WO2008092861A1 - Dérivés bicycliques utilisés comme agonistes de ep4 - Google Patents

Dérivés bicycliques utilisés comme agonistes de ep4 Download PDF

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Publication number
WO2008092861A1
WO2008092861A1 PCT/EP2008/051044 EP2008051044W WO2008092861A1 WO 2008092861 A1 WO2008092861 A1 WO 2008092861A1 EP 2008051044 W EP2008051044 W EP 2008051044W WO 2008092861 A1 WO2008092861 A1 WO 2008092861A1
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Prior art keywords
compound
cyano
halo
formula
alkyl
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PCT/EP2008/051044
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English (en)
Inventor
Joannes Theodorus Maria Linders
Guy Rosalia Eugeen Van Lommen
Louis Jozef Elisabeth Van Der Veken
Robert Jozef Maria Hendrickx
Jean Pierre Frans Van Wauwe
Jeroen Marcel Maria Roger Aerssens
Mansoor D'lavari
Sorin-Vasile Filip
Kenneth Andrew Lowerson
Petr Vladimirivich Davidenko
Mikhail Viktorovich Reynov
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Janssen Pharmaceutica N.V.
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Publication of WO2008092861A1 publication Critical patent/WO2008092861A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/28—Oxygen atom
    • C07D473/30—Oxygen atom attached in position 6, e.g. hypoxanthine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention concerns bicyclic derivatives having EP4 receptor agonistic properties.
  • the invention further relates to methods for their preparation and pharmaceutical compositions comprising them.
  • the invention also relates to the use of said compounds for the manufacture of a medicament for the prevention or the treatment of a disease by activating the EP4 receptor.
  • WO2005/047268 relates to substituted pyrimidine compositions that are capable of modulating the activity of receptors of the NGFI-B family.
  • WO2006/030031 relates to thieno -pyridine and thieno -pyrimidine derivatives that are positive allosteric modulators of metabotropic receptors-subtype 2.
  • WO2005/116010 relates to phenyl or pyridyl derivatives having EP4 agonistic activity.
  • EP 1544202 relates to herbicidal compounds.
  • US2006/128729 describes bicyclic pyrazole derivatives for the treatment of diseases associated with cellular proliferation, diseases related to glycosidase expression or inflammatory conditions.
  • EP675124 relates to purine derivatives as anti- inflammatory agents.
  • US2006/084650 discloses (pyrazolyl)(imidazopyrimidinyl)amines as kinase inhibitors.
  • the compounds of the invention differ from the prior art compounds in structure, in their pharmacological activity and/or pharmacological potency.
  • One aspect of the present invention relates to a compound of formula
  • ring E represents a partially saturated or aromatic 5-membered heterocycle wherein the dotted lines represent an optional double bond and wherein B, C and D each independently represent CH 2 , CH, N, NH, S or O and F represents N or C, provided that the 5-membered ring contains 1, 2 or 3 heteroatoms;
  • X represents a direct bond or Ci_ 4 alkanediyl;
  • Y represents N or CH;
  • R 1 represents hydrogen or fluoro;
  • R 2 represents hydrogen, halo, cyano, Ci_ 6 alkyl, Ci_ 6 alkyloxy, Ci_ 6 alkylcarbonyl or C i - ⁇ alky lcarbony lamino
  • R 3 represents hydrogen, halo, Ci_6alkyl, Ci_6alkyloxy, cyano, nitro, amino or mono-or di(C i _ 6 alkyl)amino ;
  • R 4 represents halo; hydroxyl; carboxyl; Ci_6alkyl optionally substituted with one or two substituents, each substituent independently selected from NR 10 R 11 , cyano, carboxyl or Ci_ 6 alkyloxycarbonyl; polyhaloCi- ⁇ alkyl; Ci_ 6 alkyloxycarbonyl; polyhaloCi- ⁇ alkyloxy; C 2 - 6 alkenyl optionally substituted with one or two substituents, each substituent independently selected from cyano, carboxyl or
  • R 5 and R 6 each independently represent hydrogen; Ci_ 6 alkyl optionally substituted with
  • R 7 represents hydrogen; Ci_ 6 alkyl optionally substituted with hydroxyl; C 2 - 6 alkenyl; Ci _ ⁇ alkylcarbonyl; Ci_ 6 alkyloxycarbonyl; arylCi- ⁇ alkyl; arylcarbonyl; or aryl; R 8 and R 9 each independently represent hydrogen; Ci_ 6 alkyloxy; Ci_ 6 alkylcarbonyl; arylcarbonyl; halo; amino; mono-or di(Ci_6alkyl)amino; Ci_6alkyl optionally substituted with hydroxyl; Ci_ 6 alkyloxycarbonylCi_ 6 alkyl; or C 2 - 6 alkenyl; or
  • R 10 and R 11 each independently represent hydrogen; Ci_ 6 alkyl optionally substituted with one or two substituents, each substituent independently selected from hydroxyl, Ci_
  • R 12 represents Ci_ 4 alkyl; Ci_ 4 alkyloxy; piperidinyl optionally substituted with Ci_ 4 alkylcarbonyl; or aryl; n represents an integer of value 1, 2 or 3; m represents an integer of value 1, 2 or 3; p and q each independently represent an integer of value 0, 1, 2 or 3; aryl represents phenyl or phenyl substituted with at least one substituent, in particular one, two or three substituents, each substituent independently selected from halo,
  • the present invention also relates to the use of a compound of formula (I) for the manufacture of a medicament for preventing or treating a disease by activating the EP4 receptor, in particular for treating a disease by activating the EP4 receptor, in particular for preventing or treating, in particular for treating, a disease associated with loss of bone mass, wherein the compound is a compound of formula
  • ring E represents a partially saturated or aromatic 5-membered heterocycle wherein the dotted lines represent an optional double bond and wherein B, C and D each independently represent CH 2 , CH, N, NH, S or O and F represents N or C, provided that the 5-membered ring contains 1, 2 or 3 heteroatoms;
  • X represents a direct bond or Ci_ 4 alkanediyl;
  • Y represents N or CH;
  • R 1 represents hydrogen or fluoro;
  • R 2 represents hydrogen, halo, cyano, Ci_ 6 alkyl, Ci_ 6 alkyloxy, Ci_ 6 alkylcarbonyl or C i - ⁇ alky lcarbony lamino
  • R 3 represents hydrogen, halo, Ci_6alkyl, Ci_6alkyloxy, cyano, nitro, amino or mono-or di(C i _ 6 alkyl)amino ;
  • R 4 represents halo; hydroxyl; carboxyl; Ci_6alkyl optionally substituted with one or two substituents, each substituent independently selected from NR 10 R 11 , cyano, carboxyl or Ci_ 6 alkyloxycarbonyl; polyhaloCi- ⁇ alkyl; Ci_ 6 alkyloxycarbonyl; polyhaloCi- ⁇ alkyloxy; C 2 - 6 alkenyl optionally substituted with one or two substituents, each substituent independently selected from cyano, carboxyl or
  • R 5 and R 6 each independently represent hydrogen; Ci_ 6 alkyl optionally substituted with
  • R 7 represents hydrogen; Ci_ 6 alkyl optionally substituted with hydroxyl; C 2 - 6 alkenyl; Ci _ ⁇ alkylcarbonyl; Ci_ 6 alkyloxycarbonyl; arylCi- ⁇ alkyl; arylcarbonyl; or aryl; R 8 and R 9 each independently represent hydrogen; Ci_ 6 alkyloxy; Ci_ 6 alkylcarbonyl; arylcarbonyl; halo; amino; mono-or di(Ci_6alkyl)amino; Ci_6alkyl optionally substituted with hydroxyl; Ci_ 6 alkyloxycarbonylCi_ 6 alkyl; or C 2 - 6 alkenyl; or
  • R 10 and R 11 each independently represent hydrogen; Ci_ 6 alkyl optionally substituted with one or two substituents, each substituent independently selected from hydroxyl, Ci_
  • R 12 represents Ci_4alkyl; Ci_4alkyloxy; piperidinyl optionally substituted with Ci_ 4 alkylcarbonyl; or aryl; n represents an integer of value 1, 2 or 3; m represents an integer of value 1, 2 or 3; p and q each independently represent an integer of value 0, 1, 2 or 3; aryl represents phenyl or phenyl substituted with at least one substituent, in particular one, two or three substituents, each substituent independently selected from halo,
  • Ci_4alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as methyl, ethyl, propyl, 1-methylethyl, butyl;
  • Ci_ 6 alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as the group defined for Ci_4alkyl and pentyl, hexyl, 2-methylbutyl and the like;
  • Ci_4alkanediyl defines straight or branched chain saturated bivalent hydrocarbon radicals having from 1 to 4 carbon atoms such as methylene, 1 ,2-ethanediyl or 1 ,2-ethylidene, 1,3-propanediyl or 1,3-propylidene, 1 ,4-butanediyl or 1 ,4-butylidene and the like;
  • halo is generic to fluoro, chloro, bromo and iodo.
  • polyhaloCi- ⁇ alkyl as a group or part of a group is defined as mono- or polyhalosubstituted Ci_6alkyl, for example methyl substituted with one or more fluoro atoms, for example, difluoromethyl or trifluoromethyl, 1,1-difluoro-ethyl, 1,1-difluoro- 2,2,2-trifluoro-ethyl and the like.
  • more than one halogen atoms are attached to a Ci_ 6 alkyl group within the definition of polyhaloCi- ⁇ alkyl, they may be the same or different.
  • Particular examples of 5, 6 or 7-membered saturated heterocyclic rings comprising 1 or 2 oxygen atoms are tetrahydrofuranyl, dioxolanyl, dihydrooxazolyl, isoxazolidinyl, oxadiazolidinyl, dioxanyl, morpholinyl, dioxepanyl.
  • each definition is independent.
  • salts of the compounds of formula (I) are those wherein the counterion is pharmaceutically acceptable.
  • salts of acids and bases which are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not are included within the ambit of the present invention.
  • the pharmaceutically acceptable salts as mentioned hereinbefore or hereinafter are meant to comprise the therapeutically active non-toxic acid addition salt forms which the compounds of formula (I) are able to form.
  • the latter can conveniently be obtained by treating the base form with such appropriate acids as inorganic acids, for example, hydrohalic acids, e.g.
  • the salt form can be converted by treatment with alkali into the free base form.
  • the compounds of formula (I) containing acidic protons may be converted into their therapeutically active non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases.
  • the pharmaceutically acceptable salts as mentioned hereinbefore or hereinafter are meant to also comprise the therapeutically active non-toxic metal or amine addition salt forms (base addition salt forms) which the compounds of formula (I) are able to form.
  • Appropriate base addition salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g.
  • primary, secondary and tertiary aliphatic and aromatic amines such as methylamine, ethylamine, propylamine, isopropylamine, the four butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyridine, quinoline and isoquinoline, the benzathine, JV-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)- 1 ,3-propanediol, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.
  • salt form can be converted by treatment with acid into the free acid form.
  • salt also comprises the quaternary ammonium salts (quaternary amines) which the compounds of formula (I) are able to form by reaction between a basic nitrogen of a compound of formula (I) and an appropriate quaternizing agent, such as, for example, an optionally substituted Ci_6alkylhalide, arylhalide, Ci_6alkylcarbonylhalide, arylcarbonylhalide, or arylCi- ⁇ alkylhalide, e.g. methyliodide or benzyliodide.
  • an appropriate quaternizing agent such as, for example, an optionally substituted Ci_6alkylhalide, arylhalide, Ci_6alkylcarbonylhalide, arylcarbonylhalide, or arylCi- ⁇ alkylhalide, e.g. methyliodide or benzyliodide.
  • Ci_6alkyl trifluoromethanesulfonates Ci_6alkyl methanesulfonates
  • Ci_6alkyl/?-toluenesulfonates Ci_6alkyl trifluoromethanesulfonates
  • Ci_6alkyl methanesulfonates Ci_6alkyl/?-toluenesulfonates.
  • a quaternary amine has a positively charged nitrogen.
  • Pharmaceutically acceptable counterions include chloro, bromo, iodo, trifluoroacetate, acetate, triflate, sulfate, sulfonate.
  • the counterion of choice can be introduced using ion exchange resins.
  • solvate comprises the hydrates and solvent addition forms which the compounds of formula (I) are able to form, as well as the salts thereof. Examples of such forms are e.g. hydrates, alcoholates and the like.
  • the iV-oxide forms of the present compounds are meant to comprise the compounds of formula (I) wherein one or several tertiary nitrogen atoms are oxidized to the so-called N-oxide.
  • stereochemically isomeric forms as used hereinbefore or hereinafter defines all the possible stereoisomeric forms which the compounds of formula (I), and their TV-oxides, salts, or solvates may possess.
  • the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure as well as each of the individual isomeric forms of formula (I) and their JV-oxides or salts, substantially free, i.e. associated with less than 10%, preferably less than 5%, in particular less than 2% and most preferably less than 1% of the other isomers.
  • a compound of formula (I) is for instance specified as (E)
  • this means that the compound is substantially free of the (Z) isomer.
  • stereogenic centers may have the R- or S-configuration; substituents on bivalent cyclic (partially) saturated radicals may have either the cis- or trans- configuration.
  • Compounds encompassing double bonds can have an E (ent ought) or Z (zusammen) -stereochemistry at said double bond.
  • the terms cis, trans, R, S, E and Z are well known to a person skilled in the art.
  • an R or S descriptor is assigned (based on Cahn-Ingold-Prelog sequence rule) to the lowest-numbered chiral center, the reference center.
  • the configuration of the second stereogenic center is indicated using relative descriptors [R*,R* ] or [i?*,i_>*], where the first R* is always specified as the reference center and [R*,R*] indicates centers with the same chirality and [i?*,i_>*] indicates centers of unlike chirality.
  • the stereo descriptor would be specified as S-[R*, S*]. If " ⁇ ” and " ⁇ ” are used : the position of the highest priority substituent on the asymmetric carbon atom in the ring system having the lowest ring number, is arbitrarily always in the " ⁇ " position of the mean plane determined by the ring system.
  • the position of the highest priority substituent on the other asymmetric carbon atom in the ring system relative to the position of the highest priority substituent on the reference atom is denominated " ⁇ ", if it is on the same side of the mean plane determined by the ring system, or " ⁇ ", if it is on the other side of the mean plane determined by the ring system.
  • the compounds of (I) may be synthesized in the form of racemic mixtures of enantiomers which can be separated from one another following art-known resolution procedures.
  • the racemic compounds of formula (I) may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid.
  • Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali.
  • An alternative manner of separating the enantiomeric forms of the compounds of formula (I) involves liquid chromatography using a chiral stationary phase.
  • Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically.
  • a first interesting embodiment of the present invention are those compounds of formula (I) having the following formula
  • ring E represents a partially saturated or aromatic 5-membered heterocycle wherein the dotted lines represent an optional double bond and wherein B, C and D each independently represent CH 2 , CH, N, NH, S or O provided that the 5-membered ring contains 1 or 2 heteroatoms;
  • X represents a direct bond or Ci_4alkanediyl
  • R 1 represents hydrogen or fluoro
  • R 2 represents hydrogen, halo, cyano, Ci_ 6 alkyl, Ci_ 6 alkyloxy, Ci_ 6 alkylcarbonyl or
  • R 3 represents hydrogen, halo, Ci_6alkyl, Ci_6alkyloxy, cyano, nitro, amino or mono-or di(C i _ 6 alkyl)amino ;
  • R 4 represents halo; hydroxyl; carboxyl; Ci_6alkyl optionally substituted with one or two substituents, each substituent independently selected from cyano, carboxyl or
  • R , 7' represents hydrogen, Ci_ 6 alkyl, C 2 - 6 alkenyl, Ci_ 6 alkylcarbonyl,
  • R 8 and R 9 each independently represent hydrogen, Ci_ 6 alkyloxy, halo, amino, mono-or di(Ci_ 6 alkyl)amino, C h alky!, Ci_ 6 alkyloxycarbonylCi_ 6 alkyl or C 2 - 6 alkenyl; or
  • a second interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein X represents a direct bond.
  • a third interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein X represents Ci_4alkanediyl, in particular CH 2 .
  • a fourth interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein R 1 represents hydrogen or wherein R 1 represents fluoro.
  • a fifth interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein R 2 represents hydrogen, halo, cyano, Ci_6alkyl, Ci_6alkyloxy or Ci_ ⁇ alkylcarbonylamino; in particular hydrogen, halo, cyano, Ci_6alkyl or Ci_6alkyloxy.
  • a sixth interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein R represents hydrogen, halo, Ci_ 6 alkyl or Ci_ 6 alkyloxy; more in particular hydrogen.
  • a seventh interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein R 4 represents halo; hydroxyl; carboxyl; Ci_ 6 alkyl optionally substituted with one or two substituents, in particular one substituent, each substituent independently selected from NR 10 R 11 , cyano, carboxyl or Ci_ 6 alkyloxycarbonyl; polyhaloCi- ⁇ alkyl; Ci_ 6 alkyloxycarbonyl; polyhaloCi- ⁇ alkyloxy; C 2 - 6 alkenyl optionally substituted with one or two substituents, in particular one substituent, each substituent independently selected from cyano, carboxyl or Ci_ 6 alkyloxycarbonyl; cyano; nitro; NR 10 R 11 ; Ci_6alkylthio; Ci_6alkyloxy optionally substituted with at least one substituent, in particular one, two or three substituents, more in particular one or two substituents, each substituent independently
  • R 4 represents halo; hydroxyl; Ci_ 6 alkyl optionally substituted with NR 10 R 11 ; polyhaloCi- ⁇ alkyl; Ci_ 6 alkyloxycarbonyl; C 2 - 6 alkenyl substituted with carboxyl or Ci_ 6 alkyloxyarbonyl; cyano; nitro; NR 10 R 11 ; Ci_6alkylthio; Ci_6alkyloxy optionally substituted with one or two substituents, each substituent independently selected from hydroxyl, halo, cyano, Ci_ ⁇ alkyloxycarbonyl or NR 5 R 6 ; or two adjacent R 4 substituents may be taken together to form a radical of formula
  • R 5 and R 6 each independently represent Ci_ 6 alkyl optionally substituted with Ci_ 4 alkyloxy; C 3 - 6 cycloalkyl; or R 5 and
  • R 4 represents halo; hydroxyl; Ci_ 6 alkyl; Ci_ 6 alkyloxycarbonyl; C 2 - 6 alkenyl substituted with carboxyl; cyano; Ci_6alkyloxy optionally substituted with cyano, carboxyl, Ci_
  • Ci_ 6 alkyloxy optionally substituted with cyano, Ci_ 6 alkyloxycarbonyl or a radical of
  • Ci_ 6 alkyl C 2 - 6 alkenyl substituted with carboxyl; yet even more in particular R 4 represents halo; Ci_6alkyloxy optionally substituted with cyano, Ci_6alkyloxycarbonyl or
  • a ( a- i) a radical of formula ⁇ — ' with A representing O or CH 2 ; cyano; hydroxy 1; or Ci_ 6 alkyl.
  • An eighth interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein R 4 represents halo; hydroxyl; carboxyl; Ci_ 6 alkyl optionally substituted with one or two substituents, each substituent independently selected from NR 10 R 11 , cyano, carboxyl or Ci_6alkyloxycarbonyl; polyhaloCi- ⁇ alkyl; Ci_ ⁇ alkyloxycarbonyl; polyhaloCi- ⁇ alkyloxy; C 2 - 6 alkenyl optionally substituted with one or two substituents, each substituent independently selected from cyano, carboxyl or Ci_ ⁇ alkyloxycarbonyl; cyano; nitro; NR 10 R 11 ; Ci_ 6 alkylthio; C i_ 6 alkyloxy optionally substituted with at least one substituent, in particular one, two or three substituents, each substituent independently selected from hydroxyl, halo, cyano, carboxyl,
  • -CH CH-Z- (a-3); with Z representing O, S or NH; provided that if R 4 represents hydroxyl, then said hydroxyl is placed in ortho or meta position.
  • a ninth interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein R 4 represents halo; hydroxyl; carboxyl; Ci_ 6 alkyl optionally substituted with one or two substituents, each substituent independently selected from NR 10 R 11 , cyano, carboxyl or Ci_ 6 alkyloxycarbonyl; polyhaloCi- ⁇ alkyl;
  • Ci_ 6 alkyloxycarbonyl or NR 5 R 6 ; or two adjacent R 4 substituents may be taken together to form a radical of formula
  • -CH CH-Z- (a-3); with Z representing O, S or NH; provided that if R 4 represents t-butyl, then said t-butyl is placed in ortho or para position.
  • a tenth interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein m represents 1 or 2, in particular 1.
  • An eleventh interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein n represents 1.
  • a twelfth interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein p represents 1, 2 or 3, in particular 1 or 2, more in particular 1.
  • a thirteenth interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein q represents 1 , 2 or 3, in particular 1 or 2, more in particular 1.
  • a fourteenth interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein R 1 is fluoro and R 2 is hydrogen.
  • a fifteenth interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein R 1 is hydrogen and R 2 is halo, cyano, C ⁇ aUcyl, Ci_6alkyloxy, Ci_ ⁇ alkylcarbonyl or Ci_ 6 alkylcarbonylamino; more in particular R 1 is hydrogen and R 2 represents halo, cyano, d- ⁇ alkylcarbonyl, Ci_6alkyloxy or Ci_6alkylcarbonylamino.
  • a sixteenth interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein R 1 is fluoro and R 2 is halo, cyano, Ci_6alkyl, Ci_6alkyloxy, Ci_6alkylcarbonyl or Ci_6alkylcarbonylamino; more in particular R 1 is fluoro and R 2 represents halo, cyano, Ci_6alkylcarbonyl, Ci_6alkyloxy or Ci_6alkylcarbonylamino.
  • a seventeenth interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein R 1 and R 2 are both hydrogen.
  • An eighteenth interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein Y represents N.
  • a nineteenth interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein Y represents CH.
  • a twentieth interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein F represents C and the dotted line attached to F represents a bond.
  • a twenty first interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein F represents N and the dotted line attached to F does not represents a bond.
  • a twenty second interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein B, C and D each independently represents CH 2 , CH, N, NH or O.
  • a twenty third interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein the dotted lines at B, C and D in ring E do not represent a bond.
  • a twenty fourth interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein ring E does not represent pyrazole.
  • a twenty fifth interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein ring E contains 1 or 2 heteroatoms.
  • a twenty sixth interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein R 12 represents Ci_ 4 alkyl; Ci_ 4 alkyloxy; or aryl. ; in particular wherein R 12 represents Ci_4alkyl or Chalky Io xy.
  • a twenty seventh interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein R 8 and R 9 each independently represent hydrogen; Ci_ 6 alkyloxy; Ci_ 6 alkylcarbonyl; arylcarbonyl; halo; amino; mono-or di(Ci_6alkyl)amino; Ci_6alkyl optionally substituted with hydroxyl; Ci_ 6 alkyloxycarbonylCi_ 6 alkyl; or C 2 - 6 alkenyl.
  • a twenty eighth interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein the compound of formula (I) is a compound having the following formula
  • a twenty nineth interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein the compound of formula (I) is a compound having the following formula
  • a thirtieth interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein the compound of formula (I) is a compound having the following formula
  • a thirty first interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein the compound of formula (I) is a compound having the following formula including any stereochemically isomeric form thereof; a JV-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.
  • a thirty second interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein the compound of formula (I) is a compound having the following formula
  • a thirty third interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein the compound of formula (I) is a compound having the following formula
  • a thirty fourth interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein the compound of formula (I) is a compound having the following formula
  • a thirty fifth interesting embodiment of the present invention are those compounds of formula (I), (1-1), (I-l-a), (I-l-b), (I-l-c), (I-l-d), (1-2) or (1-3) wherein one or more, preferably all, of the following restrictions apply : a) X represents a direct bond; b) R 2 represents hydrogen, halo, cyano, Ci_6alkyl or Ci_6alkyloxy; c) R 3 represents hydrogen, halo, Ci_ 6 alkyl or Ci_ 6 alkyloxy; more in particular hydrogen; d) R 4 represents halo; hydroxyl; Ci_6alkyl optionally substituted with NR 10 R 11 ; polyhaloCi- ⁇ alkyl; Ci_ 6 alkyloxycarbonyl; C 2 - 6 alkenyl substituted with carboxyl or Ci_ 6 alkyloxycarbonyl; NR 10 R 11 ; Ci_ 6 alkylthio; cyano; nitro; C i_
  • R 5 or R 6 each independently represent Ci_ 6 alkyl optionally substituted with Ci_ 4 alkyloxy; or C 3 _ 6 Cycloalkyl; or R 5 and R 6 together with the nitrogen atom to which they are attached form a radical of formula
  • R 7 represents hydrogen; Ci_ 6 alkyl optionally substituted with hydroxyl; Ci_ 6 alkylcarbonyl; aryl; i) R 8 and R 9 each independently represent hydrogen; Ci_ 6 alkyloxycarbonylCi_ 6 alkyl; Ci_ 6 alkylcarbonyl; arylcarbonyl; j) R 10 and R 11 each independently represent hydrogen; Ci_ 6 alkyl optionally substituted with one or two substituents, each substituent independently selected from hydroxyl, C
  • a thirty sixth interesting embodiment of the present invention are those compounds of formula (I) or any subgroup thereof as mentioned hereinbefore as interesting embodiment wherein the compound of formula (I) is selected from the group consisting of 4-[4-(2-Fluoro-phenoxy)-thieno[3,2-d]pyrimidin-2-yl]-benzonitrile; 4-[2-(4-Fluoro- phenyl)-thieno[3,2-d]pyrimidin-4-yloxy]-benzonitrile; 4-[4-(4-Fluoro-phenoxy)- thieno[3,2-d]pyrimidin-2-yl]-benzonitrile; 3-Fluoro-4-[2-(4-fluoro-phenyl)-thieno[3,2- d]pyrimidin-4-yloxy]-benzonitrile; l-[4-(2- ⁇ 4-[4-(2,4-Difluoro-phenoxy)-thieno[3,2- d]pyrimidin-2-
  • a suitable base such as for example K2CO3 or sodium hydride
  • a suitable solvent such as for example acetonitrile or dimethylsulfoxide.
  • compounds of formula (I-l-c) can be prepared by reacting in a first step (a), an intermediate of formula (II-a) with an intermediate of formula P-W 2 wherein P represents a suitable protective group, such as for example benzyl or Ci_ 4 alkyloxyCi_ 4 alkyl and wherein W 2 represents a suitable leaving group, such as for example halo, e.g.
  • step (a) is then reacted in a next step (b) with an intermediate of formula (III) in the presence of a suitable base, such as for example K2CO3 or sodium hydride, and a suitable solvent, such as for example acetonitrile or dimethylsulfoxide.
  • a suitable base such as for example K2CO3 or sodium hydride
  • a suitable solvent such as for example acetonitrile or dimethylsulfoxide.
  • step (b) is then deprotected in a next step (c) by reaction with a suitable acid, such as for example hydrochloric acid, in the presence of a suitable solvent, such as for example an alcohol, e.g. methanol, or acetonitrile.
  • the compounds of formula (I) may further be prepared by converting compounds of formula (I) into each other according to art-known group transformation reactions.
  • the compounds of formula (I) may be converted to the corresponding JV-oxide forms following art-known procedures for converting a trivalent nitrogen into its iV-oxide form.
  • Said JV-oxidation reaction may generally be carried out by reacting the starting material of formula (I) with an appropriate organic or inorganic peroxide.
  • Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal or earth alkaline metal peroxides, e.g. sodium peroxide, potassium peroxide;
  • appropriate organic peroxides may comprise peroxy acids such as, for example, benzenecarboperoxoic acid or halo substituted benzenecarboperoxoic acid, e.g.
  • 3-chlorobenzenecarboperoxoic acid peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g. tert.butyl hydroperoxide.
  • Suitable solvents are, for example, water, lower alcohols, e.g. ethanol and the like, hydrocarbons, e.g. toluene, ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g. dichloromethane, and mixtures of such solvents.
  • R 4 represents hydrogen, cyano, halo, carboxyl, Ci_6alkyloxycarbonyl or NR 5 R 6 , in the presence of a suitable base, such as for example K2CO3 or CS2CO3, and a suitable solvent, such as for example acetonitrile, N, N- dimethylformamide or an alcohol, e.g. butanol.
  • a suitable base such as for example K2CO3 or CS2CO3
  • a suitable solvent such as for example acetonitrile, N, N- dimethylformamide or an alcohol, e.g. butanol.
  • a suitable acid such as for example trifluoroacetic acid
  • a suitable solvent such as for example dichloromethane
  • C 2 - 6 alkenyl substituted with Ci_ 6 alkyloxycarbonyl can be converted into a compound of formula (I) wherein R 4 represents C 2 - 6 alkenyl substituted with carboxyl, by reaction with a suitable base, such as for example sodium hydroxide, and a suitable solvent, such as dioxane.
  • a suitable base such as for example sodium hydroxide
  • a suitable solvent such as dioxane
  • the compounds of formula (I) and some of the intermediates in the present invention may contain an asymmetric carbon atom.
  • Pure stereochemically isomeric forms of said compounds and said intermediates can be obtained by the application of art-known procedures.
  • diastereoisomers can be separated by physical methods such as selective crystallization or chromatographic techniques, e.g. counter current distribution, chiral liquid chromatography and the like methods.
  • Enantiomers can be obtained from racemic mixtures by first converting said racemic mixtures with suitable resolving agents such as, for example, chiral acids, to mixtures of diastereomeric salts or compounds; then physically separating said mixtures of diastereomeric salts or compounds by, for example, selective crystallization or chromatographic techniques, e.g. liquid chromatography and the like methods; and finally converting said separated diastereomeric salts or compounds into the corresponding enantiomers.
  • Pure stereochemically isomeric forms may also be obtained from the pure stereochemically isomeric forms of the appropriate intermediates and starting materials, provided that the intervening reactions occur stereospecifically.
  • An alternative manner of separating the enantiomeric forms of the compounds of formula (I) and intermediates involves liquid chromatography or SCF (Super Critical Fluid) chromatography, in particular using a chiral stationary phase.
  • Intermediates of formula (II) wherein Wi represents chloro can be prepared by reacting an intermediate of formula (IV) with SOCl 2 or phosphoric trichloride optionally in the presence of a suitable solvent, such as for example chloroform, N, ⁇ /-dimethylformamide or N, ⁇ /-dimethylbenzeneamine.
  • a suitable solvent such as for example chloroform, N, ⁇ /-dimethylformamide or N, ⁇ /-dimethylbenzeneamine.
  • a suitable base such as for example iV,jV-diisopropylethanamine
  • a suitable solvent such as for example dichloromethane .
  • Intermediates of formula (IV) wherein Y represents N, said intermediates being represented by formula (IV-a), can be prepared by cyclizing an intermediate of formula (V) in the presence of an aqueous ammoniak solution or NH 4 OH or NH 3 in acetonitrile or an alcohol, e.g. methanol.
  • Intermediates of formula (IV-a) can also be prepared by reacting an intermediate of formula (VI) in the presence of a suitable base, such as for example K2CO3, NaOCH 3 or l,8-diazabicyclo[5.4.0]undecene-7 (DBU), and a suitable solvent, such as for example water, alcohol, e.g. ethanol or isopropanol, chlororform.
  • a suitable base such as for example K2CO3, NaOCH 3 or l,8-diazabicyclo[5.4.0]undecene-7 (DBU)
  • a suitable solvent such as for example water, alcohol, e.g. ethanol or isopropanol, chlororform.
  • Intermediates of formula (IV-a) can also be prepared by reacting an intermediate of formula (XIV) with an intermediate of formula (XIII) in the presence of a suitable base such as for example potassium t-butoxide, and a suitable solvent, such as for example tetrahydrofuran.
  • a suitable base such as for example potassium t-butoxide
  • a suitable solvent such as for example tetrahydrofuran.
  • Intermediates of formula (IV-b) can be prepared by reacting an intermediate of formula (VII) with an intermediate of formula (VIII) in the presence of a suitable base, such as for example K2CO3, and a suitable solvent, such as for example water.
  • a suitable base such as for example K2CO3
  • a suitable solvent such as for example water.
  • Intermediates of formula (IV-c) can be prepared by reacting an intermediate of formula (XII) with an intermediate of formula (XIII) in the presence of lithium diisopropylamide (LDA) and a suitable solvent, such as for example tetrahydrofuran.
  • LDA lithium diisopropylamide
  • intermediates of formula (V) can be prepared by reacting an intermediate of formula (IX) with an intermediate of formula (X) wherein W 4 represents a suitable leaving group, such as for example halo, e.g. chloro and the like, in the presence of a suitable solvent, such as for example acetone or pyridine, and optionally a suitable base, such as for example pyridine or 4-dimethylaminopyridine.
  • W 4 represents a suitable leaving group, such as for example halo, e.g. chloro and the like
  • a suitable solvent such as for example acetone or pyridine
  • a suitable base such as for example pyridine or 4-dimethylaminopyridine.
  • Intermediates of formula (VI) can be prepared by reacting an intermediate of formula (XI) with an intermediate of formula (X) in the presence of a suitable base, such as for example JV,jV-dimethyl-4-pyridme amine, and a suitable solvent, such as for example pyridine.
  • a suitable base such as for example JV,jV-dimethyl-4-pyridme amine
  • a suitable solvent such as for example pyridine.
  • Intermediates of formula (VI) can also be prepared from the corresponding carboxylic acid derivative of formula (VF) by reaction with ethyl chloro formate and NH3 in the presence of a suitable base, such as for example triethylamine, a suitable solvent, such as for example acetonitrile.
  • a suitable base such as for example triethylamine
  • a suitable solvent such as for example acetonitrile.
  • Intermediates of formula (VF) can be prepared by hydrolysis of an intermediate of formula (V) in the presence of a suitable base, such as for example KOH, and a suitable solvent, such as for example an alcohol, e.g. ethanol.
  • a suitable base such as for example KOH
  • a suitable solvent such as for example an alcohol, e.g. ethanol.
  • EP4 is one of the four subtype receptors (EPl, EP2, EP3 EP4) of prostaglandine E2.
  • Prostaglandins are arachidonic acid metabolites that are synthetized by the cyclo- oxygenase pathway.
  • a major cyclo-oxygenase product is prostaglandin E 2 (PGE 2 ), which participates in a broad range of biological activities, such as smooth muscle relaxation, vasodilation, fever, inflammatory pain, enteric mucus secretion, renal regulation and bone formation.
  • PGE 2 can exert agonistic activities on four G-protein-coupled receptor subtypes, which are termed EPl, EP2, EP3 and EP4. Each of these receptor subtypes has a distinct pharmacological signature based on their ligand preference and coupling to intracellular signalling pathways.
  • EPl and EP3 receptors are coupled to calcium metabolism and inhibition of cyclic adenosine 5 -monophosphate (cAMP) via GqZG 1 G-proteins.
  • cAMP cyclic adenosine 5 -monophosphate
  • EP2 and EP4 are linked to the stimulation of adenylyl cyclase and increased cAMP synthesis via G s G-proteins.
  • EP4-def ⁇ cient mice produce a reduced vasodepressor response following PGE 2 infusion, exhibit decreased contact hypersensitivity and show reduced incidence and intensity of disease in the collagen antibody- induced arthritis model, while they have increased colitis induced by dextran sulphate treatment.
  • EP4-def ⁇ cient mice produce a reduced vasodepressor response following PGE 2 infusion, exhibit decreased contact hypersensitivity and show reduced incidence and intensity of disease in the collagen antibody- induced arthritis model, while they have increased colitis induced by dextran sulphate treatment.
  • the absence of EP4 decreases bone mass and impaired fracture healing in aged male mice, whilst PGE 2 administration fails to induce bone formation in EP4-deficient mice.
  • EP4 selective agonists suppresses dextran sulphate colitis, restores bone mass and strength in both normal and aged, ovariectomized animals, reduces indomethacin-induced small intestinal ulceration, attenuates endotoxin/galactosamine-induced liver injury, reduces mercury chloride-evoked acute kidney failure and attenuated pain responses in Freund's complete adjuvant-induced joint inflammation.
  • topical application of an EP4 agonist reduces the increased intraocular pressure.
  • EP4 antagonists block the bone anabolic effects OfPGE 2 in rats.
  • the compounds of formula (I), their JV-oxides, pharmaceutically acceptable salts, or solvates are useful for the treatment or prevention, in particular for the treatment, of a disease by activating the EP4 receptor.
  • the compounds of formula (I), their JV-oxides, pharmaceutically acceptable salts or solvates may be used as a medicine.
  • the present compounds can be used for the manufacture of a medicament for treating or preventing a disease by activating the EP4 receptor, in particular for treating a disease by activating the EP4 receptor.
  • the compounds of the invention can be used for the manufacture of a medicament for treating or preventing, preferably treating, a disease associated with loss of bone mass (primary and secondary osteoporosis, bone fracture, metastatic bone disease, rheumatoid arthritis, osteoarthritis, periodontitis, osteogenesis imperfecta, hypercalcemia), diseases associated with liver injury and acute hepatitis, renal failure and nephritis, ulcerative colitis, Crohn's disease, stomatitis, gastritis, ocular hypertension, glaucoma, neuropathic pain, bone pain, Reflex Sympathetic Dystrophy syndrome (RSD) also known as Complex Regional Pain Syndrome (CRPS)).
  • a disease associated with loss of bone mass primary and secondary osteoporosis, bone fracture, metastatic bone disease, rheumatoid arthritis, osteoarthritis, periodontitis, osteogenesis imperfecta, hypercalcemia
  • diseases associated with liver injury and acute hepatitis renal failure and neph
  • a method of treating a warm-blooded mammal, including a human, suffering from or a method of preventing a warm-blooded mammal, including a human, to suffer from a disease by activating the EP4 receptor in particular a method of treating a warm-blooded mammal, including a human, suffering from a disease by activating the EP4 receptor.
  • Said methods comprise the administration of an effective amount of a compound of formula (I), a JV-oxide form thereof, a pharmaceutically acceptable salt thereof or a solvate thereof, to a warm-blooded mammal, including a human.
  • compositions for preventing or treating a disease by activating the EP4 receptor in particular for treating a disease by activating the EP4 receptor.
  • Said compositions comprise a therapeutically effective amount of a compound of formula (I), a JV-oxide form thereof, a pharmaceutically acceptable salt thereof or a solvate thereof, and a pharmaceutically acceptable carrier or diluent.
  • compositions of the present invention may be formulated into various pharmaceutical forms for administration purposes.
  • compositions there may be cited all compositions usually employed for systemically administering drugs.
  • an effective amount of the particular compound, optionally in salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • a pharmaceutically acceptable carrier which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • These pharmaceutical compositions are desirable in unitary dosage form suitable, particularly, for administration orally, rectally, percutaneous Iy, or by parenteral injection.
  • any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules, and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are obviously employed.
  • the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included.
  • injectable solutions for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution.
  • injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations.
  • the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin.
  • Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions.
  • These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment.
  • the compounds of the present invention may also be administered via inhalation or insufflation by means of methods and formulations employed in the art for administration via this way.
  • the compounds of the present invention may be administered to the lungs in the form of a solution, a suspension or a dry powder. Any system developed for the delivery of solutions, suspensions or dry powders via oral or nasal inhalation or insufflation are suitable for the administration of the present compounds.
  • the compounds of the present invention may also be topically administered in the form of drops, in particular eye drops.
  • Said eye drops may be in the form of a solution or a suspension. Any system developed for the delivery of solutions or suspensions as eye drops are suitable for the administration of the present compounds.
  • Unit dosage form refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, suppositories, injectable solutions or suspensions and the like, and segregated multiples thereof.
  • the exact dosage and frequency of administration depends on the particular compound of formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, weight, sex, extent of disorder and general physical condition of the particular patient as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that said effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention.
  • the pharmaceutical composition will preferably comprise from 0.05 to 99 % by weight, more preferably from 0.1 to 70 % by weight, even more preferably from 0.1 to 50 % by weight of the active ingredient, and, from 1 to 99.95 % by weight, more preferably from 30 to 99.9 % by weight, even more preferably from 50 to 99.9 % by weight of a pharmaceutically acceptable carrier, all percentages being based on the total weight of the composition.
  • DMF means N, ⁇ /-dimethylformamide
  • DIPE diisopropyl ether
  • DCM dichloromethane
  • THF tetrahydrofuran
  • DMSO dimethylsulfoxide
  • TFA means CF 3 COOH.
  • Intermediate 15 was prepared according to Al.c-1, but starting from intermediate 14 and with a different work-up. After the reaction, the mixture was poured in H 2 O. The resulting mixture was stirred for 10 minutes and was then extracted with ethyl acetate. The separated organic layer was dried (MgSO 4 ), filtered and the solvent was evaporated, yielding 2.2 g of intermediate 15.
  • Intermediate 20 was prepared according to Al.c-1, but starting from intermediate 19 and with a different work-up. After the reaction, the mixture was poured in H 2 O and was stirred for 30 minutes. The precipitate was filtered off, yielding 2.7 g of intermediate 20.
  • Intermediate 70 was prepared by analogy to A14.b-1, but starting from intermediate 69. After removal of the solvent, the crude product was dissolved in DCM. The organic solution was washed with H 2 O, dried (MgSO 4 ), filtered and the solvent was evaporated. The residue was triturated in DIPE. The precipitate was filtered off and dried, yielding 0.39 g of intermediate 70 (85 %).
  • Intermediate 71 was prepared by analogy to A14.C-1, but starting from intermediate 70. After removal of the solvent, the crude intermediate 71 (48 % yield) was used as such in the next reaction step.
  • Compound 54 was prepared according to Bl.a-2 (72 %), but starting from intermediate 20.
  • Compound 52 was prepared according to Bl.a-5, but starting from intermediate 17.
  • Compound 14 was prepared according to Bl.a-7 but starting from intermediate 7.
  • Compound 24 was prepared according to Bl.a-5 starting from intermediate 9, but the residue after evaporation was further purified by column chromatography over silica gel (eluent: DCM). The product fractions were collected and the solvent was evaporated, yielding compound 24.
  • Compound 25 was prepared according to Bl.a-5 starting from intermediate 9, but the residue after evaporation was further purified by trituration under DIPE. The precipitate yielded compound 25.
  • Compound 36 was prepared according to Bl.a-1, but starting from intermediate 15, and before the column purification the residue was first triturated under CH 3 OH.
  • Compound 58 was prepared according to Bl. a- 14, but starting from intermediate 22,.
  • Compound 12 was prepared according to B2.a-1, but starting from intermediate 5.
  • Compound 95 was prepared according to B2.a-1, but starting from intermediate 26.
  • Compound 40 was prepared according to B2.a-1 but starting from intermediate 40 and with a different work-up procedure. After addition of the reaction mixture to the NaOH solution, the mixture was extracted with DCM. The separated organic layer was concentrated and purified by column chromatography (Isolute SPE column Flash Si). The desired fractions were collected and the solvent was evaporated, yielding compound 40.
  • Compound 85 was prepared according to B3.a-1 starting from intermediate 24, except that the reaction mixture was refluxed for 4 hours. After the extraction and washing procedure, the residue was first crystallized from 2-propanol and then from DIPE, yielding compound 85 (60 %).
  • Compound 94 was prepared according to B3.a-3 starting from intermediate 26, except for the purification. The residue was purified by column chromatography over silica gel (eluent: DCM). The desired fractions were collected and the solvent was evaporated, yielding compound 94.
  • Compound 90 was prepared according to B3.a-3 starting from intermediate 26, except for the purification. The residue was triturated in 2-propanol. The solid was filtered off and dried, yielding compound 90.
  • Compound 82 was prepared according to B3.b-1, but starting from compound 91 and the residue was triturated in DIPE. The precipitate was filtered off and dried, yielding compound 82.
  • Compound 112 was prepared according to B7.a-1, but starting from intermediate 46, and except that acetonitrile was used as the solvent and the mixture was refluxed for 1 hour. Yield: Compound 112 (24 %).
  • Compound 204 was prepared according to B9a), but the compound was purified by column chromatography with DCM as eluent instead of by trituration.
  • Compound 159 was prepared according to a similar procedure as compound 156 (B 10. c-1), but in this case acetic anhydride was used as the starting material and no pyridine was added. Yield: Compound 159 (88 %).
  • reaction mixture was evaporated, extracted in DCM and washed with
  • the HPLC measurement was performed using an Alliance HT 2790 (Waters) system comprising a quaternary pump with degasser, an autosampler, a column oven (set at 40 °C, unless otherwise indicated), a diode-array detector (DAD) and a column as specified in the respective methods below.
  • Flow from the column was split to a MS spectrometer.
  • the MS detector was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 100 to 1000 in 1 second using a dwell time of 0.1 second.
  • the capillary needle voltage was 3 kV and the source temperature was maintained at 140 0 C. Nitrogen was used as the nebulizer gas.
  • Data acquisition was performed with a Waters-Micromass MassLynx-Openlynx data system.
  • the LCMS analyses for the compounds were done at the Surveyor MSQTM (Thermo Finnigan, USA) comprising a photo diode array detector (PDA; 190-800 nm) and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer.
  • the MS detector was configured with APCI (atmospheric pressure chemical ionization, + or - ions). Mass spectra were acquired by scanning from 45 to 1000 (of atomic mass unit) in 0.3 seconds. Typical APCI conditions use a corona discharge current of 10 ⁇ A and a cone voltage of 30 V.
  • the APCI probe temperature was 640 0 C. Nitrogen was used as the nebulizer gas. Data acquisition was performed with an XcaliburTM data system.
  • MS Cl 8 column (3.5 ⁇ m, 4.6 x 100 mm) with a flow rate of 1.6 ml/min.
  • Three mobile phases (mobile phase A: 95% 25 mM ammoniumacetate + 5 % acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100 % A to 1 % A, 49 % B and 50 % C in 6.5 minutes, to 1 % A and 99 % B in 1 minute and hold these conditions for 1 minute and reequilibrate with 100 % A for 1.5 minutes.
  • An injection volume of 10 ⁇ l was used.
  • Cone voltage was 10 V for positive ionization mode and 20 V for negative ionization mode.
  • Chromolith (4.6 x 25 mm) with a flow rate of 3 ml/min.
  • Three mobile phases (mobile phase A: 95 % 25 mM ammoniumacetate + 5 % acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 96 % A, 2 % B and 2 % C, to 49 % B and 49 % C in 0.9 minutes, to 100 % B in 0.3 minutes and hold for 0.2 minutes.
  • An injection volume of 2 ⁇ l was used.
  • Cone voltage was 10 V for positive ionization mode and 20 V for negative ionization mode.
  • Reversed phase UPLC Ultra Performance Liquid Chromatography
  • BEH bridged ethylsiloxane/silica hybrid (BEH) Cl 8 column (1.7 ⁇ m, 2.1 x 50 mm; Waters Acquity) with a flow rate of 0.8 ml/min.
  • Two mobile phases (mobile phase A: 0.1 % formic acid in IHtO/methanol 95/5; mobile phase B: methanol) were used to run a gradient condition from 95 % A and 5 % B to 5 % A and 95 % B in 1.3 minutes and hold for 0.2 minutes.
  • An injection volume of 0.5 ⁇ l was used.
  • Cone voltage was 10 V for positive ionization mode and 20 V for negative ionization mode.
  • Reversed phase HPLC was carried out on a Waters XTerra MS Cl 8 column (3.5 ⁇ m, 2.1 x 30 mm) with a flow rate of 1.0 ml/min.
  • Two mobile phases (mobile phase A: 0.1 % aqueous solution of formic acid; mobile phase B: acetonitrile) were used. First, 100 % A was hold for 0.1 minutes. Then a gradient was applied to 5 % A and 95 % B in 3 minutes and hold for 0.8 minutes. The injection volume was 1 ⁇ l. The column was at room temperature.
  • Method 5 In addition to general procedure A: Reversed phase HPLC was carried out on an Atlantis Cl 8 column (3.5 ⁇ m, 4.6 x 100 mm) with a flow rate of 1.6 ml/min. Two mobile phases (mobile phase A: 70 % methanol + 30 % H 2 O; mobile phase B: 0.1 % formic acid in H2 ⁇ /methanol 95/5) were employed to run a gradient condition from 100 % B to 5 % B + 95 % A in 12 minutes. An injection volume of 10 ⁇ l was used. Cone voltage was 10 V for positive ionization mode and 20 V for negative ionization mode.
  • Method 6 was identical to method 5, except that the reversed phase HPLC was carried out on an Xbridge Cl 8 column (3.5 ⁇ m, 4.6 x 100 mm).
  • Reversed phase HPLC was carried out on a Chromolith (4.6 x 25 mm) with a flow rate of 3 ml/min.
  • Three mobile phases (mobile phase A: 95 % 25 mM ammoniumacetate + 5 % acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 96 % A, 2 % B and 2 % C, to 49 % B and 49 % C in 0.9 minutes, to 100 % B in 0.3 minutes and hold for 0.2 minutes.
  • An injection volume of 2 ⁇ l was used.
  • Cone voltage was 10 V for positive ionization mode and 20 V for negative ionization mode.
  • n.d. means not determined.
  • melting points were determined with a Sanyo Gallenkamp melting point apparatus.
  • the melting point (m.p.) was determined with a DSC823e (Mettler- Toledo). The melting point was measured with a temperature gradient of 30 C/minute. Maximum temperature was 400 0 C. The reported value is a peak value. m.p. compound 185: 111.9 0 C
  • HEK293 cells stably transfected with hEP4 were grown up to 80-90% confluence in T175 Falcon flasks in Dulbecco's modified Eagle's medium (DMEM) (Invitrogen) supplemented with 100 IU/ml penicillin G, 100 ⁇ g/ml streptomycin sulphate, 1 mM sodium pyruvate, 300 ⁇ g/ml L-glutamine and 10% heat inactivated foetal calf serum (Biochrom AG) in a humidified atmosphere of 5%CO 2 at 37°C.
  • DMEM Dulbecco's modified Eagle's medium
  • Biochrom AG heat inactivated foetal calf serum
  • the experiments were performed with the cAMP Dynamic HTRF kit (CIS bio international, France), used according to the supplier's instructions. Specifically, cells were thawed rapidly by warming up the vials in a warm water bath at 37°C. The thawed cell suspension (2 ml; 10 7 cells/ml) was transferred to a 50 ml Falcon tube and for each vial, 10 ml prewarmed culture medium was added. The falcon tube was as resuspended in stimulation buffer (HBSS Ix, IBMX ImM, Hepes 5mM, MgCl 2 1OmM, BSA 0.1%, pH 7.4).
  • stimulation buffer HBSS Ix, IBMX ImM, Hepes 5mM, MgCl 2 1OmM, BSA 0.1%, pH 7.4
  • the suspension was counted in a nucleocounter and further diluted in stimulation buffer at a concentration of 500,000 cells/ml.
  • the cells were seeded out in a MW384 COSTAR 3710 with the compounds using a Multidrop 384 at a density of 10,000 cells/well in 20 ⁇ l.
  • the cells were incubated for 30 minutes at room temperature in the dark in the presence of different concentrations of the compounds diluted in stimulation buffer in a final volume of 30 ⁇ l/well.
  • the final concentration of DMSO whenever needed to dissolve the compounds) did not exceed 1% (v/v) and was also included in the corresponding control samples. Reaction was stopped by adding 10 ⁇ l cAMP-d2 conjugate and subsequently 10 ⁇ l of anti-cAMP with the Multidrop.
  • Selectivity of the compounds for EP4 can also be demonstrated by determining whether the compounds have activity on the EPl receptor, for instance by [Ca 2+ J 1 measurements in response to activation or inhibition of the monkey EPl receptor as follows : The antagonistic and agonistic effect of the test compounds on intracellular Ca 2+ concentrations ([Ca 2+ J 1 ) was measured in a fluorescent based assay, using the calcium assay kit (Molecular Devices, Crawley, England).
  • HEK293 cells stably transfected with monkey EPl receptor were cultured in T 175 Falcon flasks in Dulbecco's modified Eagle's medium (DMEM) (Invitrogen) supplemented with 100 IU/ml penicillin G, 100 ⁇ g/ml streptomycin sulphate, 1 mM sodium pyruvate, 300 ⁇ g/ml L-glutamine and 10% heat inactivated foetal calf serum (Biochrom AG) in a humidified atmosphere of 5%CO 2 at 37°C. Before the experiments, the cells were grown on 384-well (black wall/transparent bottom) plates from Greiner for 1 day until they reached confluency.
  • DMEM Dulbecco's modified Eagle's medium
  • the cells were loaded with loading buffer supplied by the kit supplemented with 10 mM probenecid and 0.1% fatty acid free bovine serum albumine, adjusted to pH 7.4 with 1 M Hepes-acid, for 90 minutes at 37°C in a CO 2 incubator.
  • Ca 2+ signals were measured in a Fluorometric Imaging Plate Reader (FLIPR, from Molecular Devices).
  • FLIPR Fluorometric Imaging Plate Reader
  • the loaded cells were preincubated with the compounds for 30 minutes at room temperature before starting the experiment in the FLIPR, where 100 nM of the reference agonist prostaglandin E2 (PGE2) was added.
  • PGE2 prostaglandin E2
  • the compounds were added to the loaded cells during the measurement in the FLIPR where 1000 nM PGE2 was used as the reference agonist.
  • changes in relative fluorescence units were recorded in function of time.
  • the final concentration of DMSO whenever needed to dissolve the compounds) did not exceed 1% (v/v) and was also included in the corresponding control samples.
  • ZD6416 was used as the reference antagonist.
  • the peak fluorescence (maximum signal between 1 and 50 sec) was considered as the relevant signal.
  • PEC50 (agonism) and pICso (antagonism) values for the tested compounds were ⁇ 5.

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Abstract

L'invention concerne un composé représenté par la formule (I) comprenant une forme isomère stéréochimique quelconque de ce composé, un N-oxyde de celui-ci, un sel pharmaceutiquement acceptable de celui-ci ou un solvate de celui-ci. Dans cette formule, un noyau E représente un composé hétérocyclique à 5 éléments aromatique ou partiellement saturé, les lignes en pointillé représentant une liaison double facultative, B, C et D représentant chacun indépendamment CH2, CH, N, NH, S ou O, et F représentant N ou C, à condition que le noyau à 5 éléments contienne 1, 2 ou 3 hétéroatomes; X représente une liaison directe ou C1-4alkanédiyle; Y représente N ou CH; R1 représente hydrogène ou fluoro; R2 représente hydrogène, halo, cyano, C1-6alkyle, C1-6alkyloxy, C1-6alkylcarbonyle ou C1-6alkylcarbonylamino; R3 représente hydrogène, halo, C1-6alkyle, C1-6alkyloxy, cyano, nitro, amino ou mono- ou di(C1-6alkyl)amino; R4 représente halo, hydroxyle, carboxyle, C 1-6alkyle éventuellement substitué, polyhaloC 1-6alkyle, C 1-6alkyloxycarbonyle, polyhaloC 1-6alkyloxy, C 2-6alcényle éventuellement substitué, cyano, nitro, NR10 R11, C 1-6alkylthio, C 1-6alkyloxy éventuellement substitué, ou deux substituants R4 adjacents pouvant être pris ensemble; n représente un nombre entier de valeur 1, 2 ou 3; m représente un nombre entier de valeur 1, 2 ou 3 à condition que R3 puisse uniquement être autre qu' hydrogène si au moins l'un de R1 ou R2 est autre qu'hydrogène, et à condition que 2,6- bis(1,1-dimethylethyl)-4-[6-(2-phenylethoxy)-1H-purin-2-yl]-phenol ne soit pas inclus. Les composés précités sont utilisés pour traiter une maladie par activation du récepteur EP4.
PCT/EP2008/051044 2007-01-30 2008-01-29 Dérivés bicycliques utilisés comme agonistes de ep4 WO2008092861A1 (fr)

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WO2012075174A3 (fr) * 2010-12-02 2012-07-26 Allergan, Inc. Composés et procédés de réparation de la peau
WO2012112757A2 (fr) 2011-02-17 2012-08-23 Allergan, Inc. Compositions et procédés améliorés de remplacement de tissu mou
WO2013004291A1 (fr) 2011-07-04 2013-01-10 Rottapharm S.P.A. Dérivés aminés cycliques en tant qu'agonistes du récepteur ep4
WO2013105997A2 (fr) 2011-02-23 2013-07-18 Allergan, Inc. Compositions et procédés de remplacement de tissu mou améliorés
WO2013123272A1 (fr) 2012-02-16 2013-08-22 Allergan, Inc. Compositions et procédés perfectionnés de remplacement de tissu mou
WO2013123275A1 (fr) 2012-02-16 2013-08-22 Allergan, Inc. Compositions et procédés perfectionnés de remplacement de tissu mou
WO2013123270A1 (fr) 2012-02-16 2013-08-22 Allergan, Inc. Compositions et procédés perfectionnés de remplacement de tissu mou
WO2013123274A1 (fr) 2012-02-16 2013-08-22 Allergan, Inc. Compositions et procédés perfectionnés de remplacement de tissu mou
WO2013164061A1 (fr) 2012-05-04 2013-11-07 dedeMERCK PATENT GMBH Dérivés de pyrrolotriazinone
CN104876941A (zh) * 2014-02-28 2015-09-02 南京圣和药业股份有限公司 稠合三环类化合物及其应用
US9334262B2 (en) 2010-08-19 2016-05-10 Allergan, Inc. Methods of treating soft tissue defects
JPWO2013191244A1 (ja) * 2012-06-21 2016-05-26 大正製薬株式会社 ピリドピリミジン−４−オン誘導体
CN106279211A (zh) * 2015-06-03 2017-01-04 北京大学 一种噻唑并嘧啶酮化合物及其制备方法和应用
US9963462B2 (en) 2015-09-30 2018-05-08 Max-Planck-Gesellschaft Zur Forderung Der Wissenschaften E.V. Sepiapterin reductase inhibitors
US10588894B2 (en) 2017-06-21 2020-03-17 SHY Therapeutics LLC Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease
WO2020211751A1 (fr) * 2019-04-15 2020-10-22 武汉朗来科技发展有限公司 Inhibiteur de rock, procédé de préparation et utilisation associés
US10870657B2 (en) 2015-12-22 2020-12-22 SHY Therapeutics LLC Compounds for the treatment of cancer and inflammatory disease
US11548867B2 (en) 2017-07-19 2023-01-10 Idea Ya Biosciences, Inc. Amido compounds as AhR modulators

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Cited By (34)

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Publication number Priority date Publication date Assignee Title
US9334262B2 (en) 2010-08-19 2016-05-10 Allergan, Inc. Methods of treating soft tissue defects
WO2012075174A3 (fr) * 2010-12-02 2012-07-26 Allergan, Inc. Composés et procédés de réparation de la peau
WO2012112757A2 (fr) 2011-02-17 2012-08-23 Allergan, Inc. Compositions et procédés améliorés de remplacement de tissu mou
WO2013105997A2 (fr) 2011-02-23 2013-07-18 Allergan, Inc. Compositions et procédés de remplacement de tissu mou améliorés
WO2013004291A1 (fr) 2011-07-04 2013-01-10 Rottapharm S.P.A. Dérivés aminés cycliques en tant qu'agonistes du récepteur ep4
WO2013123272A1 (fr) 2012-02-16 2013-08-22 Allergan, Inc. Compositions et procédés perfectionnés de remplacement de tissu mou
WO2013123275A1 (fr) 2012-02-16 2013-08-22 Allergan, Inc. Compositions et procédés perfectionnés de remplacement de tissu mou
WO2013123270A1 (fr) 2012-02-16 2013-08-22 Allergan, Inc. Compositions et procédés perfectionnés de remplacement de tissu mou
WO2013123274A1 (fr) 2012-02-16 2013-08-22 Allergan, Inc. Compositions et procédés perfectionnés de remplacement de tissu mou
CN104271580B (zh) * 2012-05-04 2017-02-22 默克专利股份公司 吡咯并三嗪酮衍生物
WO2013164061A1 (fr) 2012-05-04 2013-11-07 dedeMERCK PATENT GMBH Dérivés de pyrrolotriazinone
JP2015515961A (ja) * 2012-05-04 2015-06-04 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツングＭｅｒｃｋ Ｐａｔｅｎｔ Ｇｅｓｅｌｌｓｃｈａｆｔ ｍｉｔ ｂｅｓｃｈｒａｅｎｋｔｅｒ Ｈａｆｔｕｎｇ ピロロトリアジノン誘導体
US9174995B2 (en) 2012-05-04 2015-11-03 Merck Patent Gmbh Pyrrolotriazinone derivatives
CN104271580A (zh) * 2012-05-04 2015-01-07 默克专利股份公司 吡咯并三嗪酮衍生物
EA027628B1 (ru) * 2012-05-04 2017-08-31 Мерк Патент Гмбх Производные пирролотриазинона
JPWO2013191244A1 (ja) * 2012-06-21 2016-05-26 大正製薬株式会社 ピリドピリミジン−４−オン誘導体
CN104876941A (zh) * 2014-02-28 2015-09-02 南京圣和药业股份有限公司 稠合三环类化合物及其应用
CN106279211A (zh) * 2015-06-03 2017-01-04 北京大学 一种噻唑并嘧啶酮化合物及其制备方法和应用
US10450326B2 (en) 2015-06-03 2019-10-22 Peking University Thiazolopyrimidinone compounds and preparation methods and use thereof
CN106279211B (zh) * 2015-06-03 2020-09-15 北京大学 一种噻唑并嘧啶酮化合物及其制备方法和应用
US9963462B2 (en) 2015-09-30 2018-05-08 Max-Planck-Gesellschaft Zur Forderung Der Wissenschaften E.V. Sepiapterin reductase inhibitors
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US10940139B2 (en) 2017-06-21 2021-03-09 SHY Therapeutics LLC Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease
US11000515B2 (en) 2017-06-21 2021-05-11 SHY Therapeutics LLC Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease
US11213515B1 (en) 2017-06-21 2022-01-04 SHY Therapeutics LLC Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease
US11541041B1 (en) 2017-06-21 2023-01-03 SHY Therapeutics LLC Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, Rasopathies, and fibrotic disease
US10588894B2 (en) 2017-06-21 2020-03-17 SHY Therapeutics LLC Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease
US11548867B2 (en) 2017-07-19 2023-01-10 Idea Ya Biosciences, Inc. Amido compounds as AhR modulators
CN111825675A (zh) * 2019-04-15 2020-10-27 武汉朗来科技发展有限公司 Rock抑制剂及其制备方法和用途
WO2020211751A1 (fr) * 2019-04-15 2020-10-22 武汉朗来科技发展有限公司 Inhibiteur de rock, procédé de préparation et utilisation associés
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