WO2005003103A2 - Nouveaux heterocycles 2,4,6-trisubstitues et utilisations de ceux-ci - Google Patents

Nouveaux heterocycles 2,4,6-trisubstitues et utilisations de ceux-ci Download PDF

Info

Publication number
WO2005003103A2
WO2005003103A2 PCT/GB2004/002723 GB2004002723W WO2005003103A2 WO 2005003103 A2 WO2005003103 A2 WO 2005003103A2 GB 2004002723 W GB2004002723 W GB 2004002723W WO 2005003103 A2 WO2005003103 A2 WO 2005003103A2
Authority
WO
WIPO (PCT)
Prior art keywords
amino
optionally substituted
methyl
fluorophenyl
triazin
Prior art date
Application number
PCT/GB2004/002723
Other languages
English (en)
Other versions
WO2005003103A3 (fr
Inventor
Dean Brown
Joseph Cacciola
Robert T Jacobs
Frances M Mclaren
Ashokkumar Bhikkappa Shenvi
Reed W Smith, Jr
Original Assignee
Astrazeneca Ab
Astrazeneca Uk Limited
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
Application filed by Astrazeneca Ab, Astrazeneca Uk Limited filed Critical Astrazeneca Ab
Publication of WO2005003103A2 publication Critical patent/WO2005003103A2/fr
Publication of WO2005003103A3 publication Critical patent/WO2005003103A3/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
    • C07D251/40—Nitrogen atoms
    • C07D251/48—Two nitrogen atoms
    • C07D251/52—Two nitrogen atoms with an oxygen or sulfur atom attached to the third ring carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
    • C07D251/40—Nitrogen atoms
    • C07D251/54—Three nitrogen 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
    • 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
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to novel triazines, pyrimidines, and pyridines and their pharmaceutical compositions and methods of use.
  • the present invention relates to therapeutic methods for the treatment and prevention of various diseases especially Alzheimer's disease and other diseases relating to the deposition of amyloid.
  • Alzheimer's Disease is a progressive, neurodegenerative disease characterized clinically by progressive loss of memory, cognition, reasoning, judgment and emotional stability.
  • AD is a common cause of dementia in humans and a leading cause of death in the United States. AD has been observed in races and ethnic groups worldwide and presents a major public health problem throughout the world.
  • AD Alzheimer's disease
  • amyloid or senile plaques
  • neurofibrillar tangles that are found in the regions of the brain associated with memory, reasoning and cognition. Similar alterations are observed in patients with Trisomy 21 (Down's syndrome) and hereditary cerebral hemorrhage with amyloidosis of the Dutch-type.
  • amyloid ⁇ protein is derived from the proteolytic cleavage of amyloid precursor protein (APP).
  • One embodiment of the invention is a compound of formula (I) or a pharmaceutically acceptable salt thereof:
  • Q is C, CH or N; W is N or S, when W is S, R 6 is not present; X is C or N, provided that when Y and Z are C, X is N; Y is C or N, provided that when X and Z are C, Y is N; Z is C or N, provided that when X and Y are C, Z is N; R 1 and R are at each occurrence independently selected from H, CH 3j optionally substituted C].
  • R 3 is selected from H, or optionally substituted C ⁇ - 6 alkyl;
  • R 5 is selected from H, or CH 3 ;
  • R 6 is selected from H;
  • R 7 is selected from optionally substituted carbocycle.
  • a further embodiment is a compound of formula (II) or a pharmaceutically acceptable salt thereof: (II)
  • Q is O, S, SO or SO 2; W is N or halogen, when W is halogen neither R 6 nor R 7 are present;
  • X is C or N, provided that when Y and Z are C, X is N;
  • Y is C or N, provided that when X and Z are C, Y is N;
  • Z is C or N, provided that when X and Y are C, Z is N;
  • R 2 is selected from H, optionally substituted Ci- 6 alkyl, optionally substituted carbocycle, or optionally substituted heterocycle;
  • R 3 is selected from H, or optionally substituted Cj.
  • One embodiment of the invention is a compound of formula (I) or a pharmaceutically acceptable salt thereof:
  • Q is C, CH orN; W is N or S, when W is S, R 6 is not present; X is C or N, provided that when Y and Z are C, X is N; Y is C or N, provided that when X and Z are C, Y is N; Z is C or N, provided that when X and Y are C, Z is N; R 1 and R 2 are at each occurrence independently selected from H, CH 3; optionally substituted C].
  • R 1 and R 2 in combination can form an optionally substituted heterocycle, or an optionally substituted carbocycle;
  • R 3 is selected from H, or optionally substituted C ⁇ - 6 alkyl;
  • R 5 is selected from H, or CH 3 ;
  • R 6 is selected from H;
  • R 7 is selected from optionally substituted carbocycle.
  • a further embodiment is a compound of claim 1, wherein: Q is N.
  • a further embodiment is a compound of claim 1, wherein: W is S, and R 6 is not present.
  • a further embodiment is a compound of claim 1, wherein: X is C.
  • a further embodiment is a compound of claim 1, wherein: Y is N.
  • a further embodiment is a compound of claim 1, wherein: Z is N.
  • a further embodiment is a compound of claim 1, wherein: R 1 and R 2 are at each occurrence are independently selected from H, or optionally substituted carbocycle, or optionally substituted heterocycle.
  • a compound of claim 1, wherein: R 3 is an optionally substituted C ⁇ - 6 alkyl.
  • R 5 is selected from H.
  • a further embodiment is a compound of claim 1, wherein: R 7 is an optionally substituted carbocycle.
  • a further embodiment is a compound of claim 1, wherein: Q is N or C; W is S, and R 6 is not present; X is C or N, provided that when Y and Z are C, X is N; Y is C or N, provided that when X and Z are C, Y is N; Z is C or N, provided that when X and Y are C, Z is N; ⁇ R and R are at each occurrence independently selected from H, or optionally substituted carbocycle; or optionally substituted heterocycle or optionally substituted C ⁇ .
  • R 3 is selected from H, or optionally substituted Ci- 6 alkyl
  • R 5 is selected from H
  • R 7 is selected from optionally substituted carbocycle.
  • a further embodiment is a compound of formula (I) selected from: Methyl N- ⁇ 4-[(3-fluorophenyl)amino]-6-[(2-hydroxypropyl)amino]-l,3,5-triazin-2-yl ⁇ -L- leucinate; Methyl N- ⁇ 4-[(3-fluorophenyl)amino]-6-morpholin-4-yl-l,3,5-triazin-2-yl ⁇ -L-leucinate; (2R)-2-( ⁇ 4-[(3-fluorophenyl)amino]-6-[(3-methoxypropyl)amino]-l,3,5-triazin-2-yl ⁇ amino)-
  • a further embodiment is a compound of formula (II) or a pharmaceutically acceptable salt thereof:
  • Q is O, S, SO or SO 2; W is N or halogen, when W is halogen neither R 6 nor R 7 are present; X is C or N, provided that when Y and Z are C, X is N; Y is C or N, provided that when X and Z are C, Y is N; Z is C or N, provided that when X and Y are C, Z is N; R 2 is selected from H, optionally substituted C].
  • R 3 is selected from H, or optionally substituted C ⁇ - 6 alkyl
  • a further embodiment is a compound of formula (II), wherein: Q is S; A further embodiment is a compound of formula (II), wherein: W is N; A further embodiment is a compound of formula (II), wherein: X is N; A further embodiment is a compound of formula (II), wherein: X is C; A further embodiment is a compound of formula (II), wherein: Y is N;
  • a further embodiment is a compound of formula (II), wherein: Y is C.
  • a further embodiment is a compound of formula (II), wherein: Z isN.
  • a further embodiment is a compound of formula (II), wherein: Z is C.
  • a further embodiment is a compound of formula (II), wherein: R 2 is optionally substituted carbocycle.
  • a further embodiment is a compound of formula (II), wherein: R 3 is optionally substituted C h alky!.
  • a further embodiment is a compound of formula (II), wherein: R 5 is selected from H, or CH 3 ;
  • a further embodiment is a compound of formula (II), wherein: R 6 is selected from H or CH 3 ;
  • a further embodiment is a compound of formula (II), wherein: R is optionally substituted carbocycle.
  • R 5 is H; R and R 5 in combination form an optionally substituted heterocycle; R is selected from H; R 7 is selected from, optionally substituted carbocycle, optionally substituted heterocycle, or -(CH 2 )]- 3 -optionally substituted carbocycle.
  • R 5 is H;
  • R 6 is selected from H;
  • R 7 is selected from, optionally substituted carbocycle, optionally substituted heterocycle, or -(CH 2 ) ⁇ ;- 3 -optionally substituted carbocycle.
  • R 5 is selected from H;
  • R 6 is selected from H;
  • R 7 is optionally substituted carbocycle.
  • a further embodiment is a compound of formula (II) selected from:
  • a further embodiment is a compound according to fo ⁇ nula (I) and/or formula (II), for use as a medicament.
  • a further embodiment is the use of a compound according to formula (I) and/or formula (II), in the manufacture of a medicament for the treatment or prophylaxis of disorders associated with ⁇ -amyloid production.
  • a further embodiment is the use of a compound according to formula (I) and/or formula (II), in the manufacture of a medicament for the treatment or prophylaxis of Alzheimer's disease or Down's syndrome.
  • a further embodiment is a method for the treatment of neurological disorders associated with ⁇ -amyloid production comprising administering to a warm-blooded animal in need of such treatment a therapeutically effective amount of a compound according to formula (I) and/or fo ⁇ nula (II).
  • a further embodiment is a method for inhibiting ⁇ -secretase activity comprising administering to a wa ⁇ n-blooded animal in need of such inhibition a therapeutically effective amount of a compound according to formula (I) and/or formula (II).
  • a further embodiment is a method for the treatment or prophylaxis of Alzheimer's disease or Down's syndrome comprising administring to a warm-blooded animal in need of such treatment a therapeutically effective amount of a compound according to formula (I) and/or formula (II).
  • a further embodiment is a pha ⁇ naceutical composition
  • a pha ⁇ naceutical composition comprising a compound according to formula (I) and/or formula (II), or a pharniaceutically acceptable salt or in vivo hydrolysable ester thereof, together with at least one pharmaceutically acceptable carrier, diluent or excipient.
  • a further embodiment is a process for preparing a compound of formula (I), which process comprises:
  • a further embodiment is a process for preparing a compound of formula (II) which process comprises: 1c
  • substitution means that substitution is optional and therefore it is possible for the designated atom to be unsubstituted.
  • substitution means that any number of hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the no ⁇ nal valency of the designated atom is not exceeded, and that the substitution results in a stable compound.
  • 2 hydrogens on the atom are replaced.
  • any variable e.g., R 1 , R 7 , R a , R e etc.
  • its definition at each occurrence is independent of its definition at every other occurrence.
  • R 1 e.g., R 1 , R 7 , R a , R e etc.
  • R e at each occurrence is selected independently from the definition of R e .
  • combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • the range "according to claims 1-9" means claims 1, 2, 3, 4, 5, 6, 7, 8, or 9.
  • the compounds herein described may have asymmetric centers.
  • alkyl or “alkylene” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • C ⁇ - 6 alkyl denotes alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms.
  • alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t- butyl, pentyl, and hexyl.
  • C]- 3 alkyl whether a terminal substituent or an alkylene group linking two substituents, is understood to specifically include both branched and straight-chain methyl, ethyl, and propyl.
  • alkenyl or “alkenylene” is intended to include hydrocarbon chains of either a straight or branched configuration with one or more unsaturated carbon-carbon bonds that may occur at any stable point along the chain.
  • Examples of “C 3 . 6 alkenyl” include, but are not limited to, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 2- pentenyl, 3-pentenyl, hexenyl, and the like.
  • alkynyl or “alkynylene” is intended to include hydrocarbon chains of either a straight or branched configuration with one or more carbon-carbon triple bonds that may occur at any stable point along the chain, such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, and the like.
  • alkoxy or "alkyloxy” represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge.
  • alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t- butoxy, n-pentoxy, and s-pentoxy.
  • Preferred alkoxy groups are methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy.
  • alkylthio or “thioalkoxy” represent an alkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge.
  • carbocycle is intended to mean any stable 3- to 7-membered monocyclic or bicyclic or 7- to 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic.
  • carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, bicyclooctane, bicyclononane, bicyclodecane (decalin), bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).
  • halo or halogen refers to fluoro, chloro, bromo, and iodo.
  • Counterion is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate, and the like.
  • haloalkyl examples include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, heptafluoropropyl, and heptachloropropyl.
  • Haloalkoxy is intended to mean a haloalkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge; for example trifluoromethoxy, pentafluoroethoxy, 2,2,2-trifluoroethoxy, and the like.
  • Halothioalkoxy is intended to mean a haloalkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge.
  • heterocycle refersto a ring-containing monovalent and divalent radicals having one or more heteroatoms, independently selected from N, O and S, as part of the ring structure and comprising at least 3 and up to about 20 atoms in the rings.
  • Heterocyclic groups may be saturated or unsaturated, containg one or more double bonds, and heterocyclic groups may contain more that one ring.
  • the heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, nitrogen in the heterocycle may optionally be quaternized. It is understood that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another.
  • heterocycles include, but are not limited to, lH-indazole, 2-pyrrolidonyl, 2H, 6H-1, 5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H- quinolizinyl, 6H-1, 2,5-thiadiazinyl, acridinyl, azetidine, aziridine, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH- carbazolyl, b-carbolinyl, chromanyl, chromenyl, cinnoliny
  • thiotetrahydroquinolinyl 6H-1, 2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4- thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, thiirane, triazinyl, 1,2,3- triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, xanthenyl.
  • pharmaceutically acceptable is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
  • pha ⁇ naceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like
  • organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic,
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
  • Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
  • Prodrugs are intended to include any covalently bonded carriers that release the active parent drug according to formula (I) in vivo when such prodrug is administered to a mammalian subject.
  • Prodrugs of a compound of formula (I) are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound.
  • Prodrugs include compounds of formula (I) wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug or compound of formula (I) is administered to a mammalian subject, cleaves to forni a free hydroxyl, free amino, or free sulfhydryl group, respectively.
  • Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of formula (I), and the like.
  • Solid compound and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • the compounds described herein may be provided or delivered in a form suitable for oral use, for example in a tablet, lozenge, hard and soft capsule, aqueous solution, oily solution, emulsion, and suspension.
  • the compounds may also be provided for topical administration, for example, as a cream, ointment, gel, spray, or aqueous solutions, oily solutions, emulsions or suspensions.
  • the compounds described herein may also be provided in a form suitable for nasal administration for example, as a nasal spray, nasal drops, or dry powder.
  • the compositions may also be administered to the vagina or rectum in the form of a suppository.
  • compositions described herein may also be administered parentally, for example by intravenous, intravesicular, subcutaneous, intrathoracially, intracerebroventricularly, or intramuscular injection or infusion.
  • the compounds may be administered by insufflation (for example as a finely divided powder).
  • the compounds may also be administered transdermally, sublingually, .
  • the compositions of the invention may accordingly be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art.
  • compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and/or preservative agents.
  • the amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration.
  • the size of the dose for therapeutic or prophylactic purposes of a compound described herein will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine.
  • an effective amount of a compound described herein for use in therapy of Alzheimer's Disease is an amount sufficient to symptomatically relieve in a warm-blooded animal, particularly a human the cognitive symptoms, to slow the progression of worsening cognitive symptoms, or to reduce in patients with cognitive symptoms the risk of getting worse (progressing to dementia or worsening the present degree of dementia).
  • inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories.
  • a solid carrier can be one or more substances, which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents; it can also be an encapsulating material.
  • the carrier In powders, the carrier is a finely divided solid that is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • Salts include, but are not limited to, pharmaceutically acceptable salts.
  • pharmaceutically acceptable salts of compounds of the present invention include but are not limited to the following: acetate, bicarbonate, bisulfate, bisulfite, carbonate, hydrobromide, hydrochloride, phosphate/diphosphate, sulfate, choline, diethanolamine, ethylenediamine, meglumine, aluminum, calcium, magnesium, nitrate, potassium, pyrosulfate, and sodium.
  • composition is intended to include the fo ⁇ nulation of the active component with encapsulating material as a carrier providing a capsule in which the active component (with or without other carriers) is surrounded by a carrier which is thus in association with it.
  • cachets are included. Tablets, powders, cachets, and capsules can be used, as solid dosage forms suitable for oral administration.
  • Liquid form compositions include solutions, suspensions, and emulsions.
  • Sterile water or water-propylene glycol solutions of the active compounds may be mentioned as an example of liquid preparations suitable for parenteral administration.
  • Liquid compositions can also be formulated in solution in aqueous polyethylene glycol solution.
  • Aqueous solutions for oral administration can be prepared by dissolving the active component in water and adding suitable colorants, flavoring agents, stabilizers, and thickening agents as desired.
  • Aqueous suspensions for oral use can be made by dispersing the finely divided active component in water together with a viscous material such as natural synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art.
  • the pharmaceutical compositions can be in unit dosage form.
  • the composition is divided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of the preparations, for example, packeted tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can also be a capsule, cachet, or tablet itself, or it can be the appropriate number of any of these packaged forms.
  • the compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis.
  • the compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Such methods include, but are not limited to, those described below. All references cited herein are hereby incorporated in their entirety by reference.
  • novel compounds of this invention may be prepared using the reactions and techniques described in this application.
  • the reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transfo ⁇ nations being effected.
  • all proposed reaction conditions including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art.
  • the functionality present on various portions of the molecule must be compatible with the reagents and reactions proposed. Such restrictions to the substituents, which are compatible with the reaction conditions, will be readily apparent to one skilled in the art and alternate methods must then be used.
  • Example 1 To a stirred solution of cyanuric chloride (la) (2.23 g, 12.1 mmol) in THF (50 mL) was added 3-fluoroaniline (1.17 mL, 12.1 mmol) and DIEA (8.4 mL, 48.4 mmol). The mixture was stirred for 1 hour, leucine methyl ester hydrochloride (2.23 g, 21.1 mmol) was added and the solution heated to reflux for 4 h. The mixture was cooled to room temperature and the solvent removed in vacuo. The residual oil was partitioned between CH 2 C1 2 and IN HCl (100 mL). The organic layer was separated, washed with NaCl (sat.) and dried over Na 2 S0 .
  • Example 27 Methyl N- ⁇ 4-(4-methoxyphenoxy)-6-f(thien-2-ylmethyl)amino1-l,3.5- triazin-2-yl ⁇ -L-leucinate (27).
  • Example 38 Synthesis of Methyl N- ⁇ 4-[(3-fluoropheny ⁇ amino1-6-[(4- methoxyphenyl)thio1-l.,3.,5-triazin-2-yl ⁇ g-vcinate ( ' 38).
  • Example 38 A portion of 4-chloro-N-(3 -fluoropheny l)-6- [(4-methoxypheny l)thio]-l ,3,5-triazin-2-amine 38a (0.65 g, 1.7 mmol) was dissolved in DMF (10 mL) and to this was added PS-HOBT (1.00 g, 1.4 mmol), followed by DIEA (0.60 mL, 3.3 mmol). The suspension was carefully stirred at 90° C for 2h. The resin was filtered and washed with CH 2 C1 2 (3 x 100 mL), then Et 2 O (1 x 100 inL) and dried in vacuo to give a yellow free-flowing resin 38b (1.19 g).
  • the residual oil was partitioned between CH 2 C1 2 and IN HCl (100 mL). The organic layer was separated, washed with NaCl (sat.) and dried over Na 2 SO . The residual oil was chromatographed (10:1 hexanes/ethyl acetate) to give 4-chloro-N-(3-fluorophenyl)-6-[(4- methoxyphenyl)thio]-l ,3,5-triazin-2-amine 38a (2.0 g, 92%).
  • Example 53 Methyl N-(4-[(2,3-dihydroxypropyl)thiol-6-[(3-fluorophenyl)amino1-1.3,5- triazin-2-yll-L-leucinate (53).
  • Example 65 Methyl N- ⁇ 4-r(3-fluorophenv ⁇ amino1-6-r(4-methoxyphenv ⁇ sulfinyn-l,3,5- triazin-2-yl ⁇ -L-leucinate (65).
  • Example 68 Synthesis of methyl N-r4-r(3-fluorophenvDamino1-6-(4-methoxybenzyl)- 1.3.5-triazin-2-vn-L-leucinate (68). 68a 68
  • Example 72 N 1 -r2-(DimethyIamino)ethyn-N 2 - ⁇ 4-r(3-fluorophenynamino1-6-r(4- methoxyphenyl)thio1-l,3,5-triazin-2-vU-L-leucinamide (72).
  • methyl N- ⁇ 4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]- l,3,5-triazin-2-yl ⁇ -L-leucinate 41 (10.1 g, 21.4 mmol) in THF (50 mL)
  • MeOH (50 mL) and H 2 0 (50 mL) was added LiOH (2.25 g, 53.5 mmol).
  • the reaction was stirred for thirty minutes, and then diluted with CH 2 C1 2 (50 mL).
  • the organic layers were washed with ⁇ aCl (sat. 50 mL) containing two drops of IN HCl.
  • the organic layer was separated and dried over ⁇ a 2 SO 4 , and then the residual oil chromatographed (SiO 2 , hexanes/ethyl acetate, 90/10) to give a white foam (0.135 g, 64%).
  • the resultant material was used as is in the next reaction.
  • Example 96 Methyl N- ⁇ 4-r(3-fluorophenyl)aminol-6-f(4- methoxyphenvDthiol pyrimidin-2-yl)-N-methylleucinate (96).
  • the residual oil was partitioned between CH 2 C1 (500 mL) and IN HCl (3 x 100 mL). A portion of the material was chromatographed (11 g) SiO 2 , hexanes/ethyl acetate, gradient, 100/0 to 80/20 over 38 minutes at 35 ml/min to give the title compound (4.35 g, 23%) as a white solid.
  • Example 102 N 2 -r4-[(3-Fluorophenyl)aminol-6-(quinolin-2-ylthio pyrimidin-2-yll-N 1 - (tetrahydrofuran-2-ylmethylV -leucinamide (102).
  • Example 120 Methyl N-f4-f(3-fluorophenyl)amino1-6-(4-methoxybenzyl)pyrimidin-2- yll -L-leucinate (120). 91a 120a
  • the resultant 1 1 mixture of N-[4-chloro-6-(4-methoxybenzyl)pyrimidin-2-yl]-L-leucinate 120b and methyl N-[2-chloro-6-(4-methoxybenzyl)pyrimidin-4-yl]-L-leucinate 120c was concentrated and then chromatographed (SiO 2 , hexanes/ethyl acetate, gradient, 100/0 to 0/100 over 38 minutes at 85 ml/min) to give the title compound as a white foam. The material was assigned based on NOE studies.
  • the residual oil was chromatographed (SiO 2 , hexanes/ethyl acetate, gradient, 100/0 to 0/100 over 38 minutes at 85 ml/min) to give the title compound as a colorless oil (2.15 g, 73%).
  • Example 128 was prepared in analogy to Example 122, beginning with (S)-2-[6-bromo-4-(4- methoxy-phenylsulfanyl)-pyridin-2-ylamino]-4-methyl-pentanoic acid methyl ester 128b as the starting material. Column chromatography (CH 2 C1 2 , SiO ) gave the title compound as a white solid (12%).
  • Example 129 N 3 -(3-Fluoro-phenyl)-6-(4-methoxy-phenylsulfanyl)-N ⁇ -(3-methyl-l- pyridin-2-yl-butyl)-pyrimidine-2,4-diamine (129).
  • Example 130 N ⁇ -(3-Fluoro-phenyl)-6-(4-methoxy-phenylsulfanyl)-N 2 -(3-methyl-l- pyridin-2-yl-butyl)-pyrimidine-2,4-diamine (130).
  • the compounds of the present invention have utility for the prevention and treatment of Alzheimer's disease by inhibiting amyloid ⁇ production.
  • Methods of treatment target formation of amyloid ⁇ production through enzymes involved in the proteolytic processing of ⁇ amyloid precursor protein.
  • the inhibitions of ⁇ and ⁇ secretases reduce the production of amyloid ⁇ and are thought to reduce or prevent the neurological disorders such as Alzheimer's disease.
  • the compounds of the present invention have utility for the prevention and treatment of disorders involving amyloid ⁇ production, such as cerebrovascular disorders.
  • ug denotes microgram
  • mg denotes milligram
  • g denotes gram
  • uL denotes microliter
  • mL denotes milliliter
  • L denotes liter
  • nM denotes nanomolar
  • .uM denotes micromolar
  • mM denotes millimolar
  • M denotes molar
  • nm denotes nanometer
  • DMSO denotes dimethyl sulfoxide
  • DTT denotes dithiothreitol
  • DPBS denotes
  • EDTA denotes ethylenediaminetetraacetate
  • the gamma secretase enzyme assay measures the amount of amyloid ⁇ (A ⁇ )40 product generated by the cleavage of C 100, a truncated form of amyloid precursor protein (APP).
  • the C100 substrate is a recombinant protein purified from E. coli inclusion bodies.
  • the ⁇ secretase enzyme complex is prepared by detergent extraction of HeLa 8A8 cell membranes. The enzyme reaction contains 10 ul of inhibitor at a defined concentration, diluted from a DMSO stock into 96-well microplates (final concentration of DMSO is maintained at 5%).
  • reaction buffer 50 mM MES, pH 6.5, containing 100 mM NaCl, 1 mM EDTA, 1 mM DTT, 1 mg/mL BSA, 0.25% Chapso, 0.01% PE, 0.01% PC and a protease cocktail
  • the reactions are initiated by addition of lOul enzyme at a 20-fold dilution from stock.
  • An A ⁇ 40 standard curve diluted in the reaction buffer plus C100 is included in each assay. Plates are incubated for 3 hours at 37 degrees.
  • an antibody mixture is added: rabbit anti-A ⁇ 40 antibody (Biosource #44-3481) at 0.16 ug/ml and biotinylated 4G8 (Senetek #240-10) at 0.25 ug/ml in DPBS (Fisher # MT21031CV) containing 0.5% bovine serum albumin, 0.5% Tween 20. Plates are then incubated overnight at 4 degrees.
  • HEK Human Embryonic Kidney cells stably expressing human Amyloid Precursor protein (APP) and Presenelin I were grown in DMEM media (Fisher MT10013CN) containing 10% fetal calf serum (Fisher #MT135011CV), 0.2 mg/mL G418 (Fisher #MT30234CR) and IX concentration of antibiotic/antimycotic mixture (Fisher #MT30004CI). Cells were grown in tissue culture flasks and passaged every week at a ratio of 1:30.
  • Test compounds were solubilized in DMSO at a concentration of 3.3 mM. From this stock solution a dilution series was prepared in complete growth medium of cells. Dilution series were then transferred to 96 well assay plate (Costar #3595) with 100 uL in each well. Cells (100 uL) were added to each well containing test compound. Two controls, one containing only cells (Total) and one containing only growth medium (Background) were also included. Cells were incubated with compounds for 14-16 hours in cell culture incubator.

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Neurosurgery (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Hospice & Palliative Care (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Psychiatry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne des composés de formules (I) et (II), des compositions pharmaceutiques de ceux-ci, ainsi que des procédés pour les utiliser afin de traiter des troubles neurologiques liés à la production de protéines amyloïdes β, tels que la maladie d'Alzheimer.
PCT/GB2004/002723 2003-06-30 2004-06-24 Nouveaux heterocycles 2,4,6-trisubstitues et utilisations de ceux-ci WO2005003103A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US48425003P 2003-06-30 2003-06-30
US60/484,250 2003-06-30

Publications (2)

Publication Number Publication Date
WO2005003103A2 true WO2005003103A2 (fr) 2005-01-13
WO2005003103A3 WO2005003103A3 (fr) 2005-11-03

Family

ID=33563971

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2004/002723 WO2005003103A2 (fr) 2003-06-30 2004-06-24 Nouveaux heterocycles 2,4,6-trisubstitues et utilisations de ceux-ci

Country Status (1)

Country Link
WO (1) WO2005003103A2 (fr)

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006088705A1 (fr) * 2005-02-14 2006-08-24 Wyeth Guanidine de terphenyle en tant qu'inhibiteurs de la $g(b)-secretase
WO2008074068A1 (fr) * 2006-12-20 2008-06-26 Prana Biotechnology Limited Dérivés de quinoline substitués utilisés comme agents non-amyloïdogéniques
WO2009044160A1 (fr) * 2007-10-05 2009-04-09 Senexis Limited Dérivés de pyridine pour le traitement de maladies se rapportant aux amyloïdes
EP2120573A1 (fr) * 2007-02-12 2009-11-25 Merck & Co., Inc. Dérivés de la pipéridine
WO2010040661A1 (fr) 2008-10-09 2010-04-15 F. Hoffmann-La Roche Ag Modulateurs pour l'amyloïde bêta
WO2010144423A1 (fr) 2009-06-09 2010-12-16 Abraxis Bioscience, Llc Dérivés de la styryl-triazine et leurs applications thérapeutiques
US7858782B2 (en) 2006-12-15 2010-12-28 Abraxis Bioscience, Llc Triazine derivatives and their therapeutical applications
US7928109B2 (en) 2007-04-18 2011-04-19 Pfizer Inc Sulfonyl amide derivatives for the treatment of abnormal cell growth
US8158641B2 (en) 2006-06-15 2012-04-17 Boehringer Ingelheim International Gmbh 2-anilino-4-aminoalkyleneaminopyrimidines
US8288403B2 (en) 2008-11-10 2012-10-16 Hoffmann-La Roche Inc. Heterocyclic gamma secretase modulators
US8354407B2 (en) 2006-06-15 2013-01-15 Boehringer Ingelheim International Gmbh 2-anilino-4-(heterocyclic)amino-pyrimidines
US8486967B2 (en) 2010-02-17 2013-07-16 Hoffmann-La Roche Inc. Heteroaryl substituted piperidines
US8877924B2 (en) 2009-06-09 2014-11-04 NantBio Inc. Benzyl substituted triazine derivatives and their therapeutical applications
US8962834B2 (en) 2008-02-22 2015-02-24 Hoffmann-La Roche Inc. Modulators of amyloid beta
US9078902B2 (en) 2009-06-09 2015-07-14 Nantbioscience, Inc. Triazine derivatives and their therapeutical applications
CN107304189A (zh) * 2016-04-18 2017-10-31 北京大学 一种三嗪化合物及其制备方法和应用
US10946023B2 (en) 2013-07-11 2021-03-16 Agios Pharmaceuticals, Inc. Therapeutically active compounds and their methods of use
AU2019201179B2 (en) * 2013-07-11 2021-03-25 Les Laboratoires Servier Therapeutically active compounds and their methods of use

Citations (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB929426A (en) * 1959-05-21 1963-06-26 Ici Ltd New triazine azo dyestuffs
US3271478A (en) * 1963-01-24 1966-09-06 Dal Mon Research Co Polymerizable triazines and products thereof
US3498984A (en) * 1966-10-28 1970-03-03 American Home Prod 4-amino-2-phenyl-6-thiopyrimidines
GB1405132A (en) * 1971-07-29 1975-09-03 Ciba Geigy Ag Azo dyestuffs containing hydroxypyridone residues their manufacture and use
US4140496A (en) * 1976-05-10 1979-02-20 Sumitomo Chemical Company, Limited S-Triazine derivatives
US4281103A (en) * 1978-09-18 1981-07-28 Ciba-Geigy Corporation Dicarboxylic acids containing triazine rings, and polyesters formed from these dicarboxylic acids
EP0201633A2 (fr) * 1984-12-20 1986-11-20 Abbott Laboratories Composés d'anilides substitués et leur utilisation
EP0834507A1 (fr) * 1996-10-01 1998-04-08 Janssen Pharmaceutica N.V. Dérivés de diamino-1,3,5-triazine substituée
WO1999016761A1 (fr) * 1997-09-30 1999-04-08 Mitsubishi Chemical Corporation Derives heterocycliques oxygenes
WO1999065881A1 (fr) * 1998-06-19 1999-12-23 Nissan Chemical Industries, Ltd. Composes heterocycliques utilises comme agents hypoglecymiques
WO2000025780A1 (fr) * 1998-10-29 2000-05-11 Bristol-Myers Squibb Company Composes derives d'un noyau amine inhibiteurs de l'enzyme impdh
WO2000043369A1 (fr) * 1999-01-22 2000-07-27 Elan Pharmaceuticals, Inc. Composes inhibant l'adhesion aux leucocytes a mediation assuree par vla-4
WO2001005783A1 (fr) * 1999-07-15 2001-01-25 Pharmacopeia, Inc. Antagonistes du recepteur b1 de la bradykinine
WO2002100836A2 (fr) * 2001-06-12 2002-12-19 Active Pass Pharmaceuticals, Inc. Composes, compositions et methodes de modulation de la production de beta-amyloide
WO2003007963A1 (fr) * 2001-07-17 2003-01-30 Neotherapeutics, Inc. Derives pyrimidiques et leur utilisation dans le traitement des maladies neurodegeneratives
WO2003032994A2 (fr) * 2001-10-17 2003-04-24 Boehringer Ingelheim Pharma Gmbh & Co. Kg Nouvelles pyrimidines substituees, procede permettant de les produire et leur utilisation comme medicament
WO2003045923A1 (fr) * 2001-11-28 2003-06-05 Btg International Ltd. Agents preventifs ou remedes contre la maladie d'alzheimer ou inhibiteurs de la fibrose des proteines amyloides contenant des composes heteroaryle a teneur en azote
WO2003066099A1 (fr) * 2002-02-05 2003-08-14 Yamanouchi Pharmaceutical Co., Ltd. Derives de 2,4,6-triamino-1,3,5-triazine

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS55112269A (en) * 1979-02-23 1980-08-29 Mitsubishi Chem Ind Ltd Monoazo dye for cellulose-containing fibers

Patent Citations (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB929426A (en) * 1959-05-21 1963-06-26 Ici Ltd New triazine azo dyestuffs
US3271478A (en) * 1963-01-24 1966-09-06 Dal Mon Research Co Polymerizable triazines and products thereof
US3498984A (en) * 1966-10-28 1970-03-03 American Home Prod 4-amino-2-phenyl-6-thiopyrimidines
GB1405132A (en) * 1971-07-29 1975-09-03 Ciba Geigy Ag Azo dyestuffs containing hydroxypyridone residues their manufacture and use
US4140496A (en) * 1976-05-10 1979-02-20 Sumitomo Chemical Company, Limited S-Triazine derivatives
US4281103A (en) * 1978-09-18 1981-07-28 Ciba-Geigy Corporation Dicarboxylic acids containing triazine rings, and polyesters formed from these dicarboxylic acids
EP0201633A2 (fr) * 1984-12-20 1986-11-20 Abbott Laboratories Composés d'anilides substitués et leur utilisation
EP0834507A1 (fr) * 1996-10-01 1998-04-08 Janssen Pharmaceutica N.V. Dérivés de diamino-1,3,5-triazine substituée
WO1999016761A1 (fr) * 1997-09-30 1999-04-08 Mitsubishi Chemical Corporation Derives heterocycliques oxygenes
WO1999065881A1 (fr) * 1998-06-19 1999-12-23 Nissan Chemical Industries, Ltd. Composes heterocycliques utilises comme agents hypoglecymiques
WO2000025780A1 (fr) * 1998-10-29 2000-05-11 Bristol-Myers Squibb Company Composes derives d'un noyau amine inhibiteurs de l'enzyme impdh
WO2000043369A1 (fr) * 1999-01-22 2000-07-27 Elan Pharmaceuticals, Inc. Composes inhibant l'adhesion aux leucocytes a mediation assuree par vla-4
WO2001005783A1 (fr) * 1999-07-15 2001-01-25 Pharmacopeia, Inc. Antagonistes du recepteur b1 de la bradykinine
WO2002100836A2 (fr) * 2001-06-12 2002-12-19 Active Pass Pharmaceuticals, Inc. Composes, compositions et methodes de modulation de la production de beta-amyloide
WO2003007963A1 (fr) * 2001-07-17 2003-01-30 Neotherapeutics, Inc. Derives pyrimidiques et leur utilisation dans le traitement des maladies neurodegeneratives
WO2003032994A2 (fr) * 2001-10-17 2003-04-24 Boehringer Ingelheim Pharma Gmbh & Co. Kg Nouvelles pyrimidines substituees, procede permettant de les produire et leur utilisation comme medicament
WO2003045923A1 (fr) * 2001-11-28 2003-06-05 Btg International Ltd. Agents preventifs ou remedes contre la maladie d'alzheimer ou inhibiteurs de la fibrose des proteines amyloides contenant des composes heteroaryle a teneur en azote
WO2003066099A1 (fr) * 2002-02-05 2003-08-14 Yamanouchi Pharmaceutical Co., Ltd. Derives de 2,4,6-triamino-1,3,5-triazine

Non-Patent Citations (13)

* Cited by examiner, † Cited by third party
Title
DATABASE CA [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; BRUCKNER, H. ET AL: "Design of chiral monochloro-s-triazine reagents for the liquid chromatographic separation of amino acid enantiomers" XP002339544 retrieved from STN Database accession no. 2003:428127 & JOURNAL OF CHROMATOGRAPHY, A , 998(1-2), 73-82 CODEN: JCRAEY; ISSN: 0021-9673, 2003, *
DATABASE CA [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; BRUECKNER, H. ET AL: "Chiral monochloro-s-triazines as derivatizing reagents for resolving DL-amino acids by HPLC" XP002339551 retrieved from STN Database accession no. 1992:644768 & CHROMATOGRAPHIA , 33(11-12), 586-7 CODEN: CHRGB7; ISSN: 0009-5893, 1992, *
DATABASE CA [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; BRUECKNER, HANS ET AL: "Use of chiral monohalo-s-triazine reagents for the liquid chromatographic resolution of DL-amino acids" XP002339550 retrieved from STN Database accession no. 1993:160226 & JOURNAL OF CHROMATOGRAPHY , 627(1-2), 97-105 CODEN: JOCRAM; ISSN: 0021-9673, 1992, *
DATABASE CA [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; BRUECKNER, HANS ET AL: "Use of chiral monohalo-s-triazines as novel derivatizing reagents for DL-amino acids" XP002339548 retrieved from STN Database accession no. 1995:66811 & PEPT. 1992, PROC. EUR. PEPT. SYMP., 22ND , MEETING DATE 1992, 449-50. EDITOR(S): SCHNEIDER, CONRAD H.; EBERLE, ALEX N. PUBLISHER: ESCOM, LEIDEN, NETH. CODEN: 60LUAN, 1993, *
DATABASE CA [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; GRUDZINSKI, STEFAN ET AL: "Condensation of 2,4-dichloro-6-methoxy-s-triazine (DCMT) with amines and amino acids" XP002339542 retrieved from STN Database accession no. 1978:191368 & GRUDZINSKI, STEFAN ET AL: "Condensation of 2,4-dichloro-6-methoxy-s-triazine (DCMT) with amines and amino acids" ACTA POLONIAE PHARMACEUTICA , 34(3), 285-93 CODEN: APPHAX; ISSN: 0001-6837, 1977, *
DATABASE CA [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; HARRIS, ROBERT B. ET AL: "Inhibition and affinity chromatography of human serum angiotensin converting enzyme with cysteinyl-proline derivatives" XP002339543 retrieved from STN Database accession no. 1982:138706 & ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS , 206(1), 105-12 CODEN: ABBIA4; ISSN: 0003-9861, 1981, *
DATABASE CA [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; PARASHARYA, P. M. ET AL: "Triazines: 2-(2'-anilino-1',3',4'-thiadiazol-5'-ylthi o)-4,6-di(N- arylcarbamoylmethylamino)-s-triazines" XP002339549 retrieved from STN Database accession no. 1995:64076 & JOURNAL OF THE INSTITUTION OF CHEMISTS (INDIA) , 65(3), 106-7 CODEN: JOICA7; ISSN: 0020-3254, 1993, *
DATABASE CA [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; SCHARN, DIRK ET AL: "Efficient parallel synthesis of 1,3,5-triazines on continuous surfaces" XP002339546 retrieved from STN Database accession no. 2002:46839 & INNOVATION AND PERSPECTIVES IN SOLID PHASE SYNTHESIS & COMBINATORIAL LIBRARIES: PEPTIDES, PROTEINS AND NUCLEIC ACIDS--SMALL MOLECULE ORGANIC CHEMISTRY DIVERSITY, COLLECTED PAPERS, INTERNATIONAL SYMPOSIUM, 6TH, YORK, UNITED KINGDOM, AUG. 31-SEPT. 4, 1, 2001, *
DATABASE CA [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; SCHARN, DIRK ET AL: "Spatially Addressed Synthesis of Amino- and Amino-Oxy-Substituted 1,3,5-Triazine Arrays on Polymeric Membranes" XP002339547 retrieved from STN Database accession no. 2000:355907 & JOURNAL OF COMBINATORIAL CHEMISTRY , 2(4), 361-369 CODEN: JCCHFF; ISSN: 1520-4766, 2000, *
DATABASE CA [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; WENSCHUH, H. ET AL: "Spatially addressed SPOT-synthesis on novel polymeric membranes" XP002339545 retrieved from STN Database accession no. 2002:46906 & INNOVATION AND PERSPECTIVES IN SOLID PHASE SYNTHESIS & COMBINATORIAL LIBRARIES: PEPTIDES, PROTEINS AND NUCLEIC ACIDS--SMALL MOLECULE ORGANIC CHEMISTRY DIVERSITY, COLLECTED PAPERS, INTERNATIONAL SYMPOSIUM, 6TH, YORK, UNITED KINGDOM, AUG. 31-SEPT. 4, 1, 2001, *
DATABASE CHEMABS [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; PRINS, LEONARD J. ET AL: "Complete asymmetric induction of supramolecular chirality in a hydrogen-bonded assembly" XP002298974 retrieved from STN Database accession no. 1999:255935 & NATURE (LONDON) , 1999, 398, 498-502 CODEN: NATUAS; ISSN: 0028-0836, 6727, *
DATABASE CHEMABS [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; PRINS, LEONARD J. ET AL: "Diastereoselective noncovalent synthesis of hydrogen-bonded double-rosette assemblies" XP002298973 retrieved from STN Database accession no. 2002:434936 & CHEMISTRY--A EUROPEAN JOURNAL , 8(10), 2288-2301 CODEN: CEUJED; ISSN: 0947-6539, 2002, *
WHITTEN, JEFFREY P. ET AL: "Rapid Microscale Synthesis, a New Method for Lead Optimization Using Robotics and Solution Phase Chemistry: Application to the Synthesis and Optimization of Corticotropin Releasing Factor1 Receptor Antagonists" JOURNAL OF MEDICINAL CHEMISTRY , 39(22), 4354-4357 CODEN: JMCMAR; ISSN: 0022-2623, 1996, XP002298972 *

Cited By (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006088705A1 (fr) * 2005-02-14 2006-08-24 Wyeth Guanidine de terphenyle en tant qu'inhibiteurs de la $g(b)-secretase
US8354407B2 (en) 2006-06-15 2013-01-15 Boehringer Ingelheim International Gmbh 2-anilino-4-(heterocyclic)amino-pyrimidines
US8158641B2 (en) 2006-06-15 2012-04-17 Boehringer Ingelheim International Gmbh 2-anilino-4-aminoalkyleneaminopyrimidines
US8580786B2 (en) 2006-12-15 2013-11-12 Nant Holdings Ip, Llc Triazine derivatives and their therapeutical applications
EP2923703A1 (fr) 2006-12-15 2015-09-30 Abraxis BioScience, Inc. Dérivés de triazine et leurs applications thérapeutiques
US7858782B2 (en) 2006-12-15 2010-12-28 Abraxis Bioscience, Llc Triazine derivatives and their therapeutical applications
EP2425840A1 (fr) 2006-12-15 2012-03-07 Abraxis BioScience, Inc. Dérivés de triazine et leurs applications thérapeutiques
WO2008074068A1 (fr) * 2006-12-20 2008-06-26 Prana Biotechnology Limited Dérivés de quinoline substitués utilisés comme agents non-amyloïdogéniques
EP2120573A1 (fr) * 2007-02-12 2009-11-25 Merck & Co., Inc. Dérivés de la pipéridine
EP2120573A4 (fr) * 2007-02-12 2011-05-25 Merck Sharp & Dohme Dérivés de la pipéridine
US10450297B2 (en) 2007-04-18 2019-10-22 Pfizer, Inc. Sulfonyl amide derivatives for the treatment of abnormal cell growth
US7928109B2 (en) 2007-04-18 2011-04-19 Pfizer Inc Sulfonyl amide derivatives for the treatment of abnormal cell growth
US8247411B2 (en) 2007-04-18 2012-08-21 Pfizer Inc Sulfonyl amide derivatives for the treatment of abnormal cell growth
US8440822B2 (en) 2007-04-18 2013-05-14 Michael Joseph Luzzio Sulfonyl amide derivatives for the treatment of abnormal cell growth
CN101888877A (zh) * 2007-10-05 2010-11-17 塞内希斯有限公司 用于治疗淀粉样蛋白相关性疾病的吡啶衍生物
WO2009044160A1 (fr) * 2007-10-05 2009-04-09 Senexis Limited Dérivés de pyridine pour le traitement de maladies se rapportant aux amyloïdes
US8962834B2 (en) 2008-02-22 2015-02-24 Hoffmann-La Roche Inc. Modulators of amyloid beta
JP2012504575A (ja) * 2008-10-09 2012-02-23 エフ．ホフマン−ラ ロシュ アーゲー アミロイドβのモジュレーター
WO2010040661A1 (fr) 2008-10-09 2010-04-15 F. Hoffmann-La Roche Ag Modulateurs pour l'amyloïde bêta
US8389717B2 (en) 2008-10-09 2013-03-05 Hoffmann-La Roche Inc. Modulators for amyloid beta
US8288403B2 (en) 2008-11-10 2012-10-16 Hoffmann-La Roche Inc. Heterocyclic gamma secretase modulators
US8877924B2 (en) 2009-06-09 2014-11-04 NantBio Inc. Benzyl substituted triazine derivatives and their therapeutical applications
US9078902B2 (en) 2009-06-09 2015-07-14 Nantbioscience, Inc. Triazine derivatives and their therapeutical applications
WO2010144423A1 (fr) 2009-06-09 2010-12-16 Abraxis Bioscience, Llc Dérivés de la styryl-triazine et leurs applications thérapeutiques
US9409903B2 (en) 2009-06-09 2016-08-09 Nantbioscience, Inc. Benzyl substituted triazine derivatives and their therapeutical applications
US8486967B2 (en) 2010-02-17 2013-07-16 Hoffmann-La Roche Inc. Heteroaryl substituted piperidines
US10946023B2 (en) 2013-07-11 2021-03-16 Agios Pharmaceuticals, Inc. Therapeutically active compounds and their methods of use
AU2019201179B2 (en) * 2013-07-11 2021-03-25 Les Laboratoires Servier Therapeutically active compounds and their methods of use
US11844758B2 (en) 2013-07-11 2023-12-19 Servier Pharmaceuticals Llc Therapeutically active compounds and their methods of use
CN107304189A (zh) * 2016-04-18 2017-10-31 北京大学 一种三嗪化合物及其制备方法和应用

Also Published As

Publication number Publication date
WO2005003103A3 (fr) 2005-11-03

Similar Documents

Publication Publication Date Title
WO2005003103A2 (fr) Nouveaux heterocycles 2,4,6-trisubstitues et utilisations de ceux-ci
CA2431160C (fr) Derives d'anilinopyrimidine utilises comme inhibiteurs de kinase ikk, compositions et techniques associees
AU2005317204B2 (en) Heterocyclic aspartyl protease inhibitors
US7125881B2 (en) Use of pyrimidine—or triazine—2 carbonitiles for treating diseases associated with cysteine prostease activity and novel pyrimidine-2-carbonitile derivatives
RU2326119C2 (ru) 2-циано-4-аминопиримидиновые соединения с ингибирующим действием на катепсин к, фармацевтическая композиция и способы их получения (варианты)
KR101867110B1 (ko) 트라이아진 유도체 및 그것을 함유하는 진통 작용을 갖는 의약 조성물
CN103097340B (zh) 治疗活性组合物及其使用方法
AU2008219071B2 (en) Heterocyclic aspartyl protease inhibitors
ES2216297T3 (es) Derivados de acil-piperazinil-pirimidinas, su preparacion y su aplicacion como medicamentos.
CZ296915B6 (cs) Slouceniny inhibující proteázy retroviru
AU2004299040A1 (en) Heterocyclic aspartyl protease inhibitors
CA2658362A1 (fr) Inhibiteurs des metalloproteases
HU229479B1 (en) Pyrimidine-4-one derivatives
AU2006216266A1 (en) Quinazoline derivative having tyrosine kinase inhibitory activity
AU2021201573B2 (en) Bicyclic compound and use thereof for inhibiting suv39h2
ES2404580T3 (es) Novedosos inhibidores de la ehs y uso de los mismos
KR20160143668A (ko) 오렉신 수용체 길항제로서의 피페리딘 유도체
NZ243959A (en) Substituted pyrazine derivatives and pharmaceutical compositions thereof
EP2097378B1 (fr) Nouveaux inhibiteurs de seh et utilisation de ces derniers
AU2003247445A1 (en) Peptide deformylase inhibitors
ES2334491T3 (es) Antagonistas del receptor 5-ht7.
EP1572667B1 (fr) Inhibiteurs de la protease a cystéine du type cathepsine et leur utilisation pour le traitement de troubles inflammatoires et immunitaires
CA2779989A1 (fr) Composes de quinazoline
EA031266B1 (ru) Дипептидилкетоамидные соединения и их применение для лечения и/или предотвращения накопления жира
JP2016528248A (ja) Ｎ型カルシウムチャネル拮抗薬としての置換イミダゾール

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DPEN Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed from 20040101)