisting of piperidinyl, pyrrolidinyl, hexamethyleneiminyl, heptamethyleneiminyl, azetidinyl, which may be attached to G at any appropriate place on the ring, G is C l-C 12 alkylenyl, C 2 -C 1 2 alkenylenyl, or C2-C 12 alkynylenyl, and
  • L is a bond, -O-, -S-, -S(O)-, -S(O) 2 -, or -NH-;
  • This invention also encompasses the novel compounds of Formula I as well as pharmaceutical formulations comprising a compound of Formula I in combination with one or more pharmaceutically acceptable carriers, diluents, or excipients therefor.
  • the current invention concerns the discovery that a select group of substituted indoles, those of Formula I, are useful as neuropeptide Y receptor antagonists.
  • 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, . -butoxy, pentoxy and the like.
  • Ci-C ⁇ alkoxy includes within its definition the terms “C1-C4 alkoxy” and "Ci- C 3 alkoxy”.
  • C 1 -C 12 alkyl refers to straight or branched, monovailing, 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.
  • C i-C 1 2 alkyl includes within its definition the terms "CI-CQ alkyl” and "C 1 -C 4 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, .-butanoyloxy, pentanoyloxy, hexanoyloxy, 3-methylpentanoyloxy and the like.
  • C3-C8 cycloalkyl represents a saturated hydrocarbon ring structure containing from three to eight carbon atoms.
  • Typical C3-C8 cycloalkyl groups include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
  • Halo represents chloro, fluoro, bromo or iodo.
  • Ci-C 1 0 alkylthio represents a straight or branched alkyl chain having from one to ten carbon atoms attached to a sulfur atom.
  • Typical Ci-Cio alkylthio groups include methylthio, ethylthio, propylthio, isopropylthio, butylthio and the like.
  • the term "C1-C1 0 alkylthio” includes within its definition the term “Ci-C ⁇ alkylthio" and "C 1 -C3 alkylthio".
  • C i-C 1 2 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, t butylenyl, pentylenyl, isopentylenyl, hexylenyl, octylenyl, 3-methyloctylenyl, decylenyl.
  • C1-C 6 alkylenyl is encompassed within the term “Ci-C 1 2 alkylenyl”.
  • Co alkylenyl or any term incorporating this designation, refers to a bond, for example "Cn-C ⁇ alkylenyl” refers to a bond or Ci-C ⁇ alkylenyl, as such is defined herein.
  • C i-C 10 alkylamino represents a group of the formula -NH(C ⁇ -C ⁇ o alkyl) wherein a chain having from one to ten carbon atoms is attached to an amino group.
  • Typical C1-C4 alkylamino groups include methylamino, ethylamino, propylamino, isopropylamino, butylamino, sec-butylamino and the like.
  • C2-C12 alkenyl as used herein represents a straight or branched, monovarrid, unsaturated aliphatic chain having from two to twelve carbon atoms.
  • Typical C 2 -C 12 alkenyl groups include ethenyl (also known as vinyl), 1-methylethenyl, 1-methyl- 1-propenyl, 1-butenyl, 1-hexenyl, 2-methyl-2-propenyl, 2,4-hexadienyl, 1-propenyl, 2-propenyl, 2-butenyl, 2-pentenyl, and the like.
  • C 2 -C 12 alkynyl represents a straight or branched, monovending, unsaturated aliphatic chain having from two to ten carbon atoms with at least one triple bond.
  • Typical C 2 -C 1 2 alkynyl groups include ethynyl, 1-propynyl, 1-butynyl, 1-hexynyl, 2-propynyl, 2-butynyl, 2-pentynyl, and the like.
  • C 2 -C 12 alkenylenyl represents a straight or branched, divalent, unsaturated aliphatic chain having from two to twelve carbon atoms.
  • C 2 -C1 2 alkynylenyl represents a straight or branched, divalent, unsaturated aliphatic chain having from two to ten carbon atoms with at least one triple bond.
  • C 2 -C 12 alkynylenyl groups include -C ⁇ C-, -CH 2 -C ⁇ C-, -CH2-C ⁇ C-CH 2 CH 2 -, and the like.
  • C 3 -C8 cycloalkenyl represents a hydrocarbon ring structure containing from three to eight carbon atoms and having at least one double bond within that ring.
  • 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, t butoxy, pentoxy and the like.
  • the term "Ci-C ⁇ alkoxy” includes within its definition the term “C 1 -C 3 alkoxy”.
  • C 2 -C 6 alkanoyl represents a straight or branched alkyl chain having from one to five carbon atoms attached to a carbonyl moiety.
  • Typical C2-C 6 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 Ci-C ⁇ alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, if -butoxycarbonyl and the like.
  • 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-phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl, 4-nitrobenzyloxy carbonyl
  • 2-(triphenylphosphino)-ethoxycarbonyl fluorenylmethoxy-carbonyl ("FMOC"), 2-(trimethylsilyl)ethoxycarbonyl, allyloxycarbonyl, l-(trimethylsilylmethyl)prop-l-enyloxycarbonyl, 5-benzisoxalylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl, cyclopropylmethoxycarbonyl, 4-(decyloxy)benzyloxycarbonyl, isobornyloxycarbonyl, 1-piperidyloxycarbonyl and the like; benzoylmethylsulfonyl group, 2-nitrophenylsulfenyl, diphenylphosphine oxide and like amino-protecting groups.
  • FMOC fluorenylmethoxy-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, .-butoxy carbonyl (t BoC, Boc, or t Boc), allyloxycarbonyl and benzyloxycarbonyl.
  • t BoC .-butoxy carbonyl
  • Boc Boc
  • allyloxycarbonyl allyloxycarbonyl
  • benzyloxycarbonyl benzyloxycarbonyl
  • carboxy-protecting groups include methyl, p -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, 4,4'-dimethoxybenzhydryl, 2,2',4,4'-tetramethoxybenzhydryl, .-butyl, .-amyl, trityl, 4-methoxytrityl, 4,4'-dimethoxytrityl,
  • 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.
  • hydroxy-protecting groups include methoxymethyl, benzyloxymethyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, methylthiomethyl, 2,2-dichloro-l,l- 5 difluoroethyl, tetrahydropyranyl, phenacyl, cyclopropylmethyl, allyl, Ci- C 6 alkyl, 2,6-dimethylbenzyl, o-nitrobenzyl, 4-picolyl, dimethylsilyl, ,-butyldimethylsilyl, levulinate, pivaloate, benzoate, dimethylsulfonate, dimethylphosphinyl, isobutyrate, adamantoate and tetrahydropyranyl. Further examples of these groups may be found in T
  • leaving group refers to a group of atoms that is displaced from a carbon atom by the attack of a nucleophile in a nucleophilic substitution reaction.
  • the term “leaving group” as 5 used in this document encompasses, but is not limited to, activating groups.
  • activating groups are well-known to those skilled in the art and may be, for example, succinimidoxy, phthalimidoxy, benzotriazolyloxy, benzenesulfonyloxy, methanesulfonyloxy, toluenesulfonyloxy, azido, or -O-CO-(C 4 -C 7 alkyl).
  • the compounds of the present invention are derivatives of indole which are named and numbered according to the RING INDEX, The American Chemical Society, as follows.
  • 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.
  • 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.
  • the term “S” (sinister) 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).
  • 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 (determining) 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).
  • this invention may also choose an enantiospecific 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 the pharmaceutically acceptable salts of the compounds defined by Formula I.
  • 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 acid, 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 acid, 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, 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, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate
  • Salts of amine groups may also comprise quarternary ammonium salts in which the amino nitrogen carries a suitable organic group such as an alkyl, alkenyl, alkynyl, or aralkyl moiety.
  • 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 the pharmaceutically acceptable solvates of the compounds of Formulas I.
  • Many of the Formula I compounds 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.
  • This invention also encompasses the pharmaceutically acceptable prodrugs of the compounds of Formula I.
  • 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).
  • such chemical modifications include: 1) ester or amide derivatives which may be cleaved by esterases or lipases;
  • R is hydrogen, chloro, fluoro, methyl, ethyl, hydroxy, or acetyl
  • R 1 is methyl, ethyl, or R la is phenyl, piperidinyl, pyrrolidinyl, hexamethyleneiminyl, piperazinyl, and v is 1 to 6;
  • a 1 is a bond, -NH-, -N(CH 3 K -S-, or -0-;
  • A is -CH 2 - or -CH 2 CH 2 -;
  • g) s is 0, 1, 2, or 3;
  • D is a bond, -C(O)-, -CH(OH)-, or -CH 2 -;
  • R 2 is a group of the formula -NR 4 R5 or -N+R 4a R 5a R 6a ;
  • R 4 and R 5 are independently hydrogen, methyl, ethyl, benzyl, or combine to form, together with the nitrogen to which they are attached, a piperidinyl, pyrrolidinyl, or hexamethyleneiminyl group;
  • R 4a , R 5a , R 6a are independently hydrogen, methyl, ethyl, or R 5a and R 6a combine to form, together with the nitrogen to which they are attached, a piperidinyl, pyrrolidinyl, or hexamethyleneiminyl group; and
  • R is phenyl, piperidinyl, pyrrolidinyl, hexamethyleneiminyl, heptamethyleneiminyl, naphthyl, thiazolyl, furyl, quinolinyl, isoquinolinyl, morpholinyl, cyclohexyl, cyclopentyl, pyrazinyl, triazolyl, or quinuclidinyl;
  • the preferred methods of the present invention are those methods employing compounds of Formula I in which
  • R b is hydrogen, chloro, fluoro, methyl, ethyl, hydroxy, or acetyl;
  • R 1 is methyl, ethyl, or R la is phenyl, piperidinyl, pyrrolidinyl, hexamethyleneiminyl, piperazinyl, and v is 1 to 6;
  • a l is a bond, -NH-, -N(CH 3 )-, -S-, or -O-;
  • A is -CH 2 - or -CH 2 CH 2 -;
  • g) s is 0, 1, 2, or 3;
  • D is a bond, -C(O)-, -CH(OH)-, or -CH 2 -;
  • R 2 is a group of the formula -NR 4 R 5 or -N + R 4a R 5a R 6a ;
  • R 4 and R 5 are independently hydrogen, methyl, ethyl, benzyl, or combine to form, together with the nitrogen to which they are attached, a piperidinyl, pyrrolidinyl, or hexamethyleneiminyl group;
  • R 4a , R 5a , R 6a are independently hydrogen, methyl, ethyl, or R 5a and R 6a combine to form, together with the nitrogen to which they are attached, a piperidinyl, pyrrolidinyl, or hexamethyleneiminyl group; and
  • R is phenyl, piperidinyl, pyrrolidinyl, hexamethyleneiminyl, heptamethyleneiminyl, naphthyl, thiazolyl, furyl, quinolinyl, isoquinolinyl, morpholinyl, cyclohexyl, cyclopentyl, pyrazinyl, triazolyl, or quinuclidinyl;
  • Especially preferred compounds of the present invention are those compounds of Formula I in which:
  • R b is hydrogen, fluoro, or methyl
  • R l is methyl, or R ia is piperidinyl, pyrrolidinyl, or hexamethyleneiminyl, and v is 1, 2, or 3;
  • a l is a bond, -NH-, -S-, or -O-;
  • A is -CH 2 - or -CH2CH2-;
  • g) s is 0 or 1;
  • D is a bond, or -C(O)-;
  • R 2 is a group of the formula -NR 4 R 5 ; j) R 4 and R 5 are independently methyl, or combine to form, together with the nitrogen to which they are attached, a piperidinyl, piperazinyl, or pyrrolidinyl group;
  • R is optionally substituted phenyl, naphthyl, or cyclohexyl
  • Especially preferred methods and formulations of the present invention are those methods and formulations employing especially preferred compounds.
  • Particularly preferred compounds are those of Formula I in which:
  • R b is hydrogen
  • R l is methyl, piperidinyl(C ⁇ -C 4 alkylenyl)-, or pyrroldinyl(C ⁇ -C4 alkylenyl)-;
  • a l is a bond or -O-;
  • A is -CH 2 -;
  • D is a bond, or -C(O)-;
  • R 2 is a piperidinyl, or pyrrolidinyl group, substituted with amino, di(C ⁇ -C6 alkyDamino, alkyDamino, piperidinyl, or pyrrolidinyl, or R 2 is a piperazinyl group substituted with phenyl, cyclohexyl, or benzyl;
  • R is phenyl, substituted with one to three groups selected from Ci-C ⁇ alkyl, trifluoromethyl, and halo;
  • Especially preferred methods and formulations of the present invention are those methods and formulations employing especially preferred compounds.
  • a most preferred class of compounds of the present invention are those compounds of Formula I of the Formula
  • D i is -C(O)-, or -CH2-;
  • R l is methyl,pi ⁇ eridin-3-yl-C___2-CH2-, piperidin-3-yl-CH2-CH 2 -CH2-, piperidin-2-yl-CH2-CH 2 -, piperidin-2-yl-CH 2 -CH 2 -CH2-, pvrrolidin-3-yl-CH 2 -CH2-, pyrrolidin-3-yl-CH 2 -CH2-CH 2 -, piperidin-4-yl-CH 2 -CH 2 -, or piperidin-4-yl-CH 2 -CH 2 -CH2-;
  • R 2 is piperidinyl, or pyrrolidinyl group, substituted with amino, dKCi-C ⁇ alkyDamino, (Ci-C ⁇ alkyl)amino, piperidinyl, or pyrrolidinyl, or R 2 is a piperazinyl group substituted with phenyl or cyclohexyl;
  • R* is chloro or bromo
  • R** hydrogen or chloro
  • the compounds of Formula I may be prepared by a number of methods known to those skilled in the art.
  • Many of the compounds of Formula I are prepared through the reduction of l-methyl-2-indolecarboxylic acid to the corresponding 2- hydroxymethyl-1-methylindole.
  • This reduction may be prepared by several methods known in the art including catalytic hydrogenation.
  • a most preferred method for this reduction is by using a reducing agent such as sodium borohydride, lithium borohydride, diisobutylaluminumhydride hydride, lithium triethylborohydride, borane-methyl sulfide complex in refluxing tetrahydrofuran, and triethoxysilane.
  • Another means of reducing the carboxylic acid is by means of sodium in ethanol, a method known as the Bouveault-Blanc procedure.
  • a most preferred reducing agent employed in this procedure is lithium aluminum hydride.
  • the coupling ofthe aryl group to the above alcohol may be performed using standard techniques.
  • a most preferred method involves a phenolic coupling using a Mitsunobu reagent. 0.
  • Mitsunobu et al.. Bulletin of the Chemical Society of Japan. 44:3427 (1971); O. Mitsunobu, et al.. Journal ofthe American Chemical Society. 94:679 (1972).
  • triphenylphosphine in combination with diethyl azodicarboxylate (DEAD), converts alcohols in situ to the corresponding alkoxyphosphonium salts, which are useful alkylating agents.
  • This reaction also is best carried out in the presence of an inert solvent such as, for example, toluene, benzene, or, preferably tetrahydrofuran.
  • an inert solvent such as, for example, toluene, benzene, or, preferably tetrahydrofuran.
  • the reaction is performed at temperatures from about 0° C to about 40° C, preferably at ambient temperature, until the desired compound is prepared. Typically, the reaction takes about 18 hours when run at ambient temperature, but the progress of the reaction can be monitored via standard chromatographic techniques.
  • An alternative method of arylating the alcohol involves nucleophilic aromatic substitution of an aryl fluoride with a preformed alkoxide. This reaction is performed by first adding a base to the alcohol, followed by the addition of the aryl halide.
  • An especially preferred base is sodium hydride.
  • Another preferred base is sodium hexamethyldisilazide.
  • the reaction is generally performed in a polar aprotic solvent, for example, acetonitrile, N,N-dimethylformamide, N,N-dimethylphenylacetamide, dimethylsulfoxide, or hexamethylphosphoric triamide.
  • Alkylation ofthe 1,2-disubstituted indole may be done by a variety of methods known to those skilled in the art.
  • a preferred method of alkylating this substituted indole is by way of a Mannich reaction.
  • formaldehyde or sometimes another aldehyde
  • HNR R 5 in the form of its salt, and a compound containing an active hydrogen.
  • reaction can be carried out with salts of primary (RNH 2 ) or secondary amines (R 2 NH), or with amides (RCONH 2 ), in which cases the product is substituted on the nitrogen with R, R 2 , and RCO, respectively.
  • This reaction is generally carried out in a lower alkyl alcohol, such as methanol or ethanol, or in an acid, such as acetic acid.
  • One process for preparing those compounds of Formula I in which A is an alkylenyl group is by first oxidizing the alcohol to form the corresponding aldehyde.
  • This reaction is generally performed using an oxidizing agent such as pyridinium dichromate (PDC) or pyridinium chlorochromate (PCC) in a solvent such as methylene chloride.
  • PDC pyridinium dichromate
  • PCC pyridinium chlorochromate
  • the resulting aldehyde is then reacted with a substituted phosphonate in the presence of a base.
  • This Wittig-type reaction results in the formation of an aralkenyl group.
  • a preferred base employed in this reaction is sodium hydride.
  • This reaction generally results in a mixture of the (E) and (Z) stereoisomers.
  • the double bond is then reduced using either a reducing agent as described supra or by means of catalytic hydrogenation using standard means.
  • Preferred solvents for this reaction include dichloroethane.
  • the resulting 1,2-disubstituted indole may then be substituted at the 3 position essentially as described above for the Mannich chemistry.
  • the thio derivatives and intermediates of this invention may be transformed into the corresponding sulfoxide (-SO-) compounds upon treatment with a mild oxidizing agent, such as hydrogen peroxide in methanol, meta- chloroperbenzoic acid (MCPBA) in methylene chloride at 0°C, or an alkali metal periodate in aqueous alcohol.
  • a mild oxidizing agent such as hydrogen peroxide in methanol, meta- chloroperbenzoic acid (MCPBA) in methylene chloride at 0°C, or an alkali metal periodate in aqueous alcohol.
  • MCPBA meta- chloroperbenzoic acid
  • -SO2- are prepared from the thio or sulfoxide compounds on treatment with a strong oxidizing agent, such as hydrogen peroxide in acetic acid or m-chloroperbenzoic acid in methylene chloride at 20°C-30°C.
  • Those compounds of Formula I in which the benzo ring of the indole has been substituted may be prepared by a number of ways known to those skilled in the art.
  • those compounds of Formula I in which the 4-position of the indole ring has been substituted with methyl may be prepared as described in Scheme III, infra.
  • step a) below, a Knoevenagel condensation reaction is performed, resulting (after the dehydration step of the reaction) in an olefin. This reaction is generally performed with an excess of the azide, although an equimolar mixture of the two reagents may be employed.
  • the olefin product of step a) is then cyclized to form an indole ring.
  • the usual means of this cyclization is by heating the olefin.
  • the progress of the cyclization may be followed by thin layer chromatography.
  • a chloro group can be introduced by treating with iodobenzene, chlorine, and pyridine [Murakami, et al.. Chem. Pharm. Bull.. 19:1696 (1971)] or N- chlorosuccinimide in dimethylformamide [United States Patent 4,623,657, the entire contents of which are herein incorporated by reference].
  • iodobenzene chlorine, and pyridine
  • N- chlorosuccinimide in dimethylformamide united States Patent 4,623,657, the entire contents of which are herein incorporated by reference.
  • other transformations, intraconversions, and derivatizations are either described in the Examples, infra, or are well known to those of ordinary skill in the art.
  • Proton nuclear magnetic resonance ( 2 H NMR) spectra were obtained on a GE QE-300 spectrometer at 300.15 MHz, a Bruker AM-500 spectrometer at 500 MHz, or a Bruker AC-200P spectrometer at 200 MHz, or a like model.
  • 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.
  • TLC thin layer chromatography
  • E. Merck Kieselgel 60 F 254 plates 5 cm x 10 cm, 0.25 mm thickness. Spots were detected using a combination of UV and chemical detection (plates dipped in a eerie ammonium molybdate solution [75 g of ammonium molybdate and 4 g of cerium (IV) sulfate in 500 ml of 10% aqueous sulfuric acid] and then heated on a hot plate).
  • Preparative centrifugal thin layer chromatography was performed on a Harrison Model 7924A Chromatotron using Analtech silica gel GF rotors.
  • Cation exchange chromatography was performed with Dowex® 50X8-100 ion exchange resin.
  • Anion exchange chromatography was performed with Bio-Rad AG® 1-X8 anion- exchange resin (acetate form converted to hydroxide form). Flash chromatography was performed as described by Still, et al.. Journal of Organic Chemistry. 43:2923 (1978).
  • Optical rotations are reported at the sodium-D-line (354 nm). Elemental analyses for carbon, hydrogen, and nitrogen were determined on a Control Equipment Corporation 440 Elemental Analyzer, or were performed by the Universidad Complutense Analytical Centre (Facultad de Farmacia, Madrid, Spain). Melting points were determined in open glass capillaries on a Thomas Hoover capillary melting point apparatus or a Buchi melting point apparatus, and are uncorrected.
  • 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.
  • lithium aluminum hydride (18.40 g, 0.49 mol). The resulting mixture was placed over an ice bath. An aliquot of 1- methylindole-2-carboxylic acid (84.92 g, 0.49 mol) was dissolved in an additional 475 ml of dry tetrahydrofuran and then added slowly (over about 45-50 minutes) to the lithium aluminum hydride mixture.
  • the ice was removed from around the round bottom flask and warm water was added to the bath to raise the reaction temperature.
  • the reaction mixture was then stirred at room temperature for 60-90 minutes. The progress of the reaction was monitored by thin layer chromatography.
  • reaction vessel was placed in an ice bath and 20 ml of water were slowly added to the reaction mixture. This was followed by the sequential addition of 20 ml of 5 N sodium hydroxide and then 60 ml of water. The organic fraction was dried using CELITETM followed by sodium sulfate. The organic solvents were then removed by vacuum to yield a white solid. The white solid was then dissolved in toluene heated to reflux. The mixture was then cooled to room temperature and then permitted to remain overnight in a refrigerator. The off-white crystals were then collected, washed with cool toluene, and then dried in a vacuum oven. Yield 63.65 grams (81.4%). FDMS 161. Analysis for CioHnNO:
  • l-Methyl-2-(4-chlorophenoxymethyl)-lH-indole (0.30 g, 1.10 mmol), dissolved in 2.0 ml of tetrahydrofuran, was placed in a round bottom flask under an argon atmosphere. To this solution was added oxalyl chloride (0.294 g, 2.32 mmol). The resulting mixture was stirred at room temperature for about 45 minutes. The solvents were removed in vacuo, leaving a dark brown oil.
  • the brown oil was taken up in 2.0 ml of dry tetrahydrofuran and 4-(piperidin-l-yl)piperidine (1.07 g, 6.38 mmol), dissolved in about 10 ml of dry tetrahydrofuran, was added. The resulting reaction mixture was stirred at room temperature for about 30 minutes. The progress of the reaction was monitored by thin layer chromatography.
  • phenylpiperazine (0.149 g, 0.920 mmol) was dissolved in 2.0 ml of dichloroethane.
  • the reaction vessel was placed in an ice bath.
  • the solvents were removed by vacuum and the residue was partitioned between ethyl acetate and a 10% potassium carbonate solution.
  • the organic fraction was washed with water, followed by 1.0 N hydrochloric acid.
  • the acidic aqueous fraction was basified with a 10% potassium carbonate solution.
  • the organic component was dried by dripping through sodium sulfate.
  • the solvents were removed in vacuo.
  • the desired product was recrystallized from ethyl acetate.
  • the solvents were removed by decanting and the crystals were rinsed five times with cold diethyl ether.
  • the solvents and rinses were collected, and placed in a freezer for about three days.
  • the crystals were collected and dried in a vacuum oven to yield 1.15 grams (86.3%) of the desired title product.
  • Indole-2-carboxylic acid (47.0 g, 292 mmol) was dissolved in 200 ml of methanol. To this solution was added 6 ml of concentrated sulfuric acid. The resulting mixture was heated to reflux and maintained at this temperature for about 16 hours. The reaction mixture was then cooled to room temperature and the solids were removed by filtration and then washed with 200 ml of methanol. The crystals were dried in a vacuum oven, yielding 39.5 grams (77%) of the desired title product as white needles. Analytical data obtained was consistent with the proposed title structure.
  • methyl indole-2-carboxylate (1.50 g, 8.56 mmol) was dissolved in 8.6 ml of N,N-dimethylformamide. The solution was placed in an ice bath and sodium hydride (0.377 g, 9.42 mmol) was added. The resulting mixture was stirred for 20 minutes over ice and then permitted to warm to room temperature. The reaction mixture was then stirred for about 90 minutes at room temperature, after which time it was placed again in an ice bath.
  • lithium aluminum hydride (0.325 g, 8.56 mmol) was dissolved in 8.6 ml of dry tetrahydrofuran.
  • the resulting solution was placed in an ice bath and methyl l-[2-(l- tritylpiperidin-4-yl)ethyl]indole-2-carboxylate (4.68 g, 8.52 mmol), dissolved in about 10 ml of dry tetrahydrofuran, was added.
  • the resulting mixture was stirred overnight at room temperature.
  • methyl l-[3-(l-tritylpiperidin-3- yl)propyl]indole-2-carboxylate (3.38 g, 6.23 mmol) was dissolved in 3.1 ml of dry tetrahydrofuran.
  • the reaction vessel was then placed in an ice bath and lithium aluminum hydride (0.236 g, 6.23 mmol) was added.
  • the resulting mixture was stirred in an ice bath for about ten minutes and then at room temperature overnight. The progress of the reaction was monitored by thin layer chromatography.
  • reaction mixture was then heated to 80°C and maintained at this temperature for about eight hours.
  • the reaction mixture was then cooled to room temperature and stirred at this temperature overnight.
  • Another half equivalence of sodium hydride was added and the reaction mixture was stirred at room temperature overnight again.
  • Another half equivalence of l-chloro-4-fluorobenzene was added and the reaction mixture was heated to 80°C.
  • the title compound was prepared essentially as described above for 2-[(4-chlorophenoxy)methyl]-l-[2-(piperidin-4-yl)ethyl]-lH- indole except that an equimolar amount of 2-[(4-chlorophenoxy)methyl]- l-[3-(l-tritylpiperidin-3-yl)propyl]-lH-indole was employed instead of the 2-[(4-chlorophenoxy)methyl]- 1-[2-( l-tritylpiperidin-4-yl)ethyl]- lH-indole employed therein. NMR was consistent with the proposed title strucuture. Single compound of high purity as evidenced by chromatographic methods.
  • the reaction mixture was poured over water in which 2.5 grams of sodium sulfate was dissolved, and the aqueous phase was extracted thrice with methylene chloride. The organic fractions were combined and dried over sodium sulfate. The solvents were removed in vacuo, yielding 0.26 grams (23%) of the desired compound. The solvents were removed in vacuo from the mother liquor and the resulting residue was recrystallized in ethyl acetate and hexanes to obtain an additional 0.65 grams (58%) of the desired material. Analytical data obtained was consistent with the proposed title structure.
  • reaction mixture was partitioned between 1.0 N sodium hydroxide and methylene chloride.
  • aqueous fraction was extracted twice with methylene chloride.
  • the organic fractions were combined and dried over sodium sulfate. The solvents were removed by evaporation.
  • reaction mixture was then cooled to room temperature and 10 ml of a 1:1 tetrahydrofuran:methanol solution was added. To this mixture was then added 5 ml of a saturated Rochelle's salt solution. The solvents were then removed in vacuo. The residue was then partitioned between methylene chloride and a saturated Rochelle's salt solution. The organic fraction was washed with water and brine. The organic fraction was then dried with sodium sulfate and the solvents were removed in vacuo. The desired title product was further purified by chromatography to yield 0.1112 grams (56.9%).
  • reaction mixture was stirred for about one hour and then 0.33 ml of a 1:1 tetrahydrofuran:methanol solution was added.
  • Sodium hydroxide (1.74 ml of a 5.0 N solution) was then added and the resulting mixture was heated to reflux and maintained at this temperature overnight.
  • the aqueous fraction was extracted twice more with tetrahydrofuran.
  • the organic fractions were combined, washed twice with brine, and dried over sodium sulfate. The solvents were removed in vacuo.
  • the desired products were further purified by radial chromatography.
  • borane-tetrahydrofuran complex (7.42 ml of a 1.0 M solution in THF, 7.42 mmol) was added to a round bottom flask containing 2-[(4-chlorophenoxy)methyl]-l-methyl-3- [2-[3-(dimethylamino)propylamino]-l,2-ethanedionyl]-lH-indole (0.529 g, 1.24 mmol).
  • the reaction mixture was stirred at room temperature for about one hour. The progress of the reaction was monitored by thin layer chromatography. The reaction was then quenched by the addition of a 1:1 tetrafuran:methanol solution.
  • reaction mixture was partitioned between methylene chloride and 1.0 N sodium hydroxide.
  • the aqueous fraction was extracted twice with methylene chloride.
  • the organic fractions were combined and dried over sodium sulfate. The solvents were removed in vacuo to yield the desired title product.
  • the reaction mixture was then partitioned between methylene chloride and water.
  • the aqueous fraction was extracted thrice with methylene chloride.
  • the organic fractions were combined and dried over sodium sulfate.
  • the solvents were removed in vacuo.
  • the desired title product was further purified by radial chromatography.
  • the reaction mixture was partitioned between methylene chloride and 1.0 N sodium hydroxide.
  • the aqueous fraction was extracted twice with methylene chloride.
  • the organic fractions were combined and dried over sodium sulfate.
  • the solvents were removed in vacuo.
  • the desired title product was further purified by radial chromatography.
  • reaction mixture was then placed over an oil bath and heated to 55°C and maintained at this temperature for about one hour.
  • the reaction mixture was then permitted to cool to room temperature and was then poured into water.
  • Sodium hydroxide (10 ml of a 5.0 N solution) was added and heated to reflux. The resulting mixture was cooled and the solids were then collected by filtration.
  • dimethylaminopiperidine was dissolved in 3.0 ml of methylene chloride. To this solution were added 3- ⁇ 2-[(4-chlorophenoxy)methyl]-l-methyl-lH-indol-3-yl ⁇ prop-2- enoic acid (0.050 g, 0.1462 mmol) and l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (0.0356 g, 0.278 mmol). The resulting mixture was stirred at room temperature overnight.
  • the reaction mixture was then heated to 60 °C and maintained at this temperature for about 30 minutes.
  • the solvents were removed in vacuo and the residue was partitioned between methylene chloride and water.
  • the aqueous fraction was extracted with methylene chloride again.
  • the organic fractions were combine, washed twice with water, then with brine, and then dried over sodium sulfate.
  • the solvents were removed in vacuo.
  • the desired title product was further purified by chromatography.
  • the progress of the reaction was monitored by thin layer chromatography.
  • the reaction mixture was cooled to ambient temperature and evaporated to leave an oily product. The residue was dissolved in methanol (50 ml) and tetrahydrofuran (150 ml), and solid potassium carbonate (30.54 g, 0.221 mol) was added. The resulting mixture was stirred at ambient temperature for 19 hours.
  • the progress of this reaction was monitored by thin layer chromatography.
  • the reaction mixture was partitioned between IM potassium carbonate and ethyl acetate. The aqueous fraction was back-extracted thrice with ethyl acetate. The organic fractions were combined and dried over sodium sulfate. The solvents were removed in vacuo to yield 2.6 grams ofthe desired title product. NMR was consistent with the proposed title structure.
  • the reaction mixture was diluted with hexamethylphosphoramide (5 ml), tetrahydrofuran (5 ml), cupric bromide (2.15 g, 9.65 mmol), and cupric acetate (3.85 g, 19.3 mmol), followed by the addition of water (86 ⁇ l, 4.82 mol).
  • the resulting mixture was stirred at ambient temperature for six hours.
  • the progress of the reaction was monitored by thin layer chromatography.
  • the reaction mixture was diluted with brine and extracted thrice with diethyl ether. The organic fractions were combined and dried over sodium sulfate. The solvents were removed in vacuo. The residue was further purified by liquid chromatography. Yield: 426 mg. NMR was consistent with the proposed title structure.
  • Lithium diisopropylamide was prepared by admixing diisopropylamine (5.79 ml, 41.3 mmol) in 5 ml of tetrahydrofuran. The resulting mixture was cooled to -78°C and treated with n-butyllithium in such a manner that the temperature did not raise above 64°C. After stirring the suspension for 45 minutes, the remainder of the tetrahydrofuran was added (70 ml), followed by the dropwise addition of 4-chlorophenyl fluoride (4.0 ml, 37.6 mmol). After 45 minutes N,N- dimethylformamide was added, also in a dropwise fashion.
  • the desired intermediate was prepared from the deprotection of 4-(2-fluorobenzyloxy)-N-(t;-butoxycarbonyl)-N- (isopropyl)butylamine using standard techniques.
  • the 4-(2- fluorobenzyloxy)-N-(- butoxycarbonyl)-N-(isopropyl)butylamine was admixed with a 4:1 mixture of methylene chloride and trifluoroacetic acid. The progress of the reaction was monitored by thin layer chromatography .
  • the desired intermediate was prepared essentially as described for the 4-(2-fluorobenzyloxy)-N-(isopropyl)butylamine above, except that an equimolar amount of 4-(5-chloro-2-fluorobenzyloxy)-N-(i-- butoxycarbonyl)-N-(isopropyl)butylamine was employed in place ofthe 4- (2-fluorobenzyloxy)-N-(t butoxycarbonyl)-N-(isopropyl)butylamine employed therein. Yield: 138 mg (98%).
  • the cloudy reaction mixture was diluted wtih methylene chloride and washed with 1 M potassium carbonate. The organic fraction was dried over sodium sulfate, filtered, and the solvents were removed in vacuo. The residue was further purified by preparative high performance liquid chromatography to yield 1.45 grams (52%) of the title intermediate as a colorless oil.
  • the cloudy reaction mixture was diluted wtih methylene chloride (100 ml) and washed with 1 M potassium carbonate. The organic fraction was dried over sodium sulfate, filtered, and the solvents were removed in vacuo. The residue was further purified by preparative high performance liquid chromatography to yield 1.38 grams (74%) ofthe title intermediate as a colorless oil.
  • reaction mixture was diluted wtih methylene chloride (100 ml) and washed with 1 M potassium carbonate (20 ml). The organic fraction was dried over sodium sulfate, filtered, and the solvents were removed in vacuo. The residue was further purified by preparative high performance liquid chromatography to yield 1.53 grams (74%) of the title intermediate as a colorless oil.
  • the desired intermediate was prepared essentially as described in F. Scheinmann and A.V. Stachulski, Journal of Chemical Research. 1993:414 (1993).
  • a solution of 3-methyl- l-(t- butoxycarbonyl)pyrrolidin-2-one (8.63 g, 43.3 mmol) in tetrahydrofuran (48 ml) was cooled to -78°C.
  • the solution was treated with NaN[Si(CH 3 ) 2 ]2 (56.3 ml, 56.3 mmol) and stirred for about 50 minutes prior to quenching with methyl iodide (8.1 ml, 130 mmol).
  • the reaction mixture was slowly warmed to ambient temperature, and stirring was continued for about one hour.
  • reaction mixture was diluted with methylene chloride, and washed with 25 mM phosphate buffer and brine. The organic fraction was dried over sodium sulfate and the solvents were removed in vacuo. The desired title intermediate was further purified by liquid chromatography. Yield: 517 mg (46%) as a yellow oil.
  • N,N- dimethyl-4-[2-fluoro-5-bromobenzyloxy]butylamine (215 mg, 0.707 mmol) was dissolved in dichloroethane (2.0 ml).
  • ACE • Cl (0.305 ml, 2.83 mmol) was added and the resulting mixture was heated to reflux.
  • the reaction mixture was refluxed for four hours.
  • the prgress of the reaciton was monitored by thin layer chromatography.
  • the mixture was refluxed for an additional 16 hours.
  • the solvents were removed in vacuo and the residue was taken up in methanol.
  • the methanol solution was refluxed for 1.5 hours and the solvents were removed by evaporation.
  • the reaction mixture was partitioned between 1 M potassium carbonate and methylene chloride.
  • the aqueous fraction was back-extracted with methylene chloride.
  • the organic fractions were combined, dried over sodium sulfate, and the solvents were removed in vacuo.
  • the title intermediate was further purified by silica gel.
  • N,N- dimethyl-5-[2-fluoro-5-bromobenzyloxy]pentylamine (696 mg, 1.87 mmol) was dissolved in dichloroethane (6.0 ml).
  • ACE • Cl (0.305 ml, 2.83 mmol) was added and the resulting mixture was heated to reflux.
  • the reaction mixture was refluxed for twenty hours.
  • the progress of the reaction was monitored by thin layer chromatography.
  • the mixture was refluxed for an additional 16 hours.
  • the solvents were removed in vacuo and the residue was partitioned between 1 M potassium carbonate and methylene chloride. The aqueous fraction was back extracted with methylene chloride.
  • N,N- ⁇ _methylformamide Three milliliters of N,N- ⁇ _methylformamide was added and the mass was slurried and stirred for three more hours. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was partitioned between brine and diethyl ether. The organic fraction was washed six times with brine, and then dried over sodium sulfate. The desired title product was further purified by liquid chromatography. Yield: 0.540 grams. NMR was consistent with proposed title structure.
  • N-(t butoxycarbonyl)-4-(2-fluoro-5- bromobenzyloxy)butylamine (3.5 grams) was dissolved in methylene chloride (60 ml) under a nitrogen atmosphere.
  • Trifluoroacetic acid (15 ml) was added to the solution at 0°C.
  • the resulting mixture was stirred at 0°C for thirty minutes and then at ambient temperature for 15 minutes.
  • the progress of the reaction was monitored by thin layer chromatography.
  • the reaction mixture was partitioned between 1 M potassium carbonate and methylene chloride.
  • the aqueous fraction was back-extracted with methylene chloride.
  • the organic fractions were combined and dried over sodium sulfate.
  • the solvents were removed in vacuo.
  • the desired intermediate was further purified by liquid chromatography. Yield: 1.82 g. NMR was consistent with the proposed title structure.
  • Carbon dioxide was bubbled through the reaction mixture, and the resulting mixture was stirred for thirty minutes over the dry ice/acetone bath. The reaction mixture was then stirred at room temperature for ten minutes with continued carbon dioxide bubbling. The carbon dioxide was shut off and the reaction mixture was stirred at room temperature for ninety minutes. The solvents were removed in vacuo, argon was added to the reaction vessel, which was then rinsed with 5 ml of tetrahydrofuran. The solvents were removed in vacuo. The brown solid was stored overnight at 4°C under an argon atmosphere.
  • reaction mixture was poured into a saturated ammonium chloride solution and extracted twice with diethyl ether.
  • the organic fractions were combined and the solvents were removed in vacuo and recrystallized from water to obtain 0.17 grams of the desired intermediate.
  • the aqueous fraction was acidified by adding 5% sulfuric acid and stirred for one hour at room temperature. The solids were removed by filtration to yield an additional 0.48 grams ofthe desired title intermediate. NMR was consistent with the proposed title structure.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)

Abstract

Cette invention a pour objet une série d'indoles substitués utiles pour traiter ou prévenir une pathologie associée à un excès de neuropeptide Y. On décrit les nouveaux indoles substitués ainsi que des formulations pharmaceutiques comprenant comme ingrédient actif au moins un desdits indoles substitués.
PCT/US1996/014163 1995-09-01 1996-08-30 Antagonistes du recepteur du neuropeptide y indolyle WO1997009308A1 (fr)

Priority Applications (10)

Application Number Priority Date Filing Date Title
BR9606619A BR9606619A (pt) 1995-09-01 1996-08-30 Antagonistas do receptor de neuropeptídeo y indolil
EP96930691A EP0789688A4 (fr) 1995-09-01 1996-08-30 Antagonistes du recepteur du neuropeptide y indolyle
MX9703186A MX9703186A (es) 1995-09-01 1996-08-30 Antagonistas del receptor del neuropeptido y de indolilo.
AU69650/96A AU717422B2 (en) 1995-09-01 1996-08-30 Indolyl neuropeptide Y receptor antagonists
JP9511344A JPH10508321A (ja) 1995-09-01 1996-08-30 インドリル神経ペプチドｙレセプターアンタゴニスト
IL12072496A IL120724A0 (en) 1995-09-01 1996-08-30 Indolyl neuropeptide Y receptor antagonists
NZ318228A NZ318228A (en) 1995-09-01 1996-08-30 Indolyl neuropeptide y receptor antagonists
HU9701714A HUP9701714A3 (en) 1995-09-01 1996-08-30 Indole derivatives neuropeptide y receptor antagonists, use thereof and pharmaceutical compositions containing these compounds
CZ971328A CZ132897A3 (en) 1995-09-01 1996-08-30 Antagonist of indolylneuropeptide y receptor
NO972016A NO308296B1 (no) 1995-09-01 1997-04-30 Indolyl neuropeptid Y reseptorantagonister, farmasøytisk formulering omfattende samme og anvendelse av samme for fremstilling av legemiddel

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US315095P 1995-09-01 1995-09-01
GB9523999.2 1995-11-23
GBGB9523999.2A GB9523999D0 (en) 1995-11-23 1995-11-23 Indolyl neuropeptide y receptor antagonists
US2163896P 1996-07-12 1996-07-12
US60/003,150 1996-07-12
US60/021,638 1996-07-12

Publications (1)

Publication Number Publication Date
WO1997009308A1 true WO1997009308A1 (fr) 1997-03-13

Family

ID=27267993

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1996/014163 WO1997009308A1 (fr) 1995-09-01 1996-08-30 Antagonistes du recepteur du neuropeptide y indolyle

Country Status (14)

Country Link
EP (1) EP0789688A4 (fr)
CN (1) CN1173867A (fr)
AU (1) AU717422B2 (fr)
BR (1) BR9606619A (fr)
CA (1) CA2203912A1 (fr)
CZ (1) CZ132897A3 (fr)
HU (1) HUP9701714A3 (fr)
IL (1) IL120724A0 (fr)
MX (1) MX9703186A (fr)
NO (1) NO308296B1 (fr)
NZ (1) NZ318228A (fr)
PL (1) PL320010A1 (fr)
TR (1) TR199700334T1 (fr)
WO (1) WO1997009308A1 (fr)

Cited By (54)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998046559A1 (fr) * 1997-04-16 1998-10-22 Arqule, Inc. SYNTHESE ET UTILISATION DE DERIVES ET ENSEMBLES DE α-CETOAMIDE
WO2000063171A1 (fr) * 1999-04-20 2000-10-26 Meiji Seika Kaisha, Ltd. Composes tricycliques
US6143931A (en) * 1997-04-16 2000-11-07 Arqule, Inc. Synthesis and use of α-ketoamide derivatives and arrays
US6200990B1 (en) * 1998-12-21 2001-03-13 Alcon Laboratories, Inc. Neuroprotective agents having antioxidant and NMDA antagonist activity
WO2001066110A2 (fr) * 2000-03-09 2001-09-13 Eli Lilly And Company PROCEDE DE TRAITEMENT DU DYSFONCTIONNEMENT RENAL AU MOYEN D'INHIBITEURS DE sPLA¿2?
US6303628B1 (en) 1999-07-02 2001-10-16 Pfizer Inc Bicycliccarbonyl indole compounds as anti-inflammatory/analgesic agents
US6337332B1 (en) 1998-09-17 2002-01-08 Pfizer Inc. Neuropeptide Y receptor antagonists
WO2002020488A2 (fr) * 2000-09-06 2002-03-14 F. Hoffmann-La Roche Ag Derives de quinoline et de quinazoline
US6469006B1 (en) * 1999-06-15 2002-10-22 Bristol-Myers Squibb Company Antiviral indoleoxoacetyl piperazine derivatives
WO2003024928A2 (fr) 2001-09-14 2003-03-27 Novo Nordisk A/S Nouveau derives d'aminoazetidine, d'aminopyrrolidine et d'aminopiperidine
US6653304B2 (en) 2000-02-11 2003-11-25 Bristol-Myers Squibb Co. Cannabinoid receptor modulators, their processes of preparation, and use of cannabinoid receptor modulators for treating respiratory and non-respiratory diseases
US6673829B2 (en) 2001-09-14 2004-01-06 Novo Nordisk A/S Aminoazetidine,-pyrrolidine and -piperidine derivatives
WO2004054581A2 (fr) * 2002-12-13 2004-07-01 Smithkline Beecham Corporation Composes de cyclohexyle utiles en tant qu'antagonistes du ccr5
US6800654B2 (en) 2001-06-20 2004-10-05 Wyeth Substituted naphthyl indole derivatives as inhibitors of plasminogen activator inhibitor type-1 (PAI-1)
WO2004098591A2 (fr) 2003-05-05 2004-11-18 Probiodrug Ag Inhibiteurs de glutaminyl-cyclase
US6852726B2 (en) 2002-02-01 2005-02-08 Syntex Llc Substituted indoles as alpha-1 agonists
WO2005030754A1 (fr) * 2003-09-24 2005-04-07 Janssen Pharmaceutica, N.V. Derives d'indole ou de quinoline utilises en tant qu'inhibiteurs non-peptidiques du recepteur npy y2 pour le traitement de troubles anxiolytiques et depressifs ainsi que pour le traitement de l'obesite
WO2005075436A2 (fr) 2004-02-05 2005-08-18 Probiodrug Ag Nouveaux inhibiteurs de la glutaminyl-cyclase
US7056943B2 (en) 2002-12-10 2006-06-06 Wyeth Substituted indole oxo-acetyl amino acetic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
US7074817B2 (en) 2001-06-20 2006-07-11 Wyeth Substituted indole acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
US7078429B2 (en) 2002-12-10 2006-07-18 Wyeth Substituted 3-carbonyl-1H-indol-1-yl acetic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
US7101903B2 (en) 2002-12-10 2006-09-05 Wyeth Substituted dihydropyrano indole-3,4-dione derivatives as inhibitiors of plasminogen activator inhibitor-1 (PAI-1)
US7141592B2 (en) 2003-09-25 2006-11-28 Wyeth Substituted oxadiazolidinediones
US7163954B2 (en) 2003-09-25 2007-01-16 Wyeth Substituted naphthyl benzothiophene acids
WO2007046112A1 (fr) * 2005-10-19 2007-04-26 Suven Life Sciences Inc. Derives de arylthioether tryptamine utiles en tant que ligands 5-ht6 fonctionnels
US7259182B2 (en) 2002-12-10 2007-08-21 Wyeth Aryl, aryloxy, and aklyloxy substituted 1H-indol-3-yl glyoxylic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
US7265148B2 (en) 2003-09-25 2007-09-04 Wyeth Substituted pyrrole-indoles
US7268159B2 (en) 2003-09-25 2007-09-11 Wyeth Substituted indoles
US7323483B2 (en) 2005-01-27 2008-01-29 Wyeth Processes and compounds for the preparation of substituted naphthylindole derivatives
US7332521B2 (en) 2003-09-25 2008-02-19 Wyeth Substituted indoles
US7342039B2 (en) 2003-09-25 2008-03-11 Wyeth Substituted indole oximes
US7348351B2 (en) 2002-12-10 2008-03-25 Wyeth Substituted 3-alkyl and 3-arylalkyl 1H-indol-1yl acetic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
US7351726B2 (en) 2003-09-25 2008-04-01 Wyeth Substituted oxadiazolidinediones
WO2008055945A1 (fr) 2006-11-09 2008-05-15 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
WO2008065141A1 (fr) 2006-11-30 2008-06-05 Probiodrug Ag Nouveaux inhibiteurs de glutaminylcyclase
US7411083B2 (en) 2003-09-25 2008-08-12 Wyeth Substituted acetic acid derivatives
US7420083B2 (en) 2003-09-25 2008-09-02 Wyeth Substituted aryloximes
WO2008104580A1 (fr) 2007-03-01 2008-09-04 Probiodrug Ag Nouvelle utilisation d'inhibiteurs de la glutaminyl cyclase
US7442805B2 (en) 2003-09-25 2008-10-28 Wyeth Substituted sulfonamide-indoles
US7446201B2 (en) 2003-09-25 2008-11-04 Wyeth Substituted heteroaryl benzofuran acids
US7582773B2 (en) 2003-09-25 2009-09-01 Wyeth Substituted phenyl indoles
US7683091B2 (en) 2005-08-17 2010-03-23 Wyeth Substituted indoles and methods of their use
US7754747B2 (en) 2004-08-23 2010-07-13 Wyeth Llc Oxazolo-naphthyl acids
WO2011029920A1 (fr) 2009-09-11 2011-03-17 Probiodrug Ag Dérivés hétérocycliques en tant qu'inhibiteurs de glutaminyle cyclase
EP2338490A2 (fr) 2003-11-03 2011-06-29 Probiodrug AG Combinaisons utiles pour le traitement de désordres neuronales
WO2011107530A2 (fr) 2010-03-03 2011-09-09 Probiodrug Ag Nouveaux inhibiteurs
WO2011110613A1 (fr) 2010-03-10 2011-09-15 Probiodrug Ag Inhibiteurs hétérocycliques de la glutaminyl cyclase (qc, ec 2.3.2.5)
WO2011131748A2 (fr) 2010-04-21 2011-10-27 Probiodrug Ag Nouveaux inhibiteurs
WO2012123563A1 (fr) 2011-03-16 2012-09-20 Probiodrug Ag Dérivés de benzimidazole en tant qu'inhibiteurs de la glutaminyl cyclase
WO2012168697A1 (fr) 2011-06-06 2012-12-13 Imperial Innovations Limited Procédés de prédiction de l'affinité de liaison à tspo d'agents d'imagerie
US8466282B2 (en) 2008-06-19 2013-06-18 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof
EP2865670A1 (fr) 2007-04-18 2015-04-29 Probiodrug AG Dérivés de thio-urée utilisés comme inhibiteurs de la glutaminyl cyclase
EP2707101B1 (fr) * 2011-05-12 2019-02-13 Proteostasis Therapeutics, Inc. Régulateurs de la protéostasie
EP3461819A1 (fr) 2017-09-29 2019-04-03 Probiodrug AG Inhibiteurs de la glutaminyl-cyclase

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU729590B2 (en) * 1996-10-23 2001-02-08 Sanofi-Aventis Cosmetic composition containing a neuropeptide Y receptor antagonist
CN104829465B (zh) * 2015-02-13 2018-04-27 普济生物科技（台州）有限公司 一种4-异丙氨基-1-丁醇的制备方法
CN105949135A (zh) * 2016-05-10 2016-09-21 湖南欧亚生物有限公司 一种赛乐西帕的合成方法
CN111377821A (zh) * 2018-12-28 2020-07-07 南京艾德凯腾生物医药有限责任公司 一种合成4-异丙氨基-1-丁醇的方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4374846A (en) * 1979-08-02 1983-02-22 Kali-Chemie Pharma Gmbh N-Amino alkyl indole compounds compositions containing same, and a method of using same in therapy of disorders of gastrointestinal motility
US5206382A (en) * 1991-06-27 1993-04-27 Fidia Georgetown Institute For The Neurosciences Indole derivatives, pharmaceutical compositions and methods of treating neurological and psychiatric disorders
US5264420A (en) * 1990-09-27 1993-11-23 Merck & Co., Inc. Fibrinogen receptor antagonists
US5494928A (en) * 1993-01-22 1996-02-27 Hoffmann-La Roche Inc. Indole derivatives
US5496844A (en) * 1992-05-08 1996-03-05 Otsuka Pharmaceutical Factory, Inc. Indole derivatives

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU3953795A (en) * 1994-10-20 1996-05-15 Eli Lilly And Company Bicyclic neuropeptide y receptor antagonists

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4374846A (en) * 1979-08-02 1983-02-22 Kali-Chemie Pharma Gmbh N-Amino alkyl indole compounds compositions containing same, and a method of using same in therapy of disorders of gastrointestinal motility
US5264420A (en) * 1990-09-27 1993-11-23 Merck & Co., Inc. Fibrinogen receptor antagonists
US5206382A (en) * 1991-06-27 1993-04-27 Fidia Georgetown Institute For The Neurosciences Indole derivatives, pharmaceutical compositions and methods of treating neurological and psychiatric disorders
US5496844A (en) * 1992-05-08 1996-03-05 Otsuka Pharmaceutical Factory, Inc. Indole derivatives
US5494928A (en) * 1993-01-22 1996-02-27 Hoffmann-La Roche Inc. Indole derivatives

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP0789688A4 *

Cited By (77)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6452050B1 (en) 1997-04-16 2002-09-17 Arqule, Inc. Synthesis and use of α-ketoamide derivatives and arrays
US6143931A (en) * 1997-04-16 2000-11-07 Arqule, Inc. Synthesis and use of α-ketoamide derivatives and arrays
WO1998046559A1 (fr) * 1997-04-16 1998-10-22 Arqule, Inc. SYNTHESE ET UTILISATION DE DERIVES ET ENSEMBLES DE α-CETOAMIDE
US6337332B1 (en) 1998-09-17 2002-01-08 Pfizer Inc. Neuropeptide Y receptor antagonists
US6200990B1 (en) * 1998-12-21 2001-03-13 Alcon Laboratories, Inc. Neuroprotective agents having antioxidant and NMDA antagonist activity
WO2000063171A1 (fr) * 1999-04-20 2000-10-26 Meiji Seika Kaisha, Ltd. Composes tricycliques
US6713473B1 (en) 1999-04-20 2004-03-30 Meiji Seika Kaisha, Ltd. Tricyclic compounds
US6469006B1 (en) * 1999-06-15 2002-10-22 Bristol-Myers Squibb Company Antiviral indoleoxoacetyl piperazine derivatives
US6303628B1 (en) 1999-07-02 2001-10-16 Pfizer Inc Bicycliccarbonyl indole compounds as anti-inflammatory/analgesic agents
US6653304B2 (en) 2000-02-11 2003-11-25 Bristol-Myers Squibb Co. Cannabinoid receptor modulators, their processes of preparation, and use of cannabinoid receptor modulators for treating respiratory and non-respiratory diseases
WO2001066110A3 (fr) * 2000-03-09 2002-04-25 William Louis Macias PROCEDE DE TRAITEMENT DU DYSFONCTIONNEMENT RENAL AU MOYEN D'INHIBITEURS DE sPLA¿2?
WO2001066110A2 (fr) * 2000-03-09 2001-09-13 Eli Lilly And Company PROCEDE DE TRAITEMENT DU DYSFONCTIONNEMENT RENAL AU MOYEN D'INHIBITEURS DE sPLA¿2?
WO2002020488A3 (fr) * 2000-09-06 2002-05-16 Hoffmann La Roche Derives de quinoline et de quinazoline
US7265125B2 (en) 2000-09-06 2007-09-04 Hoffmann-La Roche Inc. Neuropeptide Y antagonists
WO2002020488A2 (fr) * 2000-09-06 2002-03-14 F. Hoffmann-La Roche Ag Derives de quinoline et de quinazoline
US6900226B2 (en) 2000-09-06 2005-05-31 Hoffman-La Roche Inc. Neuropeptide Y antagonists
US6939886B2 (en) 2001-06-20 2005-09-06 Wyeth Substituted naphthyl indole derivatives as inhibitors of plasminogen activator inhibitor Type-1 (PAI-1)
US7074817B2 (en) 2001-06-20 2006-07-11 Wyeth Substituted indole acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
US7629377B2 (en) 2001-06-20 2009-12-08 Wyeth Substituted naphthyl indole derivatives as inhibitors of plasminogen activator inhibitor type-1 (PAI-1)
US7351730B2 (en) 2001-06-20 2008-04-01 Wyeth Substituted naphthyl indole derivatives as inhibitors of plasminogen activator inhibitor type-1 (PAI-1)
US6800654B2 (en) 2001-06-20 2004-10-05 Wyeth Substituted naphthyl indole derivatives as inhibitors of plasminogen activator inhibitor type-1 (PAI-1)
US7368471B2 (en) 2001-06-20 2008-05-06 Wyeth Substituted indole acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
US6673829B2 (en) 2001-09-14 2004-01-06 Novo Nordisk A/S Aminoazetidine,-pyrrolidine and -piperidine derivatives
WO2003024928A2 (fr) 2001-09-14 2003-03-27 Novo Nordisk A/S Nouveau derives d'aminoazetidine, d'aminopyrrolidine et d'aminopiperidine
US6852726B2 (en) 2002-02-01 2005-02-08 Syntex Llc Substituted indoles as alpha-1 agonists
US7566791B2 (en) 2002-12-10 2009-07-28 Wyeth Substituted 3-carbonyl-1h-indol-1yl acetic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
US7056943B2 (en) 2002-12-10 2006-06-06 Wyeth Substituted indole oxo-acetyl amino acetic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
US7078429B2 (en) 2002-12-10 2006-07-18 Wyeth Substituted 3-carbonyl-1H-indol-1-yl acetic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
US7101903B2 (en) 2002-12-10 2006-09-05 Wyeth Substituted dihydropyrano indole-3,4-dione derivatives as inhibitiors of plasminogen activator inhibitor-1 (PAI-1)
US7459478B2 (en) 2002-12-10 2008-12-02 Wyeth Substituted dihydropyrano indole-3,4-dione derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
US7160918B2 (en) 2002-12-10 2007-01-09 Hassan Mahmoud Elokdah Substituted indole oxo-acetyl amino acetic acid derivatives as inhibitors of plasminogen activator inhibitor (PAI-1)
US7674818B2 (en) 2002-12-10 2010-03-09 Wyeth Llc Aryl, aryloxy, alkyloxy substituted 1H-indol-3-yl glyoxylic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
US7348351B2 (en) 2002-12-10 2008-03-25 Wyeth Substituted 3-alkyl and 3-arylalkyl 1H-indol-1yl acetic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
US7259182B2 (en) 2002-12-10 2007-08-21 Wyeth Aryl, aryloxy, and aklyloxy substituted 1H-indol-3-yl glyoxylic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
WO2004054581A3 (fr) * 2002-12-13 2005-02-03 Smithkline Beecham Corp Composes de cyclohexyle utiles en tant qu'antagonistes du ccr5
WO2004054581A2 (fr) * 2002-12-13 2004-07-01 Smithkline Beecham Corporation Composes de cyclohexyle utiles en tant qu'antagonistes du ccr5
US7589207B2 (en) 2002-12-13 2009-09-15 Smithkline Beecham Corporation Cyclohexyl compounds as CCR5 antagonists
WO2004098591A2 (fr) 2003-05-05 2004-11-18 Probiodrug Ag Inhibiteurs de glutaminyl-cyclase
WO2005030754A1 (fr) * 2003-09-24 2005-04-07 Janssen Pharmaceutica, N.V. Derives d'indole ou de quinoline utilises en tant qu'inhibiteurs non-peptidiques du recepteur npy y2 pour le traitement de troubles anxiolytiques et depressifs ainsi que pour le traitement de l'obesite
US7317025B2 (en) 2003-09-24 2008-01-08 Johnson & Johnson Pharmaceutical Research & Development, Llc Non-peptidic NPY Y2 receptor inhibitors
US7411083B2 (en) 2003-09-25 2008-08-12 Wyeth Substituted acetic acid derivatives
US7803835B2 (en) 2003-09-25 2010-09-28 Wyeth Llc Substituted acetic acid derivatives
US7163954B2 (en) 2003-09-25 2007-01-16 Wyeth Substituted naphthyl benzothiophene acids
US7351726B2 (en) 2003-09-25 2008-04-01 Wyeth Substituted oxadiazolidinediones
US7141592B2 (en) 2003-09-25 2006-11-28 Wyeth Substituted oxadiazolidinediones
US7265148B2 (en) 2003-09-25 2007-09-04 Wyeth Substituted pyrrole-indoles
US7268159B2 (en) 2003-09-25 2007-09-11 Wyeth Substituted indoles
US7332521B2 (en) 2003-09-25 2008-02-19 Wyeth Substituted indoles
US7420083B2 (en) 2003-09-25 2008-09-02 Wyeth Substituted aryloximes
US7582773B2 (en) 2003-09-25 2009-09-01 Wyeth Substituted phenyl indoles
US7442805B2 (en) 2003-09-25 2008-10-28 Wyeth Substituted sulfonamide-indoles
US7446201B2 (en) 2003-09-25 2008-11-04 Wyeth Substituted heteroaryl benzofuran acids
US7342039B2 (en) 2003-09-25 2008-03-11 Wyeth Substituted indole oximes
EP2338490A2 (fr) 2003-11-03 2011-06-29 Probiodrug AG Combinaisons utiles pour le traitement de désordres neuronales
WO2005075436A2 (fr) 2004-02-05 2005-08-18 Probiodrug Ag Nouveaux inhibiteurs de la glutaminyl-cyclase
US7754747B2 (en) 2004-08-23 2010-07-13 Wyeth Llc Oxazolo-naphthyl acids
US7323483B2 (en) 2005-01-27 2008-01-29 Wyeth Processes and compounds for the preparation of substituted naphthylindole derivatives
US7683091B2 (en) 2005-08-17 2010-03-23 Wyeth Substituted indoles and methods of their use
WO2007046112A1 (fr) * 2005-10-19 2007-04-26 Suven Life Sciences Inc. Derives de arylthioether tryptamine utiles en tant que ligands 5-ht6 fonctionnels
WO2008055945A1 (fr) 2006-11-09 2008-05-15 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
WO2008065141A1 (fr) 2006-11-30 2008-06-05 Probiodrug Ag Nouveaux inhibiteurs de glutaminylcyclase
WO2008104580A1 (fr) 2007-03-01 2008-09-04 Probiodrug Ag Nouvelle utilisation d'inhibiteurs de la glutaminyl cyclase
EP2481408A2 (fr) 2007-03-01 2012-08-01 Probiodrug AG Nouvelle utilisation d'inhibiteurs glutaminyle cyclase
EP2865670A1 (fr) 2007-04-18 2015-04-29 Probiodrug AG Dérivés de thio-urée utilisés comme inhibiteurs de la glutaminyl cyclase
US8664380B2 (en) 2008-06-19 2014-03-04 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof
US9221836B2 (en) 2008-06-19 2015-12-29 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof
US9045436B2 (en) 2008-06-19 2015-06-02 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof
US8466282B2 (en) 2008-06-19 2013-06-18 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof
WO2011029920A1 (fr) 2009-09-11 2011-03-17 Probiodrug Ag Dérivés hétérocycliques en tant qu'inhibiteurs de glutaminyle cyclase
WO2011107530A2 (fr) 2010-03-03 2011-09-09 Probiodrug Ag Nouveaux inhibiteurs
WO2011110613A1 (fr) 2010-03-10 2011-09-15 Probiodrug Ag Inhibiteurs hétérocycliques de la glutaminyl cyclase (qc, ec 2.3.2.5)
WO2011131748A2 (fr) 2010-04-21 2011-10-27 Probiodrug Ag Nouveaux inhibiteurs
WO2012123563A1 (fr) 2011-03-16 2012-09-20 Probiodrug Ag Dérivés de benzimidazole en tant qu'inhibiteurs de la glutaminyl cyclase
EP2707101B1 (fr) * 2011-05-12 2019-02-13 Proteostasis Therapeutics, Inc. Régulateurs de la protéostasie
US10532996B2 (en) 2011-05-12 2020-01-14 Proteostasis Therapeutics, Inc. Proteostasis regulators
WO2012168697A1 (fr) 2011-06-06 2012-12-13 Imperial Innovations Limited Procédés de prédiction de l'affinité de liaison à tspo d'agents d'imagerie
EP3461819A1 (fr) 2017-09-29 2019-04-03 Probiodrug AG Inhibiteurs de la glutaminyl-cyclase

Also Published As

Publication number Publication date
CN1173867A (zh) 1998-02-18
HUP9701714A3 (en) 2000-03-28
HUP9701714A2 (hu) 1999-06-28
NO308296B1 (no) 2000-08-28
TR199700334T1 (tr) 1997-08-21
CZ132897A3 (en) 1997-11-12
NZ318228A (en) 1999-07-29
PL320010A1 (en) 1997-09-01
AU6965096A (en) 1997-03-27
IL120724A0 (en) 1997-08-14
AU717422B2 (en) 2000-03-23
CA2203912A1 (fr) 1997-03-13
EP0789688A1 (fr) 1997-08-20
EP0789688A4 (fr) 1997-11-19
BR9606619A (pt) 1997-12-23
NO972016L (no) 1997-06-17
MX9703186A (es) 1997-07-31
NO972016D0 (no) 1997-04-30

Similar Documents

Publication Publication Date Title
AU717422B2 (en) Indolyl neuropeptide Y receptor antagonists
US6403577B1 (en) Hexamethyleneiminyl tachykinin receptor antagonists
WO1997025041A1 (fr) Antagonistes benzimidazolyles du recepteur du neuropeptide y
US6329389B1 (en) Amine compounds, their production and use
CA2162786A1 (fr) Antagonistes heterocycliques des recepteurs des tachykinines
US20050245571A1 (en) Amine derivative
US6245761B1 (en) Indolyl neuropeptide Y receptor antagonists
EP0699674A1 (fr) Dérivés de 1-aryl-2-acétylamidopentanone pour utilisation comme antagonistes de récepteurs de la tachykinine
EP0686629A2 (fr) Antagonistes des récepteurs de tachycinine cyclohexyliques
KR20040017325A (ko) 페닐술포닐-1,3-디히드로-2ｈ-인돌-2-온 유도체, 이의제조 및 치료학적 용도
US6358994B1 (en) 2-acylaminopropanamines as tachykinin receptor antagonists
US6255494B1 (en) Benzimidzolyl neuropeptide Y receptor antagonists
JPH10508321A (ja) インドリル神経ペプチドｙレセプターアンタゴニスト
US5563133A (en) Hexamethyleneiminyl tachykinin receptor antagonists
US6175013B1 (en) Imidazolinyl tachykinin receptor antagonists
US5776931A (en) Naphthimidazolyl neuropeptide Y receptor antagonists
US5607947A (en) Pyrrolidinyl tachykinin receptor antagonists
US6869957B1 (en) Non-peptide tachykinin receptor antagonists
AU8692698A (en) 2-acylaminopropanamines as tachykinin receptor antagonists
AU721935B2 (en) Non-peptide tachykinin receptor antagonists
JP2000226373A (ja) アミン誘導体、その製造法および剤
MXPA00001167A (en) 2-acylaminopropanamines as tachykinin receptor antagonists

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 96191324.X

Country of ref document: CN

AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE HU IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK TJ TM TR TT UA UG UZ VN AM AZ BY KG KZ MD RU TJ TM

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): KE LS MW SD SZ UG AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM

ENP Entry into the national phase

Ref document number: 2203912

Country of ref document: CA

Ref document number: 2203912

Country of ref document: CA

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 1996930691

Country of ref document: EP

Ref document number: PV1997-1328

Country of ref document: CZ

Ref document number: PA/a/1997/003186

Country of ref document: MX

Ref document number: 1019970702871

Country of ref document: KR

Ref document number: 97-00823

Country of ref document: RO

WWE Wipo information: entry into national phase

Ref document number: 318228

Country of ref document: NZ

Ref document number: 97/00334

Country of ref document: TR

121 Ep: the epo has been informed by wipo that ep was designated in this application
WWP Wipo information: published in national office

Ref document number: 1996930691

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: PV1997-1328

Country of ref document: CZ

WWP Wipo information: published in national office

Ref document number: 1019970702871

Country of ref document: KR

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWR Wipo information: refused in national office

Ref document number: PV1997-1328

Country of ref document: CZ

WWW Wipo information: withdrawn in national office

Ref document number: 1996930691

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1019970702871

Country of ref document: KR