WO2008065500A2 - Hétéroaryl amides comme inhibiteurs du transport de la glycine de type i - Google Patents

Hétéroaryl amides comme inhibiteurs du transport de la glycine de type i Download PDF

Info

Publication number
WO2008065500A2
WO2008065500A2 PCT/IB2007/003604 IB2007003604W WO2008065500A2 WO 2008065500 A2 WO2008065500 A2 WO 2008065500A2 IB 2007003604 W IB2007003604 W IB 2007003604W WO 2008065500 A2 WO2008065500 A2 WO 2008065500A2
Authority
WO
WIPO (PCT)
Prior art keywords
alkylene
membered
alkyl
zero
heterocycloalkyl
Prior art date
Application number
PCT/IB2007/003604
Other languages
English (en)
Other versions
WO2008065500A3 (fr
Inventor
Iii John Adams Lowe
Subas Man Sakya
Mark Allen Sanner
Jotham Wadsworth Coe
Stanton Furst Mchardy
Original Assignee
Pfizer Products Inc.
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 Pfizer Products Inc. filed Critical Pfizer Products Inc.
Publication of WO2008065500A2 publication Critical patent/WO2008065500A2/fr
Publication of WO2008065500A3 publication Critical patent/WO2008065500A3/fr

Links

Classifications

    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—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
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to heteroaryl amides and to pharmaceutical compositions containing them and to their use in the treatment of central nervous system disorders, cognitive disorders, schizophrenia, dementia and other disorders in mammals, including humans. These compounds exhibit activity as inhibitors of the glycine type-1 transporter.
  • Schizophrenia a progressive neurological disease, is manifested in its early stages as thought disorders such as hallucinations, paranoid delusions, and playful thought patterns, collectively known as positive symptoms. These easily recognizable symptoms gave the disease the historical name "madness”. As the disease progresses, negative symptoms, such as social withdrawal and anhedonia, and cognitive symptoms such as dementia become more apparent. Only about one-third of schizophrenic patients can be treated successfully and returned to society, while the remainder is generally institutionalized. The burden on society of this devastating illness and the toll it takes on family members of affected patients make it one of the most costly of all CNS diseases.
  • glycine is required as a co-agonist to set the "tone" of the receptor for its response to glutamate. Enhancing this "tone” by increasing the effect of glycine would augment NMDA neurotransmission, and provide potential benefit in the treatment of schizophrenia.
  • NFPS glycine type-1 transporter
  • GIyTI removes glycine efficiently at the synapse, and that inhibition of GIyTI can augment NMDA receptor function.
  • the present invention provides GIyTI inhibitors as a treatment for disorders or conditions such as schizophrenia through its augmentation of glutamatergic neurotransmission.
  • HET is a 5 or 6 membered membered heteroaryl ring optionally substituted by one or more substituents selected from R 5 ;
  • X 2 is -(C Z ero-Cio alkylene)-(O) y -(C zero -C 10 alkylene)-, or -(C 3 -C 10 cycloalkyl)-(C zera -Ci 0 alkylene)-(O) y -(C 2ero -C 10 alkylene)-; wherein y is 0 or 1;
  • X 3 is -(Czero-Cio alkylene)-NR 1 R 2 ; -(C 3 -C 10 cycloalky)-(C zero -C 10 alkylene)-NR 1 R 2 ; -(C zero -Ci 0 alkylene)-X 4 or -(C 3 -C 10 cycloalkyl)-(C zero -C 10 alkylene)-X 4 ; wherein said cycloalkyl is optional substituted by one or more -OH;
  • X 4 is a nitrogen containing (5-15 membered) heterocycloalkyl or a nitrogen containing (5-15 membered) heteroaryl, each optionally substituted by one or more substituents selected from R 5 ; with the proviso that the 4-15 membered heterocycloalkyl of X 4 is not a 3-aza- bicyclo ⁇ 3.1.0]hex-6-yl group;
  • alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, cycloalkyl, cycloalkenyl, bi- or tricycloalkyl, bi- or tricycloalkenyl, heterocycloalkyl, aryl, heteroaryl, aryloxy and heteroaryloxy of R 6 are each optionally independently substituted with one or more substituents independently selected from the group
  • alkyl includes saturated monovalent hydrocarbon radicals having straight or branched moieties.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, pentyl, hexyl, cyclopropylmethylene (-CHa-cyclopropyl) and £-butyl.
  • alkenyl includes alkyl moieties having at least one carbon-carbon double bond wherein alkyl is as defined above.
  • alkenyl include, but are not limited to, ethenyl and propenyl.
  • alkynyl includes alkyl moieties having at least one carbon-carbon triple bond wherein alkyl is as defined above.
  • alkynyl groups include, but are not limited to, ethynyl and 2-propynyl.
  • alkoxy means “alkyl-O-", wherein “alkyl” is as defined above.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy and allyloxy.
  • alkyl means alkyl-O- alkyl-, wherein alkyl is defined above.
  • hydroxyalkyl means -alkyl-OH, wherein alkyl is defined above.
  • alkenoxy means “alkenyl-O-”, wherein “alkenyl” is as defined above.
  • alkynoxy means “alkynyl-O-”, wherein “alkynyl” is as defined above.
  • cycloalkyl includes non- aromatic saturated cyclic alkyl moieties wherein alkyl is as defined above.
  • examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • Bicycloalkyl and tricycloalkyl include non-aromatic saturated cyclic alkyl moieties consisting of two or three rings respectively, wherein said rings share at least one carbon atom.
  • Bicycloalkyl and tricycloalkyl groups also include cyclic moieties consisting of two or three rings respectively, wherein one ring is aryl or heteroaryl and wherein said rings share two carbon atoms.
  • bicycloalkyl groups include spiro groups and fused ring groups.
  • bicycloalkyl groups include, but are not limited to, bicyclo-[3.1.0]-hexyl, bicyclo — 2.2.1]-hept-1-yl, norbornyl, spiro[4.5]decyl, spiro[4.4]nonyl, spiro[4.3]octyl, spiro[4.2]heptyl, indan, teralene (1 ,2,3,4-tetrahydronaphlene) and 6, 7, 8, ⁇ -tetrahydro- ⁇ H-benzocycloheptene.
  • An example of a tricycloalkyl group is adamantanyl.
  • cycloalkyl, bicycloalkyl, and tricycloalkyl groups are known in the art, and such groups are encompassed by the definitions "cycloalkyl”, “bicycloalkyl” and “tricycloalkyl” herein.
  • cycloalkyl will also include multi-cyclic rings groups (e.g., bicycloalkyl, tricycloalkyl, etc.)
  • Cycloalkenyl “bicycloalkenyl”, and “tricycloalkenyl” refer to non-aromatic each cycloalkyl, bicycloalkyl, and tricycloalkyl moieties as defined above, except that they each include one or more carbon-carbon double bonds connecting carbon ring members (an “endocyclic” double bond) and/or one or more carbon-carbon double bonds connecting a carbon ring member and an adjacent non-ring carbon (an “exocyclic” double bond).
  • cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclobutenyl, and cyclohexenyl.
  • a non-limiting example of a bicycloalkenyl group is norbomenyl.
  • Cycloaikyl, cycloalkenyl, bicycloalkyl, and bicycloalkenyl groups also include groups that are substituted with one or more oxo moieties. Examples of such groups with oxo moieties are oxocyclopentyl, oxocyclobutyl, oxocyclopentenyl and norcamphoryl.
  • cycloalkenyl bicycloalkenyl, and tricycloalkenyl groups are known in the art, and such groups are included within the definitions "cycloalkenyl”, “bicycloalkenyl” and “tricycloalkenyl” herein.
  • aryl includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl (Ph), naphthyl, indenyl, indanyl and fluorenyl.
  • Ph phenyl
  • naphthyl naphthyl
  • indenyl indenyl
  • fluorenyl fluorenyl
  • heterocyclic and heterocycloalkyl refer to non-aromatic cyclic groups containing one or more heteroatoms, preferably from one to four heteroatoms, each selected from O, S and N.
  • heterocycloalkyl groups include non-aromatic two-ringed cyclic groups, wherein said rings share one or two atoms, and wherein at least one of the rings contains a heteroatom (O, S, or N).
  • Heterobicycloalkyl groups also include two-ringed cyclic groups, wherein said one ring is aryl or heteroaryl ring and wherein said rings share one or two atoms, and wherein at least one of the rings contains a heteroatom (O, S, or N).
  • heterobicycloalkyl groups include spiro groups and fused ring groups.
  • each ring in the heterobicycloalkyl contains up to four heteroatoms (i.e. from zero to four heteroatoms, provided that at least one ring contains at least one heteroatom).
  • the heterocyclic groups of this invention can also include ring systems substituted with one or more oxo moieties.
  • heterocycloalkyl will include multi-cyclic rings groups (e.g., heterobicycloalkyl heterotricycloalkyl, etc.)
  • non-aromatic heterocyclic groups are aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepinyl, piperazinyl, 1 ,2,3,6-tetrahydropyridinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholino, thiomorpholino, thioxanyl, pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1 ,3-dioxolanyl, pyrazolinyl, dihydr
  • heteroaryl refers to aromatic groups containing one or more heteroatoms, preferably from one to four heteroatoms, selected from O, S and N.
  • a multicyclic group containing one or more heteroatoms wherein at least one ring of the group is aromatic is a "heteroaryl” group.
  • the heteroaryl groups of this invention can also include ring systems substituted with one or more oxo moieties.
  • heteroaryl groups are pyridinyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl, isoquinolyl, 1 ,2,3,4-tetrahydroguinolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, triazinyl, 1 ,2,4-trizainyl, 1 ,3,5-triazinyl, isoindolyl, 1-oxoisoindolyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl
  • cycloalkoxy means “cycloalkyl-O-", wherein “cycloalkyl” is as defined above.
  • aryloxy means “aryl-O-”, wherein “aryl” is as defined above.
  • heterocycloalkoxy means “heterocycloalkyl-O-", wherein “heterocycloalkyl” is as defined above.
  • heteroaryloxy means “heteroaryl-O", wherein “heteroaryl” is as defined above.
  • halogen atoms e.g., -CH 2 F, -CHF 2 -CF 3 , -PhCI, etc.
  • substituents refers to from one to the maximum number of substituents possible based on the number of available bonding sites.
  • examples of one or more or at least one substituent include, but are not limited to, 1 to 10 substituents, or 1 to 6 substituents or 1 to 3 substituents).
  • All the foregoing groups derived from hydrocarbons may have up to about 1 to about 20 carbon atoms (e.g. C r C 2 o alkyl, C 2 -C 20 alkenyl, C 3 -C 20 cycloalkyl, (3-20 membered)heterocycloalkyl, C 6 -C 20 aryl, (5-20 membered)heteroaryl, etc.) or 1 to about 15 carbon atoms (e.g., C 1 -C 15 alkyl, C 2 -Ci 5 alkenyl, C 3 -Ci 5 cycloalkyl, (3-15 membered)heterocycloalkyl, C 6 -C 15 aryl, (5-15 membered)heteroaryl, etc.), or 1 to about 12 carbon atoms, or 1 to about 8 carbon atoms, or 1 to about 6 carbon atoms.
  • a group derived from pyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached).
  • the terms referring to the groups also encompass all possible tautomers.
  • a 3-aza-bicyclo ⁇ 3.1.0]hex-6-yl group has the following structure:.
  • a Cz e ro alkylene means a direct bond.
  • X 3 is -(C 2era alkylene)-X 4 , this mean that X 4 is directed bonded to the tertiary nitrogen of Formula I.
  • HET is imidazolyl, thiazolyl or isoxazolyl.
  • X 3 is -(C 3 -C 10 cycloalky)-NR 1 R 2 .
  • cycloalkyl is selected from cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • R 1 and/or R 2 are hydrogen.
  • X 3 is -(C 2S r 0 -C 1 alkylene)-X 4 and X 4 is nitrogen containing (5-15 membered) heterocycloalkyl.
  • the nitrogen containing heterocyloalkyl is azepanyl, pyrrolidinyl, azabicycloheptyl, azabicyclononyl or azabicyclodecyl
  • the present invention relates to a compound of Formula I
  • HET is imidazolyl optionally substituted by one or more substituents selected from
  • X 2 is -(C zero -C 10 alkylene)
  • X 3 is -(Czero-C-,0 alky)ene)-X 4 , -(C 3 -C 10 cycloalky)-NR 1 R 2 or -(C 3 -C 10 cycloalkyl)-X 4 ; wherein said cycloalkyl is optional substituted by one or more -OH;
  • X 4 is a nitrogen containing (4-15 membered) heterocycloalkyl or a nitrogen containing (5-15 membered) heteroaryl, each optionally substituted by one or more substituents selected from R 5 ; with the proviso that the 4-15 membered heterocycloalkyl of X 4 is not a 3-aza- bicyclo ⁇ 3.1.0]hex-6-yl group
  • X 3 is X 4 and X 4 is
  • X 3 is -(C r C 2 alkylene)-X 4 wherein X 4 is
  • X 3 is -(C 3 -C 10 cycloalky)-NR 1 R 2 or -(C 3 -CI 0 cycloalkyl)-X 4 ; wherein the cycloalkyl is cyclopentyl or cyclohexyl.
  • X 4 is azetidinyl or pyrrolidinyl
  • R 1 and R 2 are each independently hydrogen or C 1 -C 6 alkyl.
  • X 2 is -CH2- and ring A is phenyl.
  • ring A is phenyl and optionally substituted by one or more -OH, - C 1 -C 6 alkyl, -Ci-C 6 alkoxy, -C 3 -C 8 cycloalkoxy, -C 1 -C 6 haloalkyl, halogen, -C 1 -C 6 haloalkyloxy or -C 3 -C 8 cycloalkyl.
  • ring A is phenyl and optionally substituted by one or more -OH, - CF 3 , -OCF 3 or Halogen
  • Het is
  • Compounds of the Formula I may have optical centers and therefore may occur in different enantiomeric and diastereomeric configurations.
  • the present invention includes all enantiomers, diastereomers, and other stereoisomers of such compounds of the Formula I, as well as racemic compounds and racemic mixtures and other mixtures of stereoisomers thereof.
  • Pharmaceutically acceptable salts of the compounds of Formula I include the acid addition and base salts thereof.
  • Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include, but are not limited to, the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mandelates mesylate, methylsulphate, naphthylate, 2- napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate,
  • Suitable base salts are formed from bases which form non-toxic salts. Examples include, but are not limited to, the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.
  • Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.
  • compositions of Formula I may be prepared by one or more of three methods:
  • the resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent.
  • the degree of ionization in the resulting salt may vary from completely ionised to almost non-ionised.
  • the compounds of the invention may exist in a continuum of solid states ranging from fully amorphous to fully crystalline.
  • the term 'amorphous' refers to a state in which the material lacks long range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid. Typically such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid.
  • a change from solid to liquid properties occurs which is characterised by a change of state, typically second order ('glass transition')-
  • 'crystalline' refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks.
  • Such materials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is characterised by a phase change, typically first order ('melting point').
  • the compounds of the invention may also exist in unsolvated and solvated forms.
  • 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
  • solvent molecules for example, ethanol.
  • 'hydrate' is employed when said solvent is water.
  • Isolated site hydrates are ones in which the water molecules are isolated from direct contact with each other by intervening organic molecules.
  • channel hydrates the water molecules lie in lattice channels where they are next to other water molecules.
  • metal-ion coordinated hydrates the water molecules are bonded to the metal ion.
  • the complex When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water/solvent content will be dependent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.
  • the compounds of the invention may also exist in a mesomorphic state (mesophase or liquid crystal) when subjected to suitable conditions. The mesomorphic state is intermediate between the true crystalline state and the true liquid state (either melt or solution).
  • references to compounds of Formula I include references to salts, solvates, multi-component complexes and liquid crystals thereof and to solvates, multi- component complexes and liquid crystals of salts thereof.
  • the compounds of the invention include compounds of Formula I as hereinbefore defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopically- labeled compounds of Formula I.
  • 'prodrugs' of the compounds of Formula I are also within the scope of the invention.
  • certain derivatives of compounds of Formula I which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of Formula I having the desired activity, for example, by hydrolytic cleavage.
  • Such derivatives are referred to as 'prodrugs'.
  • Further information on the use of prodrugs may be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (Ed. E. B. Roche, American Pharmaceutical Association). '
  • Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of Formula I with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985).
  • prodrugs in accordance with the invention include, but are not limited to,
  • the compound of Formula I contains an alcohol functionality (-OH) 1 an ether thereof, for example, a compound wherein the hydrogen of the alcohol functionality of the compound of Formula I is replaced by (C r C 6 )alkanoyloxymethyl; and (iii) where the compound of Formula I contains a primary or secondary amino functionality (-NH 2 or -NHR where R ⁇ H), an amide thereof, for example, a compound wherein, as the case may be, one or both hydrogens of the amino functionality of the compound of Formula I is/are replaced by ((-VCioJalkanoyl.
  • metabolites of compounds of Formula I that is, compounds formed in vivo upon administration of the drug.
  • Some examples of metabolites in accordance with the invention include, but are not limited to,
  • Compounds of Formula I containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where a compound of Formula I contains an alkenyl or alkenylene group, geometric cis/trans (or Z/E) isomers are possible. Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism ('tautomerism') can occur. This can take the form of proton tautomerism in compounds of Formula I containing, for example, an imino, keto, or oxime group, or so-called valence tautomerism in compounds which contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.
  • Stereoisomers, geometric isomers and tautomeric forms of the compounds of Formula I including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof.
  • acid addition or base salts wherein the counterion is optically active for example, d-lactate or /-lysine, or racemic, for example, (//-tartrate or d/-arginine.
  • Cisltrans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallisation.
  • racemate or racemic mixture may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of Formula I contains an acidic or basic moiety, a base or acid such as 1-phenylethylamine or tartaric acid.
  • a suitable optically active compound for example, an alcohol, or, in the case where the compound of Formula I contains an acidic or basic moiety, a base or acid such as 1-phenylethylamine or tartaric acid.
  • the resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person.
  • Chiral compounds of the invention may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and from 0 to 5% by volume of an alkylamine, typically 0.1 % diethylamine. Concentration of the eluate affords the enriched mixture.
  • chromatography typically HPLC
  • a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and from 0 to 5% by volume of an alkylamine, typically 0.1 % diethylamine.
  • the first type is the racemic compound (true racemate) referred to above wherein one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts.
  • the second type is the racemic mixture or conglomerate wherein two forms of crystal are produced in equimolar amounts each comprising a single enantiomer.
  • Racemic mixtures may be separated by conventional techniques known to those skilled in the art - see, for example, Stereochemistry of Organic Compounds by E. L. ENeI and S. H. Wilen (Wiley, 1994).
  • the present invention includes all pharmaceutically acceptable isotopically-labelled compounds of Formula I wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature.
  • isotopes suitable for inclusion in the compounds of the invention include, but are not limited to, isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 11 C, 13 C and 14 C, chlorine, such as 36 CI, fluorine, such as 18 F, iodine, such as 123 I and 125 I, nitrogen, such as
  • isotopically-labelled compounds of Formula I for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • substitution with heavier isotopes such as deuterium, i.e. 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • Isotopically-labeled compounds of Formula I can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically- labeled reagent in place of the non-labeled reagent previously employed.
  • solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D 2 O, d 6 -acetone, d 6 - DMSO.
  • This invention also relates to a method of treating a disorder or condition selected from psychosis, schizophrenia, conduct disorder, disruptive behavior disorder, bipolar disorder, psychotic episodes of anxiety, anxiety associated with psychosis, psychotic mood disorders such as severe major depressive disorder; mood disorders associated with psychotic disorders such as acute mania or depression associated with bipolar disorder and mood disorders associated with schizophrenia, behavioral manifestations of mental retardation, conduct disorder and autistic disorder; movement disorders such as Tourette's syndrome, akinetic-rigid syndrome, movement disorders associated with Parkinson's disease, tardive dyskinesia and other drug induced and neurodegeneration based dyskinesias; attention deficit hyperactivity disorder; cognitive disorders such as dementias (including age related dementia, and senile dementia of the Alzheimer's type) and memory disorders in a mammal, including a human, comprising administering to a mammal in need of such treatment an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, that is effective in treating such condition or disorder.
  • a disorder or condition selected
  • This invention also relates to a pharmaceutical composition for treating a disorder or condition selected from psychosis, schizophrenia, conduct disorder, disruptive behavior disorder, bipolar disorder, psychotic episodes of anxiety, anxiety associated with psychosis, psychotic mood disorders such as severe major depressive disorder; mood disorders associated with psychotic disorders such as acute mania or depression associated with bipolar disorder and mood disorders associated with schizophrenia, behavioral manifestations of mental retardation, conduct disorder and autistic disorder; movement disorders such as Tourette's syndrome, akinetic-rigid syndrome, movement disorders associated with Parkinson's disease, tardive dyskinesia and other drug induced and neurodegeneration based dyskinesias; attention deficit hyperactivity disorder; cognitive disorders such as dementias (including age related dementia and senile dementia of the Alzheimer's type) and memory disorders in a mammal, including a human, comprising a compound of the formula I 1 or a pharmaceutically acceptable salt thereof, in an amount that is effective for treating such disorder or condition.
  • a disorder or condition selected from psychosis, schizophrenia, conduct disorder, disruptive behavior disorder
  • This invention also relates to a method of treating a disorder or condition selected from psychosis, schizophrenia, conduct disorder, disruptive behavior disorder, bipolar disorder, psychotic episodes of anxiety, anxiety associated with psychosis, psychotic mood disorders such as severe major depressive disorder; mood disorders associated with psychotic disorders such as acute mania or depression associated with bipolar disorder and mood disorders associated with schizophrenia, behavioral manifestations of mental retardation, conduct disorder and autistic disorder; movement disorders such as Tourette's syndrome, akinetic-rigid syndrome, movement disorders associated with Parkinson's disease, tardive dyskinesia and other drug induced and neurodegeneration based dyskinesias; attention deficit hyperactivity disorder; cognitive disorders such as dementias (including age related dementia and senile dementia of the Alzheimer's type) and memory disorders in a mammal, including a human, comprising administering to a mammal in need of such treatment a glycine transport-inhibiting amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof.
  • a disorder or condition selected from
  • This invention also relates to a pharmaceutical composition for treating a disorder or condition selected from psychosis, schizophrenia, conduct disorder, disruptive behavior disorder, bipolar disorder, psychotic episodes of anxiety, anxiety associated with psychosis, psychotic mood disorders such as severe major depressive disorder; mood disorders associated with psychotic disorders such as acute mania or depression associated with bipolar disorder and mood disorders associated with schizophrenia, behavioral manifestations of mental retardation, conduct disorder and autistic disorder; movement disorders such as Tourette's syndrome, akinetic-rigid syndrome, movement disorders associated with Parkinson's disease, tardive dyskinesia and other drug induced and neurodegeneration based dyskinesias; attention deficit hyperactivity disorder; cognitive disorders such as dementias (including age related dementia and senile dementia of the Alzheimer's type) and memory disorders in a mammal, including a human, comprising a compound of the formula I, or a pharmaceutically acceptable salt thereof, in a glycine transport-inhibiting amount.
  • a disorder or condition selected from psychosis, schizophrenia, conduct disorder, disruptive behavior
  • treating refers to reversing, alleviating or inhibiting the progress of a disease, disorder or condition, or one or more symptoms of such disease, disorder or condition, to which such term applies.
  • treating may also refer to decreasing the probability or incidence of the occurrence of a disease, disorder or condition in a mammal as compared to an untreated control population, or as compared to the same mammal prior to treatment.
  • treating may refer to preventing a disease, disorder or condition, and may include delaying or preventing the onset of a disease, disorder or condition, or delaying or preventing the symptoms associated with a disease, disorder or condition.
  • treating may also refer to reducing the severity of a disease, disorder or condition or symptoms associated with such disease, disorder or condition prior to a mammal's affliction with the disease, disorder or condition. Such prevention or reduction of the severity of a disease, disorder or condition prior to affliction relates to the administration of the composition of the present invention, as described herein, to a subject that is not at the time of administration afflicted with the disease, disorder or condition.
  • treating may also refer to preventing the recurrence of a disease, disorder or condition or of one or more symptoms associated with such disease, disorder or condition.
  • treatment and “therapeutically,” as used herein, refer to the act of treating, as “treating” is defined above.
  • the compounds of the present invention exhibit glycine transport inhibiting activity and therefore are of value in the treatment of a wide variety of clinical conditions that are characterized by the deficit of glutamateric neurotransmission in mammalian subjects, especially humans. Such conditions include the positive and negative symptoms of schizophrenia and other psychoses, and cognitive deficits.
  • the compounds of this invention can be administered via either the oral, parenteral (such as subcutaneous, intraveneous, intramuscular, intrasternal and infusion techniques), rectal, intranasal or topical routes to mammals.
  • these compounds are most desirably administered to humans in doses ranging from about 1mg to about 2000 mg per day, although variations will necessarily occur depending upon the weight and condition of the subject being treated and the particular route of administration chosen.
  • a dosage level that is in the range of from about 0.1 mg to about 20 mg per kg of body weight per day is most desirably employed. Nevertheless, variations may still occur depending upon the species of animal being treated and its individual response to said medicament, as well as on the type of pharmaceutical formulation chosen and the time period and interval at which such administration is carried out.
  • dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effects provided that such higher dose levels are first divided into several small doses for administration throughout the day.
  • the compounds of this invention are administered as adjunctive therapy with known antipsychotics such as Ziprasidone (Geodon), Clozapine, Molindone, Loxapine, Pimozide, Risperidone, Olanzapine, Remoxipride, Sertindole, Amisulpride, Quetiapine, Prochlorperazine, Fluphenazine, Trifluoroperazine, Thioridazine, Haloperidol, Chloropromazine, Flupentixol and Pipotiazine.
  • Ziprasidone Garodon
  • Clozapine Molindone
  • Loxapine Pimozide
  • Risperidone Olanzapine
  • Remoxipride Remoxipride
  • Sertindole Amisulpride
  • Quetiapine Prochlorperazine
  • Fluphenazine Trifluoroperazine
  • Thioridazine Haloperidol
  • the compounds of the present invention may also be used in combination with CNS agents such as antidepressants (such as sertraline), anti-Parkinsonian drugs (such as deprenyl, L-dopa, Requip, Mirapex, MAOB inhibitors such as selegine and rasagiline, comP inhibitors such as Tasmar, A-2 inhibitors, dopamine reuptake inhibitors, NMDA antagonists, Nicotine agonists, Dopamine agonists and inhibitors of neuronal nitric oxide synthase), anti-Alzheimer's drugs such as donepezil, tacrine, ⁇ 2 ⁇ 5 inhibitors, COX-2 inhibitors, gaba pentenoids, propentofylline or metryfonate, and antipyschotics such as PDE10 inhibitors, 5HT2C agonists, alpha 7 nicotinic receptor agonists, CB1 antagonists and compounds having activity antagonizing dopamine D2 receptors.
  • CNS agents such as anti
  • the compounds of the present invention may be administered alone or in combination with pharmaceutically acceptable carriers or diluents by either of the above routes previously indicated, and such administration can be carried out in single or multiple doses. More particularly, the novel therapeutic agents of the invention can be administered in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like.
  • Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc.
  • oral pharmaceutical compositions can be suitably sweetened and/or flavored.
  • the therapeutically effective compounds of this invention are present in such dosage forms at concentration levels ranging about 5.0% to about 70% by weight.
  • tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various disintegrants such as starch and preferably corn, potato or tapioca starch, alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • disintegrants such as starch and preferably corn, potato or tapioca starch, alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes.
  • compositions of a similar type may also be employed as fillers in gelatine capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols.
  • preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols.
  • the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
  • solutions of a compound of the present invention in either sesame or peanut oil or in aqueous propylene glycol may be employed.
  • the aqueous solutions should be suitably buffered (preferably pH>8) if necessary and the liquid diluent first rendered isotonic, These aqueous solutions are suitable for intravenous injection purposes.
  • the oily solutions are suitable for intra-articular, intra-muscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well-known to those skilled in the art.
  • the compounds of the present invention were assayed utilizing the GIyTI radioligand binding assay described below:
  • Test compound preparation Compounds are dissolved in DMSO, sonicated if necessary, diluted to a concentration of 0.2 mM in DMSO and then diluted with de-ionized water to a concentration of 10 uM.
  • Tissue preparation The GIyTIc transporter is expressed in HEK-293 cells and the frozen cell pellet weighed and polytroned, with 1 gram cell pellet in 30 ml_ assay buffer (50 mM Tris base, 120 mM NaCI, and 5 mM KCI, pH'd to 7.4 with 6N HCI). The mixture is centrifuged at 40000 G for 10 min., the supernatant decanted, and the pellet resuspended at 1 mg wet weight per 25 uL assay buffer.
  • ml_ assay buffer 50 mM Tris base, 120 mM NaCI, and 5 mM KCI, pH'd to 7.4 with 6N HCI.
  • Assay The assay incubation is carried out for 60 min. at room temperature in 96 well plates (Beckman 2 mL polypropylene), which are vortexed upon addition of the tissue preparation. To each well is added 25 uL test drug solution or control, 200 uL of 0.7 nM [3H]- NPTS (Lowe, John A.; Drozda, Susan E.; Fisher, Katherine; Strick, Christine; Lebel, Lorraine; Schmidt, Christopher; Hiller, Donna; Zandi, Kathleen S. [3H]-(R)-NPTS, a radioligand for the type 1 glycine transporter. Bioorganic & Medicinal Chemistry Letters (2003), 13(7), 1291- 1292.), and 25 uL tissue.
  • the plates are filtered using a Brandel cell harvester with GF/B filters, the filters are washed with 3 X 1.5 mL assay buffer, air-dried overnight, and counted on a LKB beta plate counter the next day.
  • Compounds of the invention analyzed by this assay have been found to have significant activity in inhibiting glycine reuptake in synaptosomes, having greater than 20% inhibition at 1 ⁇ M.
  • the compounds of the Formula I may be prepared by the methods described below, together with synthetic methods known in the art of organic chemistry, or modifications and derivatisations that are familiar to those of ordinary skill in the art. Preferred methods include, but are not limited to, those described below.
  • Flash column chromatography was carried out using Merck silica gel 60 (230-400 mesh ASTM). Low-resolution mass spectral data (El) were obtained on a Automass 120 (JEOL) mass spectrometer. Liquid Chromatography data was collected on a Hewlett Packard 1100 Liquid Chromatography/ Mass Selective Detector (LC/MSD). Analysis was performed on a Luna C-18 column with dimensions of 3.0x150 mm. The flow rate was 0.425 ml/minute running a gradient of 50% 0.1% aqueous formic acid and 50% acetonitrile to 100% acetonitrile in 15 minutes.
  • the ionization type for the mass detector of the Mass Spectrophotometer was atmospheric pressure electrospray in the positive ion mode with a fragmentor voltage of 50 volts.
  • a compound of the formula 1 is reacted with 1 ,4- cyclohexanedionemonoethylene ketal in the presence of a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, (method b) or sodium triacetoxyborohydride (method A), with an optional additive such as acetic acid or triethylamine, in a solvent such as 1 ,2-dichloroethane, tetrahydrofuran, or methanol at a temperature from room temperature to 100°C for a time from 1 hour to 72 hours.
  • a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, (method b) or sodium triacetoxyborohydride (method A)
  • an optional additive such as acetic acid or triethylamine
  • the resulting compound, 2 is treated with a compound of the formula 3 in the presence of a base, such as an organic amine such as triethylamine or diisopropylethylamine, in a solvent such as tetrahydrofuran, acetonitrile, dimethylformamide, or N-methylpyrrolidinone, at a temperature from 0° C to 100°C for a time from 1 hour to 72 hours.
  • a base such as an organic amine such as triethylamine or diisopropylethylamine
  • a solvent such as tetrahydrofuran, acetonitrile, dimethylformamide, or N-methylpyrrolidinone
  • the resulting compound, 4 is hydrolyzed using, for example, acidic conditions such as aqueous HCI in a solvent such as ethyl acetate or tetrahydrofuran, or aqueous trifluoroacetic acid in dichloromethane, at a temperature from room temperature to 100 0 C for a time from 1 hour to 72 hours.
  • acidic conditions such as aqueous HCI in a solvent such as ethyl acetate or tetrahydrofuran, or aqueous trifluoroacetic acid in dichloromethane
  • the resulting intermediate 5 is treated with a primary and secondary amines, such as morpholine shown, in the presence of a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride, with an optional additive such as acetic acid or triethylamine, in a solvent such as 1 ,2-dichloroethane, tetrahydrofuran, or methanol at a temperature from room temperature to 100 0 C for a time from 1 hour to 72 hours.
  • a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride
  • an optional additive such as acetic acid or triethylamine
  • N-f3-(trifluoromethoxy)benzvn-1 ,4-dioxaspiroF4.51decan-8-amine A solution of the 1 ,4-dioxaspiro[4.5]decan-8-one (6.0 g, 38.7 mmol) in dry THF (200 ml) at room temperature was added 3-trifluoromethoxy benzylamine (1 equiv, 7.4 g, 38.7 mmol), sodium acetoxyborohydride (1.5 equiv, 12.3 g, 58.1 mmol) and acetic acid (10 ml) and the resulting slurry was stirred at room temperature overnight. The reaction mixture was diluted with 1 N NaOH and extracted with EtOAc.
  • Example 2 i-methyl-IH-imidazole-4-carbonyl chloride: A slurry of the 1 -methyl imidazol-4-yl acid (10 g, 79.3 mmol) iin dry DCM (100 ml) at room temperature was treated with dropwise addition of oxalyl chlodide ( 12 ml, mmol) and catalytic DMF ( pipette drops). The reaction bubbled immediately and the slurry was stirred for 1 hr. Removal of the solvent in vacuo followed by drying under high vacuum gave the title compound (9.1 g) as a tan white solid.
  • 1 H NMR 400MHz, MD 3 OD
  • ⁇ 9.09 (s, 1H), 8.24 (s, 1H), 3.98 (s, 3H).
  • Example 3 N-1 ,4-dioxaspiror4.51dec-8-yl-1 -methyl-N-f3-trifluoromethoxybenzvn -1 H-imidazole-4-carboxamide: A solution of the 2 (65815-162) (5.7 g, 17.22 mmol) and triethylamine (2.5 equiv, 6.0 ml) in dry DCM (50 ml) under nitrogen was added 3 (1.4 equiv, 3.5 g). The reaction, which warmed up as the acid chloride was added, was stirred at room temperature until reaction was complete.
  • Example 4 1 -methyl-N-(4-oxocvclohexyl)-N-r3-(trif luoromethoxy)benzv ⁇ -1 H- imidazole-4-carboxamide: A solution of 4 in THF (50 ml) was added 80 ml of 1 N HCI and heated to 7O 0 C for 48 hr. Added additional 2N HCI and stirred at room temperature for another 48hr. The reaction was neutralized with slow addition of potassium carbonate (vigorous foaming) and extracted with ethylacetate. The organics were dried (MgSO 4 ) and concentrated to give the title compound (4.6g, 79%), which was taken forward as is.
  • Example 5 1 -methyl-N-fcis ⁇ -azetidin ⁇ -ylcyclohexyD-N-fS-ftrif luoromethoxy) benzv ⁇ -IH-imidazole-4-carboxamide: A solution of 5 (285 mg, 0.72 mmol) in dry DCM (2 ml) at room temperature was added azetidine hydrochloride (1 equiv, 67.5 mg, 0.72 mmol) and triethylamine (0.15 ml, 1.08 mmol) and stirred the reaction for 20 min. Then sodiumacetoxyborohydride (1.5 equiv, 214 mg, 1.08 mmol) was added and the resulting slurry was stirred at room temperature (6 hr).
  • the reaction mixture was diluted with saturated bicarbonate and extracted with DCM.
  • the organic layer was dried (Na 2 SO 4 ) and concentrated to give crude amine, which was purified by ISCO chromatography system to provide with the cis isomer (151 mg), colorless oil, as the top stop and the trans isomer (105 mg), colorless oil, as the bottom spot,
  • the cis and trans products were converted to the HCL salt by adding 4N HCI/Dioxane to a solution of the free base in methyline chloride and removing the solvent in vauo to obtain the salt as a white solid.
  • a compound of the formula 2 is hydrolyzed using, for example, acidic conditions such as aqueous HCI in a solvent such as ethyl acetate or tetrahydrofuran, or aqueous trifluoroacetic acid in dichloromethane, at a temperature from room temperature to 100 0 C for a time from 1 hour to 72 hours.
  • acidic conditions such as aqueous HCI in a solvent such as ethyl acetate or tetrahydrofuran, or aqueous trifluoroacetic acid in dichloromethane
  • the resulting compound, 7, is treated with a compound of the formula 3 in the presence of a base, such as an organic amine such as triethylamine or diisopropylethylamine, in a solvent such as tetrahydrofuran, acetonitrile, dimethylformamide, or N-methylpyrrolidinone, at a temperature from 0° C to 100 0 C for a time from 1 hour to 72 hours to provide intermediate 5 from Scheme 1.
  • a base such as an organic amine such as triethylamine or diisopropylethylamine
  • a solvent such as tetrahydrofuran, acetonitrile, dimethylformamide, or N-methylpyrrolidinone
  • intermediate 7 is treated with a primary and secondary amines, such as morpholine shown, in the presence of a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride, with an optional additive such as acetic acid or triethylamine, in a solvent such as 1 ,2-dichloroethane, tetrahydrofuran, or methanol at a temperature from room temperature to 100 0 C for a time from 1 hour to 72 hours to provide diamine intermediate 8.
  • a solvent such as 1 ,2-dichloroethane, tetrahydrofuran, or methanol
  • Example 6 4-fr3-(trifluoromethoxy)benzyl1amino ⁇ cvclohexanone: A solution of the ketal 2 (3.5g, 10.6 mmol) in THF (25 ml) was treated with 2 N HCI (30 ml) and heated to 8O 0 C (72 h). The reaction was cooled to room temperature and neutralized (pH-7.5-8) with 1N NaOH and extracted with EtOAc. The organic layer was dried and concentrated in vacuo and concentrated to give the title ketone 7 (2.9 g) as a brown oil.
  • Example 7 1 -methyl-N-(4-oxocvclohexyl)-N-r3-(trifluoromethoxy)ben2v ⁇ -1 H- im idazole-4-carboxam ide : Prepared using example 4. 1 H NMR (400MHz, CDCI 3 ) ⁇ 7.06 - 7.72 (m, 6H), 5.85 (br s, 1H), 5.31 (br s, 1H), 4.70-4.84 (br d, 2 H), 3.74 (3H), 1.84 -2.40 (m, 8H) ;LCMS (m/z) 396.0 (M+H); RT (Method A, std LCMS method), 2.0 min.
  • Example 8 4-morpholin-4-yl-N-r3-(trifluoromethoxy)benzyllcyclohexanamine: Prepared using example 1 procedure to make cis 8 (454.9 mg) and trans 8 (269 mg).
  • Cis-8 1 H NMR (400MHz, CDCI 3 ) ⁇ 1 H NMR (400MHz, CDCI 3 ) ⁇ 7.33 (t, 1H), 7.26 (d, 1 H), 7.21 (s, 1H), 7.09 (d, 1H), 3.78 (s, 2H), 3.73 (app t, 4H), 2.75 (m, 1H), 2.54 (s, 4H), 2.19 (br s, 1H), 1.67 - 1.74 (m, 4H), 1.46 - 1.58 (m, 4H); LCMS (m/z) 359.0 (M+H); RT (Method A, std LCMS method), 0.3 min.
  • Example 9. 1 -methyl-N-fcis ⁇ -morpholin ⁇ -vIcvclohexyD-N-rS-ftrif luoromethoxy) benzv ⁇ -1H-pyrazole-3-carboxamide: Prepared using example 3 to make 144 mg of title compound 9.
  • a ketones and aldehydes such as cyclobutanone shown
  • a ketones and aldehydes such as cyclobutanone shown
  • a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride
  • an optional additive such as acetic acid or triethylamine
  • a solvent such as 1 ,2-dichloroethane, tetrahydrofuran, or methanol
  • Example 9a N-(cis-4-am ⁇ ' nocyclohexyO-1 -methyl-N-f3-(trif luoromethoxy) benzv ⁇ -IH-imidazole-4-carboxamide: A solution of 11 (1.74g) in dry dichloromethane (10 ml) was added 4N HCI/dioxane at room temperature and stirred until reaction was complete (1-2 hrs). The resulting slurry was diluted with ether and filtered off to obtain the desired product as a white solid.
  • a compound of the formula 18 and the intermediates to make 18 can also be done by starting with protected ketone following procedures used in Schemes 1 , 2, and 3.
  • tert-butyl rcis-4-(dimethylamino)cyclohexyncarbamate (15): Prepared according to Example 1, Scheme 1.
  • a compound of the formula 19 can also be made by reacting amine 12, made according to scheme 3, with di-halides or sulfonates (any suitable leaving groups) in a suitable solvent such as dichloromethane, DMF, THF or alcoholic solvents such as methanol, ethanol, and like at temperatures ranging from 0° C to 100 0 C.
  • a suitable solvent such as dichloromethane, DMF, THF or alcoholic solvents such as methanol, ethanol, and like at temperatures ranging from 0° C to 100 0 C.
  • a compound of the formula 20 (prepared according to literature reference: J. Orp. Chem. 1988, 53, 3841) is esterified and protected as a ketal 21 by reacting with an alcohol such as methanol with catalytic acid such as p-toluene sulfonic acid, HCI, H2SO4, etc.
  • the ester 21, can be reduced with a suitable reducing agent such as LAH, NaBH4, Dibal, etc to provide the alcohol 22.
  • Preparation of 22 has also been reported in the literature Antiviral Chemistry & Chemotherapy 2002, 73(4), 251-262.
  • Oxidation of the alcohol using standard Swern conditions (oxalyl chloride, DMSO, Et 3 N) known to chemists provides the aldehyde 23.
  • a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride
  • an optional additive such as acetic acid or trie
  • the resulting amine can be acylated with acid chlorides such as N-methyl imidazolyl acid chloride in the presense of suitable base such as triethyl amine or organic and inorganic bases in suitable solvents such as dichloromethane or THF at temperatures ranging from 0° C to 100° C.
  • suitable base such as triethyl amine or organic and inorganic bases
  • suitable solvents such as dichloromethane or THF
  • the resulting ketone can be reduced to the alcohol with suitable reducing agents such as sodium borohydride and other agents well known to practicing chemists under suitable solvents such as methanol and ethanol at 0° C to 100° C.
  • suitable reducing agents such as sodium borohydride and other agents well known to practicing chemists under suitable solvents such as methanol and ethanol at 0° C to 100° C.
  • the resulting alcohol can then be reacted with appropriate phenols such as 3- chlorophenol under what's known in the chemistry community as Mitsunobu condition with activating reagents such as DEAD or DIAD and triphenylphosphine or trialkyl phospine in appropriate solvents such as THF at temperatures ranging from 0° C to 100° C.
  • the resulting ether 28 can be deprotected of the protecting group such as BOC using acidic condition using acids such as acetic acid or HCL or sulfuric acid or trifluoroacetic acid in solvents such as dichloromethane or ether solvents at room temperatures to 100° C.
  • the resulting amine can then be reacted under reductive amination conditions as described previously using suitable aldehydes and ketones.
  • Example 9c methyl S ⁇ -dimethoxycyclobutanecarboxylate (21): A solution of 3- oxocyclobutanecarboxylic acid (20) (3.5 g, 31 mmol) and p-toluenesulfonic acid (0.04 equiv, 233 mg, 1.2 mmol) in MeOH (100 ml) was refluxed overnight. The reaction mixture was concentrated down to a small volume and diluted with water and extracted with dichloromethane. The orgnic layer was dried and concentrated down to provide the title compound (5.03 g) as a colorless oil.
  • 1 H NMR 400MHz, CDCI 3 ) ⁇ 3.69 (s, 3H, CO2Me), 3.16 (S, 3H), 3.14 (s, 3H), 2.88 (p, 1 H), 2.43 (m, 4H)
  • Example 9d (3,3-dimethoxycvclobutyl)methanol (22): A solution of the methyl 3,3-dimethoxycyclobutane carboxylate (21) (5.03 g, 28.9 mmol) in anhydrous THF (50 ml) was cooled in an ice bath and 1 M solution of lithium aluminum hydride (LAH) in THF (30.4 ml, 30.4 mmol) was added dropwise. After complete addition, the ice bath was removed and the reaction stirred at room temperature for 1 hr. The reaction was quenched with water (2.2 ml) and 10 g celite was added and stirred vigorously.
  • LAH lithium aluminum hydride
  • Example 9e S.S-dimethoxycvclobutanecarbaldehvde (23): A solution of oxalyl chloride (0.33 ml, 3.8 mmol) in dichloromethane (8 ml) was cooled to -78 0 C and DMSO (0.54 ml, 7.5 mmol) added dropwise and stirred for 30 min. A solution of (3,3- dimethoxycyclobutyl)methanol (500 mg, 3.4 mmol) in DCM (5 ml) was added to the reaction mixture and stirred for 30 min. Then triethylamine (2.39 ml, 17.1 mmol) was added dropwise to the reaction mixture and stirred for 1 hr.
  • Example 9f tert-butyl (cis-4-fr(1-methyl-1H-imidazol-4-yl)carbonvnr(3- oxocyclobutvDmethv ⁇ amino ⁇ cvclohexyDcarbamate (26): A mixture of 25 (1.23 g, 2.7 mmol) and p-toluenesufonic acid (0.2 equiv, 104 mg, 0.54 mmol) in acetone:water (2:1 :15 ml) was stirred at 5O 0 C (6 h) and overnight at room temperature. The reaction was poured into aqueous bicarbonate and extracted with ethyl acetate.
  • Example 9h tert-butyl (cis-4- ⁇ r3-(3-chlorophenoxy)cvclobutvnmethyl>f(1- methyl-1H-imidazol-4-yl)carbonvnamino>cvclohexy ⁇ carbamate (28):
  • the alcohol 27 250 mg, 0.62 mmol
  • 3-chlorophenol 2.5 equiv, 198.1 mg, 1.54 mmol
  • triphenyl phosphine was mixed in THF (3 ml) in a microwave tube and warmed (40°C)until the mixture went into solution.
  • Example 9i N-(cis-4-aminocvclohexyl)-N- ⁇ T3-(3-chlorophenoxy)cvclobutyll methyl>-1-methyl-1H-imidazole-4-carboxamide (29): A solution of 28 (872 mg, 1.91 mmol) in DCM (3 ml) at room temperature was added 4N HCI/dioxane (3 ml) and stirred until reaction was complete ( ⁇ 2hr). The reaction was concentrated down and the residue taken up in ether and the solid precipitate filtered to obtain the title compound (937 mg) as a white solid.
  • the keto ester 31 can be reacted with (cis)-tert-butyl 4-aminocyclohexylcarbamate in the presence of a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride, with an optional additive such as acetic acid or triethylamine, in a solvent such as 1 ,2-dichloroethane, tetrahydrofuran, or methanol at a temperature from room temperature to 10O 0 C.
  • a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride
  • an optional additive such as acetic acid or triethylamine
  • the resulting amine 32 can be acylated with acid chlorides such as N-methyl imidazolyl acid chloride in the presense of suitable base such as triethyl amine or organic and inorganic bases in suitable solvents such as dichloromethane or THF at temperatures ranging from 0° C to 100° C. for a time from 1 hour to 72 hours.
  • suitable solvents such as dichloromethane or THF at temperatures ranging from 0° C to 100° C. for a time from 1 hour to 72 hours.
  • the methyl ester of 33 can be reduced with a suitable reducing agent such as LAH 1 NaBH 4 , Dibal, or LiBH 4 etc in alcoholic solvents or non-alcoholics solvents such as methanol and THF at rom temperature to 100° C to provide the alcohol 34.
  • the alcohol 34 can then be reacted with appropriate phenols such as 4-fluorophenol under what's known in the chemistry community as Mitsunobu condition with activating reagents such as DEAD or DIAD and triphenylphosphine or trialkyl phospine in appropriate solvents such as THF at temperatures ranging from 0° C to 100° C.
  • the resulting ether 35 can be deprotected of the protecting group such as BOC using acidic condition using acids such as acetic acid or HCL or sulfuric acid or trifluoroacetic acid in solvents such as dichloromethane or ether solvents at room temperatures to 100° C.
  • methyl S-oxocyclobutanecarboxylate (31) Prepared according to example 9f.
  • Example 9j methyl 3-Ucis-4-r(tert-butoxycarbonyl)amino1cvcloh6xyl ⁇ f(1-methyl- 1H-imidazol-4-yl)carbonvnamino> cvclobutanecarboxylate (33): A mixture of the amine 32 (500 mg, 1.5 mmol), N-methyl-imidazol-4-yl carboxylic acid ( 212 mg, 1.7 mmol), HOBT (218 mg, 1.6 mmol), DCC (353 mg, 1.8 mmol) and triethyl amine (0.64 ml, 4.6 mmol) in dry dichloromethane (15 ml) was stirred at room temperature for 5 days.
  • the reaction mixture was poured into ethyl acetate and washed with 1 N NaOH (1 X), brine (1 X), dried and concentrated.
  • the crude product was purified by chromatography using the ISCO purification system to provide the desired product 33 (590 mg) as a solid.
  • Example 9k tert-butyl (cis ⁇ -ire-fhvdroxymethvDcvclobutyllKI-rnethyl-IH- imidazol-4-yl)carbonv ⁇ amino ⁇ cvclohexyl)carbamate (34): A solution of ester 33 (488mg, 1.1 mmol) in THF (3 ml) was cooled to 0° C and added lithium borohydride (5.6 ml, 2 M in THF) slowly. The mixture was brought to room temperature and stirred for 5 day. The reaction was poured into 1 N NaOH and extracted with ehtylacetate. The organic layer was washed with brine, dried and concentrated to provide the alcohol (416 mg, 91%) as oily solid.
  • Example 9L tert-butyl (cis ⁇ -US-rt ⁇ -fluorophenoxylmethv ⁇ cvclobutylWI- methyl-1 H-imidazol-4-yl)carbonv ⁇ amino ⁇ cvclohexyl)carbamate (35): The reaction was set up and worked up as in example 17 but reaction run at room temperature to provide the desired product. LCMS (m/z) 501.0 (M+H).
  • a commercially available 1 ,3-diaminocyclohexane can be reacted with a protecting group tert-butyldicarbonate (BOC 2 O) in a solvent such as THF at OoC to 80° C for 1 hr to 72 h to provide the monoprotected compound 37.
  • BOC 2 O tert-butyldicarbonate
  • the amine of 37 can be reacted with aldehydes such as 3-trifluoromethoxy benzaldehyde in the presence of a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, (method b) or sodium triacetoxyborohydride with an optional additive such as acetic acid or triethylamine, in a solvent such as 1 ,2-dichloroethane, tetrahydrofuran, or methanol at a temperature from room temperature to 100 0 C for a time from 1 hour to 72 hours.
  • a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, (method b) or sodium triacetoxyborohydride with an optional additive such as acetic acid or triethylamine, in a solvent such as 1 ,2-dichloroethane, tetrahydrofuran, or methanol
  • the resulting amine 38 can be treated with acid chlorides such as N-methyl imidazolyl acid chloride in the presense of suitable base such as triethyl amine or organic and inorganic bases in suitable solvents such as dichloromethane or THF at temperatures ranging from O 0 C to 100° C. for a time from 1 hour to 72 hours.
  • suitable solvents such as dichloromethane or THF at temperatures ranging from O 0 C to 100° C. for a time from 1 hour to 72 hours.
  • the resulting product 39 can be deprotected of the BOC protecting group using acids such as acetic acid or HCL or sulfuric acid or trifluoroacetic acid in solvents such as dichloromethane or ether solvents at room temperatures to 100° C.
  • the amine of 40 can be reacted with aldehydes such as cyclopropane carboxaldehyde in the presence of a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, (method b) or sodium triacetoxyborohydride with an optional additive such as acetic acid or triethylamine, in a solvent such as 1 ,2-dichloroethane, tetrahydrofuran, or methanol at a temperature from room temperature to 100 0 C for a time from 1 hour to 72 hours.
  • a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, (method b) or sodium triacetoxyborohydride with an optional additive such as acetic acid or triethylamine, in a solvent such as 1 ,2-dichloroethane, tetrahydrofuran, or methanol
  • Example 9m tert-butyl O-aminocvclohexyQcarbamate (37): Prepared according to US 2004019058 A1: A solution of the 1 ,3-diaminocyclohexane (5.0 g, 43.7mmol) in dry chloroform (100 ml) under nitrogen was treated with a solution of di-t-butylcarbonate (0.5 equiv, 21.8 mmol) in dry chloroform (60 ml) over a period of several hours and stirred the reaction slurry overnight at room temperature. After complete reaction, the solid precipitate was filtrated and washed with dichloromethane.
  • the cis isomer of 40 was prepared in similar manner: 1 H NMR (400MHz, CD 3 OD) ⁇ 9.05 (s, 1H), 8.15 (br s, 1H), 7.46 (br s, 1H), 7.35 (d, 1H), 7.25 (s, 1H), 7.
  • the resulting imine was cooled down to O 0 C and NaBH 4 (1.5 equiv., 14 mg) was added slowly and the reaction warmed to room temperature. After two hrs, the reaction was quenched with saturated aueous bicarbonate and extracted with dichloromethane. The organic layer was dried, concentrated and the crude product purified by chromatography to provide the title compound 41 (75.2 mg) as colorless oil.
  • the product was isolated as the HCI salt by treating a DCM solution of 41 with 4N HCI/dioxane.
  • 3-oxocyclobutane carboxylic acid 20 can subjected to Curtius rearrangement with diphenylphosphoryl azide in the presence of base such as triethyl amine or diisopropylethyl amine at temperatures ranging from 0° C to 110° C in appropriate solvent such as toluene and after the initial conversion to the intermediate add benzyl alcohol to trap the isocyanate generated to provide the protected product 42 (Reference: EP1256578 A1, p22).
  • the ketone 42 can be reacted with amines such as 2-chlorophenyl ethyl amine in the presence of a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride, with an optional additive such as acetic acid or triethylamine, in a solvent such as 1 ,2-dichloroethane, tetrahydrofuran.'or methanol at a temperature from room temperature to 100 0 C.
  • a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride
  • an optional additive such as acetic acid or triethylamine
  • solvent such as 1 ,2-dichloroethane, tetrahydrofuran.'or methanol at a temperature from room temperature to 100 0 C.
  • the resulting amine 43 can be sulfonylated with sulfonyl chlorides such as N-meyl-4-sulfonylchloride in the presence of base such as dimethylamino pyridine in appropriate solvent such as dichloroethane at temperatures ranging from room temperature to 100° C for periods ranging from 1 hr to 72 hr.
  • the resulting sulfonamide 44 can be reacted under acidic condition such as hydrogen bromide in acetic acid at temperatures ranging from room temperature to 100° C for period ranging from 1 hr to 72 hr to give the amine product 45.
  • Example 9o (3-rr2-(2-Chloro-phenyl)- ⁇ thv ⁇ -(1-methvMHwmidazole-4-sulfonyl)- aminoi-cvclobutyll-carbamic acid benzyl ester (44): A mixture of the amine 43 (115 mg, 0.32 mmol), N-methyl-IH-imidazole-4-sulfonylchloride (75 mg, 0.42 mmol) and dimethylaminopyridine (51 mg, 0.42 mmol) in dry dichloroethane (2.5 ml) was heated at reflux for 16 hr.The reaction mixture was added methylene chloride and washed with water.
  • Example 9p i-MethvHH-imidazole-4-sulfonic acid (3-amino-cvclobutyl)-r2-(2- chloro-phenyQ-ethv ⁇ -amide (45): A solution of 44 (73 mg) in acetic acid ( 1 ml) was added 30% HBr/acetic acid (2 ml) and the resulting mixture was stirred at room temperature for 1 hr. The mixture was concentrated down and 1 N NaOH added and extracted with dichloromethane (2X), dried and concentrated to give crude residue. Purified by chromatography to provide the desired product 45 (16 mg) as a solid.
  • a commericially available compound methyl 3- oxocyclohexanecarboxylate is reacted with amines such as 3-trifluoromethoxy benzyl amine in the presence of a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, (scheme 1 , method b) or sodium triacetoxyborohydride (scheme 1 , method A), with an optional additive such as acetic acid or triethylamine, in a solvent such asdichloromethane, 1 ,2-dichloroethane, tetrahydrofuran, or methanol at a temperature from room temperature to 10O 0 C for a time from 1 hour to 72 hours.
  • a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, (scheme 1 , method b) or sodium triacetoxyborohydride (scheme 1 , method A)
  • the resulting ester 1 can be reduced to the alcohol with reducing agents such as DIBAL 1 LAH, LiBH 4 , etc. in solvent such as THF, ether, and so on at temperatures ranging from -60° C to 100° C.
  • the amino alcohol 2 can be separated using chiral separation or other chiral salt formation to get the pure cis and trans diastereomers 3 and 4.
  • the aminoalcohol 3 or 4 can then be acylated independently with acid chlorides such as N-methylimidazo-4-yl carbonylchloride in the presence of a base, such as an organic amine such as triethylamine or diisopropylethylamine, in a solvent such as tetrahydrofuran, acetonitrile, dimethylformamide, or N-methylpyrrolidinone, at a temperature from 0° C to 100 0 C for a time from 1 hour to 72 hours.
  • reducing agents such as DIBAL 1 LAH, LiBH 4 , etc.
  • the resulting alcohol 5 can then be oxidized with various reagents, such as Dess-Martin periodinane, MnO 2 , Swern oxidation conditions, etc. at temperatures ranging from 0° C to 100 0 C for a time from 1 hour to 72 hours.
  • various reagents such as Dess-Martin periodinane, MnO 2 , Swern oxidation conditions, etc. at temperatures ranging from 0° C to 100 0 C for a time from 1 hour to 72 hours.
  • the resulting aldehyde 6 can be treated with either primary or secondary amines, such as azetidine shown, in the presence of a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride, with an optional additive such as acetic acid or triethylamine, in a solvent such as 1 ,2-dichloroethane, tetrahydrofuran, or methanol at a temperature from room temperature to 100 0 C for a time from 1 hour to 72 hours to give the desired amine 7.
  • a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride
  • an optional additive such as acetic acid or triethylamine
  • solvent such as 1 ,2-dichloroethane, tetrahydrofuran, or methanol
  • Methyl 3-(3-(trifluoromethoxy)benzylamino)cyclohexanecarboxylate (1) Prepared according to Example 1. 1 H NMR (400 MHz, CHLOROFORM-d) ⁇ ppm 1.08 (s, 1 H) 1.29 (s, 3 H) 1.84 (s, 1 H) 1.94 (s, 2 H) 2.24 (s, 1 H) 2.31 (s, 1 H) 2.50 (s, 1 H) 3.66 (s, 3 H) 3.85 (s, 2 H) 7.09 (s, 1 H) 7.24 (s, 2 H) 7.33 (s, 1 H); LCMS (m/z) 332.0
  • Example 9q. (3-(3-(trifluoromethoxy)benzylamino)cvclohexyl)methanol: A solution of the ester 1 (14.4g, 41.7 mmol) in dry THF at -78 0 C under N 2 atmosphere was added DIBAL (8.4 ml of 1 M in cyclohexane, 83.4 mmol) via dropwise addition and the resulting solution was allowed to warm to room temperature and stirred for 3 hr. The reaction mixture was quenched with sodium sulfate decahydrate and stirred at room temperature for a while and the resulting solids filtered out.
  • N-(3-(trifluoromethoxy)benzv ⁇ -N-(3-(hvdroxymethyl)cyclohexyl)-1-methyl-1 H- imidazole-4-carboxamide Prepared according Example 3.
  • a compound of the formula Il is reacted with N-t- butylcarboxy-octahydro-cyclopenta[c]pyrrol-5-one)-amine in the presence of a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride, with an optional additive such as acetic acid or triethylamine, in a solvent such as 1 ,2-dichloroethane, tetrahydrofuran, or methanol at a temperature from room temperature to 100 0 C for a time from 1 hour to 72 hours.
  • a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride
  • an optional additive such as acetic acid or triethylamine
  • solvent such as 1 ,2-dichloroethane, tetrahydrofuran, or methanol
  • the resulting compound, III is treated with a compound of the formula IV in the presence of a base, such as an organic amine such as triethylamine or diisopropylethylamine, in a solvent such as tetrahydrofuran, acetonitrile, dimethylformamide, or N-methylpyrrolidinone, at a temperature from room temperature to 100°C for a time from 1 hour to 72 hours.
  • a base such as an organic amine such as triethylamine or diisopropylethylamine
  • a solvent such as tetrahydrofuran, acetonitrile, dimethylformamide, or N-methylpyrrolidinone
  • the resulting compound, V is deblocked using, for example, acidic conditions such as HCI in a solvent such as ethyl acetate or tetrahydrofuran, or trifluoroacetic acid in dichloromethane, at a temperature from room temperature to 100 0 C for a time from 1 hour to 72 hours.
  • acidic conditions such as HCI in a solvent such as ethyl acetate or tetrahydrofuran, or trifluoroacetic acid in dichloromethane
  • the resulting intermediate is treated with a compound of the formula Vl in the presence of a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride, with an optional additive such as acetic acid or triethylamine, in a solvent such as 1 ,2-dichloroethane, tetrahydrofuran, or methanol at a temperature from room temperature to 100 0 C for a time from 1 hour to 72 hours.
  • a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride
  • an optional additive such as acetic acid or triethylamine
  • N-(t-ButylcarboxyM3-chloro-benzylMoctahvdro-cvclopentafcipyrrol-5-yl)-arnine (referring to Scheme 10): To a 125 mL round-bottomed flask equipped with N 2 inlet were added 1.02 g (4.53 mmol) N-t-butylcarboxy-octahydro-cyclopenta[c]pyrrol-5-one)-amine (preared as described in Becker, Daniel P.; Flynn, Daniel L.
  • the reaction was heated at 4O 0 C for 16 hours, cooled, diluted with ethyl acetate, washed with aqueous sodium bicarbonate solution and brine, dried over sodium sulfate, and evaporated to an oil.
  • the residue was chromatographed on silica gel using methanol/ethyl acetate/ammonium hydroxide as eluant to afford 1.33 g (64%) of the cis isomer as an oil.
  • a compound of the formula H is reacted with 4- benzyloxy-butylamine in the presence of a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride, with an optional additive such as acetic acid or triethylamine, in a solvent such as 1 ,2- dichloroethane, tetrahydrofuran, or methanol at a temperature from room temperature to 10O 0 C for a time from 1 hour to 72 hours.
  • a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride
  • an optional additive such as acetic acid or triethylamine
  • the resulting compound, III is treated with a compound of the formula IV in the presence of a base, such as an organic amine such as triethylamine or diisopropylethylamine, in a solvent such as tetrahydrofuran, acetonitrile, dimethylformamide, or N-methylpyrrolidinone, at a temperature from room temperature to 10O 0 C for a time from 1 hour to 72 hours.
  • a base such as an organic amine such as triethylamine or diisopropylethylamine
  • a solvent such as tetrahydrofuran, acetonitrile, dimethylformamide, or N-methylpyrrolidinone
  • a hydrogen source such as ammonium formate or 1- methylcyclohexadiene may be used, typically in an alcohol solvent such as ethanol, with the above palladium catalyst, at room temperature to reflux for 1 to 24 hours.
  • the resulting intermediate is converted to compound Vl by oxidation using any of a wide range of standard conditions.
  • Vl may be treated with oxalyl chloride and DMSO in methylene chloride, followed by addition of an organic base such as triethylamine or diisopropylamine, at -70 0 C to reflux, for 1 to 24 hours.
  • the resulting intermediate Vl is treated with a compound of the formula VII in the presence of a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride, with an optional additive such as acetic acid or triethylamine, in a solvent such as 1,2-dichloroethane, tetrahydrofuran, or methanol at a temperature from room temperature to 100 0 C for a time from 1 hour to 72 hours.
  • a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride
  • an optional additive such as acetic acid or triethylamine
  • the reaction was heated at 40 0 C for 24 hours, cooled, diluted with ethyl acetate, washed with aqueous sodium bicarbonate solution and brine, dried over sodium sulfate, and evaporated to an oil.
  • the residue was chromatographed on silica gel using methanol/dichloromethane as eluant to afford 1050 mg (76%) of the product as an oil.
  • the reaction was stirred at - 70 0 C for 10 minutes, then a solution of the alcohol in 7 ml_ dry dichloromethane was added, and stirring continued for 30 minutes. Then 1.88 ml_ (10.7 mmol) dry diisopropylethylamine was added, and the reaction warmed and stirred at 0 0 C for 50 minutes.
  • reaction was stirred at room temperature for 2 hours, diluted with ethyl acetate, washed with aqueous sodium bicarbonate solution and brine, dried over sodium sulfate, and evaporated to an oil, which was chromatographed on silica gel using methanol/dichloromethane as eluant to afford 100 mg (42%) of the product as an oil.
  • a compound of the formula Il is reacted with N-t- butoxycarbonylazepan-4-one in the presence of a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride, with an optional additive such as acetic acid or triethylamine, in a solvent such as 1 ,2-dichloroethane, tetrahydrofuran, or methanol at a temperature from room temperature to 10O 0 C for a time from 1 hour to 72 hours.
  • a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride
  • an optional additive such as acetic acid or triethylamine
  • the resulting compound, III is treated with a compound of the formula IV in the presence of a base, such as an organic amine such as triethylamine or diisopropylethylamine, in a solvent such as tetrahydrofuran, acetonitrile, dimethylformamide, or N-methylpyrrolidinone, at a temperature from room temperature to 10O 0 C for a time from 1 hour to 72 hours.
  • a base such as an organic amine such as triethylamine or diisopropylethylamine
  • a solvent such as tetrahydrofuran, acetonitrile, dimethylformamide, or N-methylpyrrolidinone
  • the resulting compound, V is deblocked using, for example, acidic conditions such as HCI in a solvent such as ethyl acetate or tetrahydrofuran, or trifluoroacetic acid in dichloromethane, at a temperature from room temperature to 100 0 C for a time from 1 hour to 72 hours.
  • acidic conditions such as HCI in a solvent such as ethyl acetate or tetrahydrofuran, or trifluoroacetic acid in dichloromethane
  • the resulting intermediate Vl is treated with a compound of the formula VII in the presence of a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride, with an optional additive such as acetic acid or triethylamine, in a solvent such as 1 ,2-dichloroethane, tetrahydrofuran, or methanol at a temperature from room temperature to 100 0 C for a time from 1 hour to 72 hours.
  • a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride
  • an optional additive such as acetic acid or triethylamine
  • the reaction was heated at 40 0 C for 24 hours, cooled, diluted with ethyl acetate, washed with aqueous sodium bicarbonate solution and brine, dried over sodium sulfate, and evaporated to an oil.
  • the residue was chromatographed on silica gel using methanol/dichloromethane as eluant to afford 880 mg (89%) of the product as an oil.
  • a compound of the formula Il is reacted with N-t- butoxycarbonyl-(2-aza-bicyclo[3.3.1]non-6-one), which is prepared according to a method reported in Tetrahedron Letters, 23 (44), 4559 (1982) using a t-BOC group instead of a methyl carbamate group, in the presence of a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride, with an optional additive such as acetic acid or triethylamine, in a solvent such as 1 ,2-dichloroethane, tetrahydrofuran, or methanol at a temperature from room temperature to 10O 0 C for a time from 1 hour to 72 hours.
  • a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride
  • an optional additive such as
  • the resulting compound, III is treated with a compound of the formula IV in the presence of a base, such as an organic amine such as triethylamine or diisopropylethylamine, in a solvent such as tetrahydrofuran, acetonitrile, dimethylformamide, or N-methylpyrrolidinone, at a temperature from room temperature to 100 0 C for a time from 1 hour to 72 hours.
  • a base such as an organic amine such as triethylamine or diisopropylethylamine
  • a solvent such as tetrahydrofuran, acetonitrile, dimethylformamide, or N-methylpyrrolidinone
  • the resulting compound, V is deblocked using, for example, acidic conditions such as HCI in a solvent such as ethyl acetate or tetrahydrofuran, or trifluoroacetic acid in dichloromethane, at a temperature from room temperature to 100 0 C for a time from 1 hour to 72 hours.
  • acidic conditions such as HCI in a solvent such as ethyl acetate or tetrahydrofuran, or trifluoroacetic acid in dichloromethane
  • the resulting intermediate Vl is treated with a compound of the formula VII in the presence of a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride, with an optional additive such as acetic acid or triethylamine, in a solvent such as 1 ,2-dichloroethane, tetrahydrofuran, or methanol at a temperature from room temperature to 100 0 C for a time from 1 hour to 72 hours.
  • a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride
  • an optional additive such as acetic acid or triethylamine
  • N-t-Butoxycarbonyl-(2-aza-bicvclof3.3.11non-6-yl)-(3-trifluoromethoxy-ben2v ⁇ - amine (referring to Scheme 13): To a 125 mL round-bottomed flask equipped with N 2 inlet were added 500 mg (2.09 mmol) N-t-butoxycarbonyl-(2-aza-bicyclo[3.3.1]non-6-one) (prepared according to a method reported in Tetrahedron Letters, 23 (44), 4559 (1982) using a t-BOC group instead of a methyl carbamate group), 600 uL (3.14 mmol) 3- (trifluoromethoxy)benzylamine, 500 uL acetic acid, 1.33 g (6.28 mmol) sodium triacetoxy borohydride, and 20 mL dry 1,2-dichloroethane.
  • N-(t-Butoxycarbonyl)-1-methyl-1 H-imidazole-4-sulfonic acid (2-aza- bicvclof3.3.nnon-6-yl)-(3-trifluoromethoxy-benzyl)-amide To a 125 mL round-bottomed flask equipped with N 2 inlet were added 302 mg (730 umol) N-t-butoxycarbonyl-(2-aza- bicyclo[3.3.1]non-6-yl)-(3-trifluoromethoxy-benzyl)-amine, 197 mg (1.09 mmol) N- methylimidazole-4-carbonyl chloride hydrochloride, 141 mg (1.09 mmol) diisopropylethylamine, and 10 mL dry acetonitrile.
  • the reaction was heated at 80 0 C for 72 hours, cooled, diluted with ethyl acetate, washed with aqueous sodium bicarbonate solution and brine, dried over sodium sulfate, and evaporated to an oil.
  • the residue was chromatographed on silica gel using hexane/ethyl acetate as eluant to afford 198 mg (49%) of a mixture of isomers as an oil.
  • Example 1 This is a ring-expanded analogue of Example 1, prepared in analogy with Example 1, with the starting ketone treated with ethyl diazoacetate and boron trifluoride etherate to produce a mixture of four isomers, each of which was converted to final product, one of which gave the following characterization:
  • a compound of the formula Il is reacted with 4-t- butoxamido-cycloheptanone in the presence of a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride, with an optional additive such as acetic acid or triethylamine, in a solvent such as 1,2-dichloroethane, tetrahydrofuran, or methanol at a temperature from room temperature to 10O 0 C for a time from 1 hour to 72 hours.
  • a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride
  • an optional additive such as acetic acid or triethylamine
  • the resulting compound, III is treated with a compound of the formula IV in the presence of a base, such as an organic amine such as triethylamine or diisopropylethylamine, in a solvent such as tetrahydrofuran, acetonitrile, dimethylformamide, or N-methylpyrrolidinone, at a temperature from room temperature to 10O 0 C for a time from 1 hour to 72 hours.
  • a base such as an organic amine such as triethylamine or diisopropylethylamine
  • a solvent such as tetrahydrofuran, acetonitrile, dimethylformamide, or N-methylpyrrolidinone
  • the resulting compound, V is deblocked using, for example, acidic conditions such as HCI in a solvent such as ethyl acetate or tetrahydrofuran, or trifluoroacetic acid in dichloromethane, at a temperature from room temperature to 100 0 C for a time from 1 hour to 72 hours.
  • acidic conditions such as HCI in a solvent such as ethyl acetate or tetrahydrofuran, or trifluoroacetic acid in dichloromethane
  • the resulting intermediate Vl is treated with a compound of the formula VII in the presence of a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride, with an optional additive such as acetic acid or triethylamine, in a solvent such as 1 ,2-dichloroethane, tetrahydrofuran, or methanol at a temperature from room temperature to 100 0 C for a time from 1 hour to 72 hours.
  • a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride
  • an optional additive such as acetic acid or triethylamine
  • the reaction was heated at room temperature for 3 days, cooled, diluted with ethyl acetate, washed with aqueous sodium bicarbonate solution and brine, dried over sodium sulfate, and evaporated to an oil.
  • the residue was chromatographed on silica gel using methanol/dichloromethane as eluant to afford 90 mg (71 %) of the product as a cis/trans mixture of isomers as an oil.
  • a compound of the formula Il is reacted with a compound of the formula III in the presence of a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride, with an optional additive such as acetic acid or triethylamine, in a solvent such as 1 ,2-dichloroethane, tetrahydrofuran, or methanol at a temperature from room temperature to 100 0 C for a time from 1 hour to 72 hours.
  • a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride
  • an optional additive such as acetic acid or triethylamine
  • the resulting compound, IV is treated with a compound of the formula V in the presence of a base, such as an organic amine such as triethylamine or diisopropylethylamine, in a solvent such as tetrahydrofuran, acetonitrile, dimethylformamide, or N-methylpyrrolidinone, at a temperature from room temperature to 100 0 C for a time from 1 hour to 72 hours.
  • a base such as an organic amine such as triethylamine or diisopropylethylamine
  • a solvent such as tetrahydrofuran, acetonitrile, dimethylformamide, or N-methylpyrrolidinone
  • the resulting compound, Vl is deblocked to compound VII, using, for example, acidic conditions such as HCI in a solvent such as ethyl acetate or tetrahydrofuran, or trifluoroacetic acid in dichloromethane, at a temperature from room temperature to 100 0 C for a time from 1 hour to 72 hours.
  • acidic conditions such as HCI in a solvent such as ethyl acetate or tetrahydrofuran, or trifluoroacetic acid in dichloromethane
  • a carbobenzyloxy group may be used as a protecting group, in which case the deprotection is carried out by hydrogenolytic cleavage using hydrogen at a pressure form atmospheric to 10 atmospheres, and a catalyst consisting of a noble metal such as palladium on carbon, or HBr in acetic acid, at a temperature from room temperature to 100 0 C for a time from 1 hour to 72 hours.
  • the reaction was heated at 70 0 C for 40 hours, cooled, diluted with ethyl acetate, washed with aqueous sodium bicarbonate solution and brine, dried over sodium sulfate, and evaporated to an oil.
  • the residue was chromatographed on silica gel using methanol/dichloromethane as eluant to afford 245 mg (86%) of an oil.
  • a compound of the formula VIII is reacted with cyclohexanone ethyleneketal in the presence of a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride, with an optional additive such as acetic acid or triethylamine, in a solvent such as 1,2-dichloroethane, tetrahydrofuran, or methanol at a temperature from room temperature to 10O 0 C for a time from 1 hour to 72 hours.
  • a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride
  • an optional additive such as acetic acid or triethylamine
  • the resulting compound, IX is treated with a compound of the formula V in the presence of a base, such as an organic amine such as triethylamine or diisopropylethylamine, in a solvent such as tetrahydrofuran, acetonitrile, dimethylformamide, or N-methylpyrrolidinone, at a temperature from room temperature to 10O 0 C for a time from 1 hour to 72 hours.
  • a base such as an organic amine such as triethylamine or diisopropylethylamine
  • a solvent such as tetrahydrofuran, acetonitrile, dimethylformamide, or N-methylpyrrolidinone
  • Compound X is converted to compound XII using a compound of the formula Xl in the presence of a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride, with an optional additive such as acetic acid or triethylamine, in a solvent such as 1 ,2-dichloroethane, tetrahydrofuran, or methanol at a temperature from room temperature to 100 0 C for a time from 1 hour to 72 hours.
  • a reducing agent such as an alkaline borohydride, such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride
  • an optional additive such as acetic acid or triethylamine
  • a compound of the formula Il is reacted with 1 ,4- epoxy-1 ,2,3,4-tetrahydronaphthalene according to a method reported in Jour. Org. Chem., 52, 1680-1686, (1987), using dimethyl boronbromide in the presence of triethylamine, in a solvent such as 1 ,2-dichloroethane, tetrahydrofuran, or methanol at a temperature from -70 0 C to 100°C for a time from 1 hour to 72 hours.
  • the resulting compound, III is treated with a compound of the formula IV in the presence of a base, such as an organic amine such as triethylamine or diisopropylethylamine, in a solvent such as tetrahydrofuran, acetonitrile, dimethylformamide, or N-methylpyrrolidinone, at a temperature from room temperature to 10O 0 C for a time from 1 hour to 72 hours.
  • a base such as an organic amine such as triethylamine or diisopropylethylamine
  • a solvent such as tetrahydrofuran, acetonitrile, dimethylformamide, or N-methylpyrrolidinone
  • the resulting compound, V is treated with triphenylphosphine and an azodicarboxylate ester, such as diethyl or diisopropyl azodicarboxylate, and diphenylphosphoryl azide in a solvent such as tetrahydrofuran, ether, toluene, or benzene at a temperature from room temperature to 10O 0 C for a time from 1 hour to 72 hours.
  • a solvent such as tetrahydrofuran, ether, toluene, or benzene
  • the reaction was heated at 80 0 C for 8 hours, cooled, diluted with ethyl acetate, washed with aqueous sodium bicarbonate solution and brine, dried over sodium sulfate, and evaporated to an oil.
  • the residue was chromatographed on silica gel using hexane/ethyl acetate as eluant to afford 150 mg (53%) of a mixture of isomers as an oil.
  • reaction was cooled to -5 0 C, and 80 uL (389 umol) diisopropylazodicarboxylate added, followed by 84 uL (389 umol) diphenylphosphoryl azide.
  • the reaction was warmed to room temperature and stirred 14 hours, then concentrated and used directly in the next step.
  • the reaction was stirred at room temperature for 24 hours, 3 mL 1 N aqueous hydrochloric acid added, and stirring continued for 4 days.
  • the reaction was diluted with ethyl acetate, extracted into dilute hydrochloric acid, and the aqueous layer basified with aqueous sodium hydroxide solution and extracted into ethyl acetate.
  • the organic phase was dried over sodium sulfate and evaporated, and the residue (40 mg, 27%) converted to the HCI salt, mp 65-81 0 C.
  • the Ki (inhibition constant) for Examples 20 to 3360 are shown below.

Abstract

La présente invention concerne une série d'hétéroayl amides substitués de formule I, dans laquelle les groupes HET, A, X1 à X4, et R1 à R12 sont définis tels que dans la spécification, qui révèlent une activité en tant qu'inhibiteurs du transport de la glycine. La présente invention concerne également leurs sels pharmaceutiquement acceptables, les compositions pharmaceutiques les contenant, et leur utilisation dans l'amélioration de la cognition et le traitement des symptômes positifs et négatifs de la schizophrénie et d'autres psychoses chez les mammifères, y compris les humains.
PCT/IB2007/003604 2006-11-30 2007-11-19 Hétéroaryl amides comme inhibiteurs du transport de la glycine de type i WO2008065500A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US86789506P 2006-11-30 2006-11-30
US60/867,895 2006-11-30

Publications (2)

Publication Number Publication Date
WO2008065500A2 true WO2008065500A2 (fr) 2008-06-05
WO2008065500A3 WO2008065500A3 (fr) 2008-11-13

Family

ID=39251256

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2007/003604 WO2008065500A2 (fr) 2006-11-30 2007-11-19 Hétéroaryl amides comme inhibiteurs du transport de la glycine de type i

Country Status (1)

Country Link
WO (1) WO2008065500A2 (fr)

Cited By (36)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009016221A1 (fr) * 2007-07-31 2009-02-05 Bayer Cropscience Sa Dérivés fongicides de n-(hétéro)aryl-méthylène-n-cycloalkyle carboxamide condensé à 6 chaînons
WO2010107115A1 (fr) 2009-03-19 2010-09-23 大正製薬株式会社 Inhibiteur de transporteur de glycine
FR2944284A1 (fr) * 2009-04-14 2010-10-15 Sanofi Aventis Derives de n-°7-aza-bicyclo°2.2.1!hept-1-yl)-aryl-methyl! -benzamide, leur preparation et leur application en therapeutique
WO2011007899A1 (fr) * 2009-07-15 2011-01-20 Taisho Pharmaceutical Co., Ltd. Inhibiteurs des transporteurs de la glycine
US20110212968A1 (en) * 2008-10-14 2011-09-01 Hamed Aissaoui Phenethylamide derivatives and their heterocyclic analogues
WO2012036276A1 (fr) * 2010-09-17 2012-03-22 大正製薬株式会社 Substance inhibitrice du transport de la glycine
WO2012036278A1 (fr) 2010-09-17 2012-03-22 大正製薬株式会社 Inhibiteur de transporteur de glycine
WO2012036268A1 (fr) * 2010-09-16 2012-03-22 大正製薬株式会社 Substance inhibitrice du transporteur de la glycine
WO2012010579A3 (fr) * 2010-07-20 2012-08-16 Bayer Cropscience Ag Benzocycloalcènes à titre d'agents antifongiques
US8273900B2 (en) 2008-08-07 2012-09-25 Novartis Ag Organic compounds
WO2013014354A1 (fr) 2011-07-25 2013-01-31 Diverchim Nouveaux analogues de ceramides, leurs procedes de preparation et leurs applications
JP2013533843A (ja) * 2010-01-25 2013-08-29 カレウス セラピューティクス エスエー Ａβ４２の生成を減少させる新規な組成物及びアルツハイマー病（ＡＤ）の治療におけるその使用
US20140275104A1 (en) * 2013-03-15 2014-09-18 Abbvie Inc. Acylaminocycloalkyl compounds suitable for treating disorders that respond to modulation of dopamine d3 receptor
WO2014157672A1 (fr) * 2013-03-28 2014-10-02 宇部興産株式会社 Composé biaryle substitué
JPWO2013058258A1 (ja) * 2011-10-18 2015-04-02 アステラス製薬株式会社 二環式ヘテロ環化合物
US9376396B2 (en) 2012-10-22 2016-06-28 AbbVie Deutschland GmbH & Co. KG Acylaminocycloalkyl compounds suitable for treating disorders that respond to modulation of dopamine D3 receptor
US9388148B2 (en) 2013-03-15 2016-07-12 Abbvie Inc. Acylaminocycloalkyl compounds suitable for treating disorders that respond to modulation of dopamine D3 receptor
EP2398770B1 (fr) * 2009-02-17 2016-12-28 Bayer Intellectual Property GmbH Dérivés de n-(phénylcycloalkyl)-carboxamide, n-(benzylcycloalkyl)-carboxamide et -thiocarboxamide fongicides
TWI594695B (zh) * 2012-04-20 2017-08-11 拜耳作物科學公司 Ｎ－環烷基－ｎ－［（雜環基苯基）亞甲基］－（硫代）甲醯胺衍生物
US10106510B2 (en) * 2014-09-10 2018-10-23 Epizyme, Inc. Substituted isoxazoles for treating cancer
US10154988B2 (en) 2012-11-14 2018-12-18 The Johns Hopkins University Methods and compositions for treating schizophrenia
WO2019079783A1 (fr) * 2017-10-20 2019-04-25 Vanderbilt University Antagonistes du récepteur muscarinique de l'acétylcholine m4
US10369134B2 (en) 2017-12-05 2019-08-06 Sunovion Pharmaceuticals Inc. Nonracemic mixtures and uses thereof
US10377708B2 (en) 2017-12-05 2019-08-13 Sunovion Pharmaceuticals Inc. Crystal forms and production methods thereof
US10927082B2 (en) 2017-03-15 2021-02-23 Metacrine, Inc. Farnesoid X receptor agonists and uses thereof
US11084817B2 (en) 2018-09-18 2021-08-10 Metacrine, Inc. Farnesoid X receptor agonists and uses thereof
US11160758B2 (en) 2019-06-04 2021-11-02 Sunovion Pharmaceuticals Inc. Modified release formulations and uses thereof
US11214538B2 (en) 2015-09-16 2022-01-04 Metacrine, Inc. Farnesoid X receptor agonists and uses thereof
US11236071B1 (en) 2017-03-15 2022-02-01 Metacrine, Inc. Farnesoid X receptor agonists and uses thereof
US11352344B2 (en) 2017-10-31 2022-06-07 Vanderbilt University Antagonists of the muscarinic acetylcholine receptor M4
US11414406B2 (en) 2018-02-02 2022-08-16 Vanderbilt University Antagonists of the muscarinic acetylcholine receptor M4
US11426412B2 (en) 2017-10-18 2022-08-30 Jubilant Epipad LLC Imidazo-pyridine compounds as PAD inhibitors
US11459338B2 (en) 2017-11-24 2022-10-04 Jubilant Episcribe Llc Heterocyclic compounds as PRMT5 inhibitors
US11529341B2 (en) 2018-03-13 2022-12-20 Jubilant Prodel LLC Bicyclic compounds as inhibitors of PD1/PD-L1 interaction/activation
US11629135B2 (en) 2017-11-06 2023-04-18 Jubilant Prodell Llc Pyrimidine derivatives as inhibitors of PD1/PD-L1 activation
US11833156B2 (en) 2017-09-22 2023-12-05 Jubilant Epipad LLC Heterocyclic compounds as pad inhibitors

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002066456A2 (fr) * 2001-02-16 2002-08-29 Allelix Neuroscience, Inc. Inhibiteurs de glyt-1
EP1284257A2 (fr) * 2001-08-16 2003-02-19 Pfizer Products Inc. Ethers aromatiques difluorométhylène et leur utilisation en tant qu'inhibiteurs de transporteur de glycine type 1
WO2005037216A2 (fr) * 2003-10-14 2005-04-28 Pfizer Products Inc. Derives [3.1.0] bicycliques utilises comme inhibiteurs des transporteurs de glycine
WO2006106425A1 (fr) * 2005-04-08 2006-10-12 Pfizer Products Inc. Heteroarylamides bicycliques [3.1.0 ] comme inhibiteurs de transport de la glycine

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002066456A2 (fr) * 2001-02-16 2002-08-29 Allelix Neuroscience, Inc. Inhibiteurs de glyt-1
EP1284257A2 (fr) * 2001-08-16 2003-02-19 Pfizer Products Inc. Ethers aromatiques difluorométhylène et leur utilisation en tant qu'inhibiteurs de transporteur de glycine type 1
WO2005037216A2 (fr) * 2003-10-14 2005-04-28 Pfizer Products Inc. Derives [3.1.0] bicycliques utilises comme inhibiteurs des transporteurs de glycine
WO2006106425A1 (fr) * 2005-04-08 2006-10-12 Pfizer Products Inc. Heteroarylamides bicycliques [3.1.0 ] comme inhibiteurs de transport de la glycine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BERGERON R ET AL: "MODULATION OF N-METHYL-D-ASPARTATE RECEPTOR FUNCTION BY GLYCINE TRANSPORT" PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF USA, NATIONAL ACADEMY OF SCIENCE, WASHINGTON, DC, US, vol. 95, December 1998 (1998-12), pages 15730-15734, XP002305700 ISSN: 0027-8424 cited in the application *

Cited By (75)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8226966B2 (en) 2007-07-31 2012-07-24 Bayer Cropscience Ag Fungicide N-6-membered fused (hetero) aryl-methylene-N-cycloalkyl carboxamide derivatives
CN103172570B (zh) * 2007-07-31 2015-09-30 拜尔农科股份公司 杀真菌剂n-6元稠合(杂)芳基-亚甲基-n-环烷基羧酰胺衍生物
WO2009016221A1 (fr) * 2007-07-31 2009-02-05 Bayer Cropscience Sa Dérivés fongicides de n-(hétéro)aryl-méthylène-n-cycloalkyle carboxamide condensé à 6 chaînons
CN103172570A (zh) * 2007-07-31 2013-06-26 拜尔农科股份公司 杀真菌剂n-6元稠合(杂)芳基-亚甲基-n-环烷基羧酰胺衍生物
AU2008281773B2 (en) * 2007-07-31 2013-05-02 Bayer Intellectual Property Gmbh Fungicide N-6-membered fused (hetero)aryl-methylene-N-cycloalkyl carboxamide derivatives
US8614213B2 (en) 2008-08-07 2013-12-24 Novartis Ag Cyclohexyl amide derivatives and their use as CRF-1 receptor antagonists
US8273900B2 (en) 2008-08-07 2012-09-25 Novartis Ag Organic compounds
US20110212968A1 (en) * 2008-10-14 2011-09-01 Hamed Aissaoui Phenethylamide derivatives and their heterocyclic analogues
EP2398770B1 (fr) * 2009-02-17 2016-12-28 Bayer Intellectual Property GmbH Dérivés de n-(phénylcycloalkyl)-carboxamide, n-(benzylcycloalkyl)-carboxamide et -thiocarboxamide fongicides
JPWO2010107115A1 (ja) * 2009-03-19 2012-09-20 大正製薬株式会社 グリシントランスポーター阻害物質
EP2409976A1 (fr) * 2009-03-19 2012-01-25 Taisho Pharmaceutical Co., Ltd. Inhibiteur de transporteur de glycine
WO2010107115A1 (fr) 2009-03-19 2010-09-23 大正製薬株式会社 Inhibiteur de transporteur de glycine
EP2409976A4 (fr) * 2009-03-19 2012-09-19 Taisho Pharmaceutical Co Ltd Inhibiteur de transporteur de glycine
US8623898B2 (en) 2009-03-19 2014-01-07 Taisho Pharmaceutical Co., Ltd. Glycine transporter inhibiting substances
FR2944284A1 (fr) * 2009-04-14 2010-10-15 Sanofi Aventis Derives de n-°7-aza-bicyclo°2.2.1!hept-1-yl)-aryl-methyl! -benzamide, leur preparation et leur application en therapeutique
WO2010119222A1 (fr) * 2009-04-14 2010-10-21 Sanofi-Aventis Derives de n-[(7-aza-bicyclo[2.2.1]hept-1-yl)-aryl-methyl]-benzamide, leur preparation et leur application en therapeutique
WO2011007899A1 (fr) * 2009-07-15 2011-01-20 Taisho Pharmaceutical Co., Ltd. Inhibiteurs des transporteurs de la glycine
US20120116095A1 (en) * 2009-07-15 2012-05-10 Taisho Pharmaceutical C0., Ltd. Glycine transporter inhibitors
JP2013533843A (ja) * 2010-01-25 2013-08-29 カレウス セラピューティクス エスエー Ａβ４２の生成を減少させる新規な組成物及びアルツハイマー病（ＡＤ）の治療におけるその使用
JP2013532648A (ja) * 2010-07-20 2013-08-19 バイエル・クロップサイエンス・アーゲー 抗菌剤としてのベンゾシクロアルケン類
US10093611B2 (en) 2010-07-20 2018-10-09 Bayer Intellectual Property Gmbh Benzocycloalkenes as antifungal agents
WO2012010579A3 (fr) * 2010-07-20 2012-08-16 Bayer Cropscience Ag Benzocycloalcènes à titre d'agents antifongiques
US9173399B2 (en) 2010-07-20 2015-11-03 Bayer Intellectual Property Gmbh Benzocycloalkenes as antifungal agents
WO2012036268A1 (fr) * 2010-09-16 2012-03-22 大正製薬株式会社 Substance inhibitrice du transporteur de la glycine
WO2012036276A1 (fr) * 2010-09-17 2012-03-22 大正製薬株式会社 Substance inhibitrice du transport de la glycine
WO2012036278A1 (fr) 2010-09-17 2012-03-22 大正製薬株式会社 Inhibiteur de transporteur de glycine
US8729271B2 (en) 2010-09-17 2014-05-20 Taisho Pharmaceutical Co., Ltd Glycine transporter inhibiting substances
WO2013014354A1 (fr) 2011-07-25 2013-01-31 Diverchim Nouveaux analogues de ceramides, leurs procedes de preparation et leurs applications
JPWO2013058258A1 (ja) * 2011-10-18 2015-04-02 アステラス製薬株式会社 二環式ヘテロ環化合物
TWI594695B (zh) * 2012-04-20 2017-08-11 拜耳作物科學公司 Ｎ－環烷基－ｎ－［（雜環基苯基）亞甲基］－（硫代）甲醯胺衍生物
US9376396B2 (en) 2012-10-22 2016-06-28 AbbVie Deutschland GmbH & Co. KG Acylaminocycloalkyl compounds suitable for treating disorders that respond to modulation of dopamine D3 receptor
US10624875B2 (en) 2012-11-14 2020-04-21 The Johns Hopkins University Methods and compositions for treating schizophrenia
EP3610890A1 (fr) 2012-11-14 2020-02-19 The Johns Hopkins University Procédés et compositions de traitement de la schizophrénie
US10154988B2 (en) 2012-11-14 2018-12-18 The Johns Hopkins University Methods and compositions for treating schizophrenia
US20140275104A1 (en) * 2013-03-15 2014-09-18 Abbvie Inc. Acylaminocycloalkyl compounds suitable for treating disorders that respond to modulation of dopamine d3 receptor
US9388141B2 (en) * 2013-03-15 2016-07-12 Abbvie Inc. Acylaminocycloalkyl compounds suitable for treating disorders that respond to modulation of dopamine D3 receptor
US9388148B2 (en) 2013-03-15 2016-07-12 Abbvie Inc. Acylaminocycloalkyl compounds suitable for treating disorders that respond to modulation of dopamine D3 receptor
CN105308023A (zh) * 2013-03-28 2016-02-03 宇部兴产株式会社 取代联芳基化合物
WO2014157672A1 (fr) * 2013-03-28 2014-10-02 宇部興産株式会社 Composé biaryle substitué
US9676720B2 (en) 2013-03-28 2017-06-13 Ube Industries, Ltd. Substituted biaryl compound
JPWO2014157672A1 (ja) * 2013-03-28 2017-02-16 宇部興産株式会社 置換ビアリール化合物
US10106510B2 (en) * 2014-09-10 2018-10-23 Epizyme, Inc. Substituted isoxazoles for treating cancer
US11214538B2 (en) 2015-09-16 2022-01-04 Metacrine, Inc. Farnesoid X receptor agonists and uses thereof
IL258011B (en) * 2015-09-16 2022-10-01 Metacrine Inc Farnesoid x receptor agonists and uses thereof
IL258011B2 (en) * 2015-09-16 2023-02-01 Metacrine Inc Farnesoid x receptor agonists and uses thereof
US10927082B2 (en) 2017-03-15 2021-02-23 Metacrine, Inc. Farnesoid X receptor agonists and uses thereof
US10961198B2 (en) 2017-03-15 2021-03-30 Metacrine, Inc. Farnesoid X receptor agonists and uses thereof
US11236071B1 (en) 2017-03-15 2022-02-01 Metacrine, Inc. Farnesoid X receptor agonists and uses thereof
US11833156B2 (en) 2017-09-22 2023-12-05 Jubilant Epipad LLC Heterocyclic compounds as pad inhibitors
US11426412B2 (en) 2017-10-18 2022-08-30 Jubilant Epipad LLC Imidazo-pyridine compounds as PAD inhibitors
US11820757B2 (en) 2017-10-20 2023-11-21 Vanderbilt University Antagonists of the muscarinic acetylcholine receptor M4
CN111491920A (zh) * 2017-10-20 2020-08-04 范德比尔特大学 毒蕈碱性乙酰胆碱受体m4的拮抗剂
AU2018351651B2 (en) * 2017-10-20 2023-01-05 Vanderbilt University Antagonists of the muscarinic acetylcholine receptor M4
CN111491920B (zh) * 2017-10-20 2024-01-30 范德比尔特大学 毒蕈碱性乙酰胆碱受体m4的拮抗剂
WO2019079783A1 (fr) * 2017-10-20 2019-04-25 Vanderbilt University Antagonistes du récepteur muscarinique de l'acétylcholine m4
US11299481B2 (en) 2017-10-20 2022-04-12 Vanderbilt University Antagonists of the muscarinic acetylcholine receptor M4
US11352344B2 (en) 2017-10-31 2022-06-07 Vanderbilt University Antagonists of the muscarinic acetylcholine receptor M4
US11629135B2 (en) 2017-11-06 2023-04-18 Jubilant Prodell Llc Pyrimidine derivatives as inhibitors of PD1/PD-L1 activation
US11459338B2 (en) 2017-11-24 2022-10-04 Jubilant Episcribe Llc Heterocyclic compounds as PRMT5 inhibitors
US10660875B1 (en) 2017-12-05 2020-05-26 Sunovion Pharmaceuticals Inc. Nonracemic mixtures and uses thereof
US11767293B2 (en) 2017-12-05 2023-09-26 Sunovion Pharmaceuticals Inc. Crystal forms and production methods thereof
US10369134B2 (en) 2017-12-05 2019-08-06 Sunovion Pharmaceuticals Inc. Nonracemic mixtures and uses thereof
US10377708B2 (en) 2017-12-05 2019-08-13 Sunovion Pharmaceuticals Inc. Crystal forms and production methods thereof
US11370753B2 (en) 2017-12-05 2022-06-28 Sunovion Pharmaceuticals Inc. Crystal forms and production methods thereof
US11517558B2 (en) 2017-12-05 2022-12-06 Sunovion Pharmaceuticals Inc. Nonracemic mixtures and uses thereof
US10800738B2 (en) 2017-12-05 2020-10-13 Sunovion Pharmaceuticals Inc. Crystal forms and production methods thereof
US10874639B2 (en) 2017-12-05 2020-12-29 Sunovion Pharmaceuticals Inc. Nonracemic mixtures and uses thereof
US10576058B2 (en) 2017-12-05 2020-03-03 Sunovion Pharmaceuticals Inc. Nonracemic mixtures and uses thereof
US10577317B2 (en) 2017-12-05 2020-03-03 Sunovion Pharmaceuticals Inc. Crystal forms and production methods thereof
US11414406B2 (en) 2018-02-02 2022-08-16 Vanderbilt University Antagonists of the muscarinic acetylcholine receptor M4
US11529341B2 (en) 2018-03-13 2022-12-20 Jubilant Prodel LLC Bicyclic compounds as inhibitors of PD1/PD-L1 interaction/activation
US11773094B2 (en) 2018-09-18 2023-10-03 Organovo, Inc. Farnesoid X receptor agonists and uses thereof
US11084817B2 (en) 2018-09-18 2021-08-10 Metacrine, Inc. Farnesoid X receptor agonists and uses thereof
US11654113B2 (en) 2019-06-04 2023-05-23 Sunovion Pharmaceuticals Inc. Modified release formulations and uses thereof
US11160758B2 (en) 2019-06-04 2021-11-02 Sunovion Pharmaceuticals Inc. Modified release formulations and uses thereof

Also Published As

Publication number Publication date
WO2008065500A3 (fr) 2008-11-13

Similar Documents

Publication Publication Date Title
WO2008065500A2 (fr) Hétéroaryl amides comme inhibiteurs du transport de la glycine de type i
EP1869019B1 (fr) Heteroarylamides bicycliques [3.1.0] comme inhibiteurs de transport de la glycine
EP1730119B1 (fr) Composes d'imidazole destines au traitement de troubles neurodegeneratifs
JP5586632B2 (ja) ５員の複素環式化合物のアザスピラニル−アルキルカルバメートの誘導体、この調製およびこの治療的使用
US11046654B2 (en) Urea compounds and their use as enzyme inhibitors
EP1483228B1 (fr) Antagonistes de nk1
WO2007121389A2 (fr) Inhibiteurs des transporteurs de la nk-1 et de la sérotonine
CA3106354A1 (fr) Derives d'amino-pyridinyle-azetidinyle-carboxamide et compositions pharmaceutiques connexes utiles comme inhibiteurs d'histone-desacetylase
CA2787427C (fr) Procede de preparation de 2-(cyclohexylmethyl)-n-{2-[(2s)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide
TWI449700B (zh) 作為組織胺ｈ３受體拮抗劑之三亞甲亞胺類
CA2688208A1 (fr) Derives de 4,5-dihydro-(1h)-pyrazole en tant que modulateurs des recepteurs cb1 cannabinoides
US20080312276A1 (en) 4,5 Dihydro-(1H)-Pyrazole Derivatives as Cannabinoid CB1 Receptor Modulators
EP2396334A1 (fr) Derives de n-[(2-aza-bicyclo[2.1.1]hex-1-yl]-aryl-methyl]-benzamide, leur preparation et leur application en therapeutique

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 07825717

Country of ref document: EP

Kind code of ref document: A2

NENP Non-entry into the national phase in:

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 07825717

Country of ref document: EP

Kind code of ref document: A2