OA12372A - Phenoxybenzylamine derivatives as selective seotonin re-uptake inhibitors. - Google Patents

Phenoxybenzylamine derivatives as selective seotonin re-uptake inhibitors. Download PDF

Info

Publication number
OA12372A
OA12372A OA1200300056A OA1200300056A OA12372A OA 12372 A OA12372 A OA 12372A OA 1200300056 A OA1200300056 A OA 1200300056A OA 1200300056 A OA1200300056 A OA 1200300056A OA 12372 A OA12372 A OA 12372A
Authority
OA
OAPI
Prior art keywords
methyl
mhz
compounds
compound
formula
Prior art date
Application number
OA1200300056A
Other languages
French (fr)
Inventor
Mavis Diane Adam
Mark David Andrew
Mark Leonard Elliot
Geoffrey Edward Gymer
David Hepworth
Howard Harry Ralph Jr
Donald Stuart Moddleton
Alan Stobie
Original Assignee
Pfizer
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GB0021593A external-priority patent/GB0021593D0/en
Priority claimed from GB0107116A external-priority patent/GB0107116D0/en
Application filed by Pfizer filed Critical Pfizer
Publication of OA12372A publication Critical patent/OA12372A/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/37—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/39—Heterocyclic compounds having sulfur as a ring hetero atom having oxygen in the same ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/08—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/10—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C323/18—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C07C323/20—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton with singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/74—Quinazolines; Hydrogenated quinazolines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to ring carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D327/00—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D327/02—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms one oxygen atom and one sulfur atom
    • C07D327/06—Six-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/72—Benzo[c]thiophenes; Hydrogenated benzo[c]thiophenes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Endocrinology (AREA)
  • Psychiatry (AREA)
  • Reproductive Health (AREA)
  • Addiction (AREA)
  • Gynecology & Obstetrics (AREA)
  • Pain & Pain Management (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Hydrogenated Pyridines (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Quinoline Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

A compound of general formula (I) wherein R<1> and R<2> are H, C1-C6alkyl or (CH2)d(C3-C6cycloalkyl) wherein d = 0, 1, 2 or 3; or R<1> and R<2> together with the nitrogen to which they are attached from an azetidine ring; Z or Y is -SR<3> and the other Z or Y is halogen or -R<3>; wherein R<3> is C1-C4 alkyl optionally substituted with fluorine; except that R<3> is not CF3; or Z and Y are linked so that, together with the interconnecting atoms, Z and Y form a fused 5 to 7-membered carbocyclic or heterocyclic ring, and wherein when Z and Y form a heterocyclic ring, in addition to carbon atoms, the linkage contains one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; R<4> and R<5>, which may be the same or different, are: A-X, wherein A = -CH=CH- or -(CH2)p- where p is 0, 1 or 2; X is hydrogen, F, CI, Br, I, CONR<6>R<7>, SO2NR<6>R<7>, SO2NHC(=O)R<6>, OH, C1-4alkoxy, NR<8>SO2R<9>, NO2, NR<6>R<11>, CN, CO2R<10>, CHO, SR<10>, S(O)R<9> or SO2R<10>; or a 5- or 6-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, S and O, optionally substituted independently by one or more R<13>; wherein R<13> is hydroxy, C1-C4alkoxy, F, C1-C6alkyl, haloalkyl, haloalkoxy, -NH2, NH(C1-C6alkyl) or -N(C1-C6alkyl)2. The compounds of general formula (I) inhibit monoamine reuptake and in particular exhibit activity as selective serotonin reuptake inhibitors.

Description

012372
PHENOXYBENZYLAMINE DERIVATIVES AS SELECTIVE SEROTONIN RE-UPTAKE INHIBITORS
This invention relates to novel diphenyl ether compounds which inhibit monoamine re-uptake. In particular compounds of the présent invention exhibit activity as sélective 5 serotonin re-uptake inhibitors (SSRIs) and hâve utility therefore in a variety of therapeutic areas. Notably the compounds of the présent invention are useful in thetreatment or prévention of a variety of disorders, including those in which the régulationof monoamine transporter function is implicated, such as dépréssion, attention déficithyperactivity disorder, obsessive-compulsive disorder, post-traumatic stress disorder, 10 substance abuse disorders and sexual dysfunction including prématuré éjaculation, andto pharmaceutical formulations containing such compounds.
According to a first aspect, the invention provides a compound of general formula (l),pharmaceutically acceptable salts, solvatés or polymorphs thereof; NR1R2
15 20 wherein; R1 and R2, which may be the same or different, are H, C.,-C6alkyl or (CH2)d(C3-C6cycloalkyl) wherein d = 0,1, 2 or 3; or R1and R2 together with thenitrogen to which they are attached form an azetidine ring; Z or Y is -SR3 and the other Z or Y is halogen or -R3; wherein R3 is independently CrC4alkyl optionally substituted with fluorine; except that R3 is not CF3; or Z and Y are linked so that, together with the interconnecting atoms, Z and Y form afused 5 to 7-membered carbocyclic or heterocyclic ring which may be saturated,unsaturated or aromatic, and wherein when Z and Y form a heterocyclic ring, inaddition to carbon atoms, the linkage contains one or two heteroatomsindependently selected from oxygen, sulfur and nitrogen; with the proviso thatwhen R5 is fluorine and R2 is methyl then the fused ring is not 1,3-dioxolane andZ and Y together do not form a fused phenyl ring; 25 012372 R4 and R5, which may be the same or different, are: » A-X, wherein A = -CH=CH- or -(CH2)P- where p is 0,1 or 2; X is hydrogen, F, Cl,
Br, I, CONR6R7, SO2NR6R7, SO2NHC(=O)R6, OK, CMalkoxy, NRBSO2R9, iNO2, NRsR11, CN, CO2R10, CHO, SR10, S(O)R9 or SO2R10; R6, R7, R8 andR10 which may be the same or different, are hydrogen or C^alkyloptionally substituted independentiy by one or more R12; R9is CV6 alkyloptionally substituted independentiy by one or more R12; R11 is hydrogen,C-,_6 alkyl optionally substituted independentiy by one or more R12, C(O)R6,CO2R9, C(O)NHRs or SO2NRSR7; R12 is F (preferably up to 3), OH, CO2H,C3.6cycloalkyl, NH2, CONH2l C^alkoxy, Cvgalkoxycarbonyl or a 5- or 6-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selectedfrom N, S and O optionally substituted independentiy by one or more R13; (or R6 and R7, together with the nitrogen to which they are attached, form a4-, 5- or 6-membered heterocyclic ring optionally substituted independentiy by one or more R13; or a 5- or 6-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selectedfrom N, S and O, optionally substituted independentiy by one or more R13;wherein R13 is hydroxy, C1-C4alkoxy, F, CrC6alkyl, haloalkyl, haloalkoxy,-NH2, -NHiCrCealkyl) or -NtCrCsaikyl^.
Unless otherwise indicated, any alkyl group may be straight or branched and is of 1 to 6carbon atoms, preferably 1 to 4 and particularly 1 to 3 carbon atoms.
Unless otherwise indicated, any carbocyclyl group contains 3 to 8 ring-atoms, and maybe saturated, unsaturated or aromatic. Preferred saturated carbocyclyl groups arecyclopropyl, cyclopentyl or cyclohexyl. Preferred unsaturated carbocyclyl groups containup to 3 double bonds. A preferred aromatic carbocyclyl group is phenyl. The termcarbocylic should be similariy construed. In addition, the term carbocyclyl includes anyfused combination of carbocyclyl groups, for example naphthyl, phenanthryl, indanyl andindenyl.
Unless otherwise indicated, any heterocyclyl group contains 5 to 7 ring-atoms up to 4 ofwhich may be hetero-atoms such as nitrogen, oxygen and sulfur, and may be saturated,unsaturated or aromatic. Examples of heterocyclyl groups are furyl, thienyl, pyrrolyl,pyrrolinyl, pyrrolidinyl, imidazolyl, dioxolanyl, oxazolyl, thiazolyl, imidazolyl, imidazolinyl, 012372 3 imidazoiidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, oxadiazolyl,trïazolyl, thiadiazolyl, pyranyl, pyridyl, piperidinyl, dioxanyl, morpholino, dithianyl,thiomorpholino, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, sulfolanyl, tetrazolyl,triazinyl, azepinyl, oxazepinyl, thiazepinyl, diazepinyl and thiazolinyl. In addition, the term 5 heterocyclyl includes fused heterocyclyl groups, for example benzimidazolyl,benzoxazolyl, imidazopyridinyl, benzoxazinyl, benzothiazinyi, oxazolopyridinyl,benzofuranyl, quinolinyl, quinazoiinyl, quinoxalinyl, dihydroquinazolinyl, benzothiazolyl,phthalimido, benzofuranyl, benzodiazepinyl, indolyl and isoindolyl. The term heterocyclicshould be similarly construed. 10
Halo means fluoro, chloro, bromo or iodo.
Preferably R1 and R2, which may be the same or different, are hydrogen or C,-C6alkyl.More preferably hydrogen or methyl. 15
When Z or Y is -SR3, R3 is preferably methyl or ethyl.
When Z and Y form a fused ring, the ring is preferably a heterocyclic ring. Morepreferably, the linkage contains one or two sulfur atoms. 20
Preferably R4 and Rs are not both hydrogen.
Preferably R4 and R5, which may be the same or different, are -(CH2)P-X, where p is 0, 1 or 2 (preferably 0 or 1); X is hydrogen, hydroxy, CONR6R7, 25 SO2NR6R7, NR8SO2R9, SR10, SOR9 or SO2R10 wherein R6, R7, R8, R9 and R10 are as defined in the first aspect, or a 5- or 6-membered heterocyclic ring containing 1,2 or 3 heteroatoms selected from N, S and O (preferably oxadiazolyl, trïazolyl, imidazolyl, oxazolyl, pyrazolyl, pyridinylor pyrimidinyl). 30
More preferably R4 and R5, which may be the same or different, are: -(CH2)P-X, where p is 0 or 1 ; X is hydrogen, hydroxy, CONR6R7, SO2NR6R7 or NR8SO2R9; wherein R6 and R7, which may be the same or different, are hydrogen orCrC3alkyl optionally substituted by hydroxy, -CONH2 or CrC3alkoxy (preferably 012372 4 methoxy); R8 is hydrogen, hydroxyethyl or methyl; or R9 is methyl, ethyï,isopropyl, trifluoromethyl or methoxyethyl; or triazolyl, imidazolyl or pyrazolyl.
More preferably still R4 is hydrogen.
Preferably R6 and R7, which may be the same or different, are hydrogen, C.,-C3alkyloptionaily substituted by hydroxy, -CONH2 or CrC3alkoxy (preferably methoxy). Morepreferably R6 and R7, which may be the same or different, are hydrogen or methyl, morepreferably still hydrogen.
When présent, R12 is preferably oxadiazoiyl, triazolyl, imidazolyl, oxazolyl, pyrazolyl,pyridinyl or pyrimidinyl. More preferably triazolyl, imidazolyl or pyrazolyl.
In the case where R6 and R7, together with the nitrogen to which they are attached, forma heterocyclic ring, preferred rings are pyrrolidine or piperidine rings each of which maybe substituted by OH or CONH2 or a morpholine ring which may be substituted byCONH2.
Preferably R11 is hydrogen or CV6 alkyl.
Preferably R8 is hydrogen, hydroxyethyl or methyl. More preferably hydrogen.
Preferably R9 is methyl, ethyl, isopropyl, trifluoromethyl or methoxyethyl. More preferablymethyl or ethyl (preferably methyl).
Preferably R10 is methyl or ethyl.
Preferably p is 1 or 0, more preferably 0.
Preferably R1 and R2, which may be the same or different, are hydrogen or methyl; when présent, R3 is methyl or ethyl; or Z and Y are linked so that, together with the interconnecting atoms, Z and Y form a fused 5 to 7-membered carbocyclic orheterocyclic ring which may be saturated, unsaturated or aromatic, and wherein 5 012372 when Z and Y form a heterocyclic ring, in addition to carbon atoms, the linkagecontains one or two heteroatoms independently selected from oxygen, sulfur andnitrogen; and R4 and R5, which may be the same or different, are (CH2)P-X, where p is 0 or 1; X is hydrogen, hydroxy, CONR6R7, SO2NR6R7, NR8SO2R9,SR10, SOR9 or SO,R10 and wherein R6 and R7, which may be the same ordifferent, are hydrogen, CrC3alkyl optionally substituted by hydroxy, -CONH2 orCrC3alkoxy (preferably methoxy); or R6 and R7, together with the nitrogen towhich they are attached, may form a morpholine, pyrrolidine or piperidine ringeach of which may be substituted by OH or CONH2; R8 is hydrogen, hydroxyethylor methyl (preferably hydrogen); R9 is methyl, ethyl, iSopropyl, trifluoromethyl ormethoxyethyl; and R10 is methyl or ethyl; or an oxadiazolyl, triazolyl, imidazolyi, oxazolyl, pyrazolyl, pyridinyl or pyrimidinyl group.
More preferably R1 and R2, which may be the same or different, are hydrogen or methyl; when présent, R3 is methyl or ethyl; or Z and Y are linked so that, together with the interconnecting atoms, Z and Y form a fused 5 to 7-membered heterocyclic ringcontaining 1 or 2 sulfur atoms; and R4 and Rs, which may be the same or different, are -(CH2)P-X, where p is 0 or 1 ; X is hydrogen, hydroxy, CONR6R7, SO2NR8R7 or NR8SO2R9;wherein R6 and R7, which may be the same or different, are hydrogen, CcCsalkyloptionally substituted by hydroxy, -CONH2 or CrC3alkoxy (preferably methoxy);R8 is hydrogen, hydroxyethyl or methyl; Rs is methyl, ethyl, isopropyl,trifluoromethyl or methoxyethyl; or triazolyl, imidazolyi or pyrazolyl.
More preferably still R1 and R2, which may be the same or different, are hydrogen or methyl; when présent R3 is methyl or ethyl; or Z and Y are linked so that, together with the interconnecting atoms, Z and Y form a fused saturated 5 to 7-memberedheterocyclic ring containing 1 or 2 sulfur atoms; R4 is hydrogen, andR5is 012372 -(CH2)P-X, where p is 0 or 1; X is hydrogen, hydroxy, CONR6R7, SO2NRsR7 or NR8SO2R9; *wherein R6 and R7, which may be the same or different, are hydrogen, CrC3alkyloptionaliy substituted by hydroxy, -CONH2 or CpCaalkoxy (preferably methoxy); R8 is hydrogen, hydroxyethyi or methyl; R9 is methyl, ethyl, isopropyl,trifluoromethyi or methoxyethyi; or triazolyl, imidazolyl or pyrazolyl.
More preferably stiïl R4 and R5 are not both hydrogéné
Preferred compounds are: 4-(2,3-dihydro-1-benzothien-5-yloxy)-3-[(methylamino)methyl]-benzenesulfonamide(Example 2); 3- [(dimethylamino)methyl]-4-[3-methyl-4-(methylsulfanyl)phenoxy]-benzenesulfonamide(Example 12); 4- (2,3-dihydro-1-benzothien--5-yloxy)-3-[(dimethylamino)methyl]-benzenesulfonamide(Example 16); 4-[3-chloro-4-(methylsulfanyl)phenoxy]-3-[(dimethylamino)methyl]-benzenesulfonamide(Example 17); 3-[(dimethylamino)methyl]-4-[3-fluoro-4-(methylsulfanyl)phenoxy]-benzenesulfonamide(Example 18); A/,/V-dimethyl-/V-[2-(6-quinolinyloxy)benzyl]amine (Example 29); 3- [(methylamino)methyl]-4-(6-quinolinyloxy)benzenesulfonamide (Example 35); 4- (2,3-dihydro-1 -benzothien-5-yloxy)-3~[(methylamino)methyl]benzamide (Example 60);4-(2,3-dihydro-1-benzothien-5-yloxy)-/V-methyl-3-[(methylamino)methyl]-benzamide(Example 62); /V-{3-[(methylamino)methyl]-4-[3-methyl-4-(methylsulfanyl)phenoxy]benzyl}methanesulfonamide (Example 75); 3- [(methylamino)methyl]-4-[3-methyl-4-(methylsulfanyl)phenoxy]benzamide (Example79); 4- (2,3-dihydro-1,4-benzoxathiin-7-yioxy)-3-[(dimethylamino)methyl]benzamide (Example88); {3-[(dimethylamino)methyi]-4-I3-fluoro-4-(methylsulfanyl)phenoxy]phenyl}-methanol(Example 90); 3-[(dimethylamino)methyl]-4-(6-quinolinyloxy)benzamide (Example 100);3-[(methylamino)methyl]-4-(6-quinolinyloxy)benzamide (Example 102); 012372 /V-methyl-/\/-{3-[(methylamino)methyl]-4-[3-methyl-4-(methylsulfanyl)phenoxyl-phenyljmethanesulfonamide (Example 116) and /\/-{4-(2,3-dihydro-1,4-benzoxathiin-7-yloxy)-3-[(dimethylamino)methyl]phenyl}-methanesulfonamide (Example 124).
According ίο a second aspect the invention provides compound of formula (I) or (XIX)NR1R2
10 15 20 and pharmaceutically acceptable salts or solvatés thereof wherein (in this aspect): R1and R2 independently represent H, CrC6 alkyl or (CH2)d(C3-C6cycloalkyl) wherein d = 0, 1, 2 or 3, or wherein NR’R2 when taken together represent a 4-membered ring whereinR1 and R2 together represent C3 alkyl; 2 and Y both independently represent -SR3wherein, when Z = -SR3 then Y - halogen, -ORa, -Raor -SRa; or when Y = -SR3 then Z =halogen, ~ORa, Ra or-SRa; and R3 and Ra independently represent: C,-C4 alkyl (optionallysubstituted with fluorine atoms e.g. -CF3); or Z and Y when taken together canrepresent a fused 5 to 7 membered ring as illustrated by general formula XIX, whereinsaid 5 to 7 membered ring may be saturated, unsaturated or aromatic, and wherein said5 to 7 membered ring may optionally contain one or more heteroatoms P and Q,wherein P and Q = may be independently O, S or N, and wherein E, F, or Gindependently represent CH or CH2 and wherein k and p may independently be = 0, 1,2or 3, and m = 1,2 or 3; and
(XIX)
V 012372 8 R4 and R5 independently represent A-X wherein A = -(CH2)n-, wherein n représente 0,1 *or 2 and wherein X represents: H, F, Cl, Br, I, CONR6R7 or SO2NR6R7, OH, NR8SO2R9,NO2, NReR11, CN, CO2R10, CHO, S(O)mR10 wherein m = 0, 1 or 2 and wherein R6, R7, R8 *and R10 independently represent H or aikyl, wherein R9 represents aikyl, R11
5 represents H, C,.6 aikyl, C(O)R6, CO2R9, C(O)NHR6 or SO2NR6R6 and wherein saidaikyl group is optionally substituted by one or more groups selected from OH, CO2H,cycioalkyl, NH2, CONHZ, aikoxy, alkoxycarbonyl and a 5- or 6-memberedheterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, S and O; or with theproviso that when P=Q= oxygen then both k and p are not zéro; with the proviso that Z 10 and Y together do not form a fused phenyl ring; R4 or R5 may be représentative of a 5- or6-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, S andO; and in addition, R6 and R7 may, together with the N atom to which they are attached,represent a 5- or 6- membered heterocyclic ring which may be optionally substituted;and pharmaceutically acceptable salts or solvatés thereof with the proviso that both R4 15 and R5 are not H.
For the avoidance of doubt, unless otherwise indicated, the term substituted meanssubstituted by one or more defined groups. In the case where groups may be selectedfrom a number of alternatives groups, the selected groups may be the same or different. 20
For the avoidance of doubt, the term independently means that where more than onesubstituent is selected from a number of possible substituents, those substituents maybe the same or different. 25 According to a third aspect, the invention provides a compound of general formula I andpharmaceutically acceptable salts thereof, wherein R1, R2, R3, Z and Y are as defined inthe first aspect; and R4 and R5, which may be the same or different, are -(CH2)P-A’,wherein p is 0,1 or 2 and A’ is a polar group. in this aspect, polar groups may be definedas those having a négative π-value (see C Hansch and A Léo, ‘Substituent Constants for 30 Corrélation Analysis in Chemistry and Biology’, Wiley, New York, 1979). In this System, H has a π-value of 0.00, -OCH3 has a π-value of -0.02, and -SO2NH2 has a π-value of -1.82, for example [see Table Vl-I, ‘Well-Characterized Aromatic Substituents’, p 49, ibid],More preferred polar groups hâve a more négative π-value: thus, preferred groups hâveπ-values of a greater négative value than -0.1, more preferably a greater négative value 35 than -0.5, and most preferably a greater négative value than -1.0. Even when p is other 012372 9 than zéro in the above définition, the définition of A’ is based on the above reference asif p was zéro.
Unless otherwise specified, the compounds of the first, second and third aspects arehereinafter defined as compounds of the invention.
The compounds of the invention hâve the advantage that they are sélective inhibitors ofthe re-uptake of serotonin (SRIs) (and so are iikely to hâve reduced side effects), theyhâve a rapid onset of action (making them suitable for administration shortly before aneffect is required), they hâve désirable potency and associated properties. Compoundsthat selectively inhibit the re-uptake of serotonin, but not noradrenaline or dopamine, arepreferred.
We hâve found that compounds of formula I which possess these properties hâve arelatively polar group at R4/R5.
The pharmaceutically or veterinarily acceptable salts of the compounds of formula Iwhich contain a basic centre are, for example, non-toxic acid addition salts formed withinorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoricacid, with carboxylic acids or with organo-sulfonic acids. Examples înclude the HCl, HBr,Hl, sulfate or bisulfate, nitrate, phosphate or hydrogen phosphate, acetate, benzoate,succinate, saccharate, fumarate, maleate, lactate, citrate, tartrate, gluconate, camsylate,methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoatesalts. Compounds of the invention can also provide pharmaceutically or veterinarilyacceptable métal salts, in particular non-toxic alkali and alkaline earth métal salts, withbases. Examples înclude the sodium, potassium, aluminium, calcium, magnésium, zinc,diolamine, olamine, ethylenediamine, tromethamine, chloine, megulamine anddiethanolamine salts. For reviews on suitable pharmaceutical salts see Berge et al, J.Pharm, Sci., 66, 1-19, 1977; P L Gould, International Journal of Pharmaceutics, 33(1986), 201-217; and Bighley et al, Encyclopedia of Pharmaceutical Technology, MarcelDekker Inc, New York 1996, Volume 13, page 453-497.
Hereinafter, the compounds, their pharmaceutically acceptable salts, their solvatés andpolymorphs, defined in any aspect of the invention (except intermediate compounds inChemical processes) are referred to as "compounds of the invention". 012372 10 ’
The pharmaceutically acceptable solvatés of the compounds of the Invention include thehydrates thereof. „
The compounds of the invention may possess one or more chiral centres and so exist ina number of stereoisomeric forms. Ail stereoisomers and mixtures thereof are includedin the scope of the présent invention. Racemic compounds may either be separatedusing préparative HPLC and a column with a chiral stationary phase or resolved to yieldindividual enantiomers utilising methods known to those skilled in the art. In addition,chiral intermediate compounds may be resolved and used to préparé chiral compoundsof the invention.
S
In cases where the compounds of the invention exist as the E and Z isomers, theinvention includes individual isomers as well as mixtures thereof.
In cases where compounds of the invention exist as tautomeric isomers, the inventionincludes individual tautomers as well as mixtures thereof. .
In cases where the compounds of the invention exist as optical isomers, the inventionincludes individual isomers as well as mixtures thereof.
In cases where the compounds of the invention exist as diastereoisomers, the inventionincludes individual diastereoisomers as well as mixtures thereof. Séparation of diastereoisomers or E and Z isomers may be achieved by conventionaltechniques, e.g. by fractional crystallisation, chromatography or H.P.L.C. An individualenantiomer of a compound of the invention may be prepared from a correspondingoptically pure intermediate or by resolution, such as by H.P.L.C. of the correspondingracemate using a suitable chiral support or by fractional crystallisation of thediastereoisomeric salts formed by reaction of the corresponding racemate with a suitableoptically active acid or base, as appropriate.
The compounds of the invention may exist in one or more tautomeric forms. Ailtautomers and mixtures thereof are included in the scope of the présent invention. Forexample, a claim to 2-hydroxypyridinyl would also cover its tautomeric form, a-pyridonyl. 012372 11
It will be appreciated by those skilled in the art that certain protected dérivatives ofcompounds of the invention, which may be made prior to a final deprotection stage, maynot possess pharmacological activity as such, but may, in certain instances, be 5 administered oraliy or parenterally and thereafter metabolised in the body to form compounds of the invention which are pharmacologically active. Such dérivatives maytherefore be described as "prodrugs”. Further, certain compounds of the invention may actas prodrugs of other compounds of the invention. 10 Ali protected dérivatives and prodrugs of compounds of the invention are included withinthe scope of the invention. Examples of suitable pro-drugs for the compounds of theprésent invention are described in Drugs of Today, Volume 19, Number 9,1983, pp 499 -538 and in Topics in Chemistry, Chapter 31, pp 306 - 316 and in “Design of Prodrugs” byH. Bundgaard, Elsevier, 1985, Chapter 1 (the disclosures in which documents are 15 incorporated herein by reference).
It will further be appreciated by those skilled in the art, that certain moieties, known tothose skilled in the art as “pro-moieties”, for example as described by H. Bundgaard in“Design of Prodrugs” (the disclosure in which document is incorporated herein by 20 reference) may be placed on appropriate functionalities when such functionalities areprésent within the compounds of the invention.
Preferred prodrugs for compounds of the invention include: esters, carbonate esters, hemi-esters, phosphate esters, nitro esters, sulfate esters, sulfoxides, amides, carbamates, azo- 25 compounds, phosphamides, glycosides, ethers, acetals and ketals.
The invention also includes ail suitable isotopic variations of the compounds of theinvention. An isotopic variation is defined as one in which at least one atom is replacedby an atom having the same atomic number but an atomic mass different from the 30 atomic mass usually found in nature. Examples of isotopes that can be incorporated intocompounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorus, sulphur, fluorine and chlorine such as 2H, 3H, 13C, 14C, 1SN, 170,180,31P, 32P,35S, 18F and 36CI, respectively. Certain isotopic variations of the invention, for example,those in which a radioactive isotope such as 3H or 14C is incorporated, are useful in drug
35 and/or substrate tissue distribution studies. Tritiated, i.e. 3H, and carbon-14, i.e. 14C 012372 12 isotopes are particularly preferred for their ease of préparation and detectability. *
Further, substitution with isotopes such as deuterium, i.e. 2H, may afford certaintherapeutic advantages resulting from greater metabolic stability, for example, increased *in vivo half-life or reduced dosage requirements and hence may be preferred in somecircumstances. Isotopic variations of the compounds of the invention can generally beprepared by conventionai procedures such as by the methods or préparations describedin the Examples and Préparations hereafter using appropriate isotopic variations ofsuitable reagents.
Compounds of the invention may be prepared, in known manner in a variety of ways. Inthe following reaction schemes and hereafter, unless otherwise stated, R1 to R13, Z and Yare as defined in the first aspect. These processes form further aspects of the invention.
Throughout the spécification, general formulae are designated by Roman numerals I, 11, III, IV etc. Subsets of these general formulae are defined as la, Ib, le etc.....IVa, IVb, IVc etc.
Compounds of general formula (I) may be prepared from compounds of formula (II) byreaction with an amine of general formula HNR’R2, or with a suitable sait form thereof,together with a hydride reducing agent in a suitable solvent (see Scheme 1). Wheneither R1 or R2 is hydrogen, suitable solvents include protic solvents such as éthanol,and sodium borohydride is an appropriate reducing agent as exemplified by Example 36herein. When neither R1 or R2 are hydrogen, tetrahydrofuran/ dichloromethane is asuitable solvent System and sodium triacetoxyborohydride is a suitable reducing agent.
In such reactions the use of a sait form of HNR1R2, such as the hydrochloride ispréférable, and an auxiliary base, to aid solubility of the HNR1R2 sait, such astriethylamine may optionally be added along with acetic acid, as exemplified by Example25 herein. 01237 2 SCHEME 1
Compounds of formula (II) may be prepared in turn from the coupling of compounds ofgeneral formula (IV) with aldéhyde compounds of general formula (111), wherein L is asuitable leaving group such as halogen (F, Cl, Br or l) or a sulfonate ester such astrifluoromethanesulfonate or methanesulfonate, preferably L is F or Cl. Such couplingreaction may be accomplished by techniques known in the art, such as via reaction withpotassium carbonate in a suitable solvent such as dimethylformamide under appropriatereaction conditions such as elevated température and in an inert atmosphère. 10 Thus according to a further aspect, the invention provides a process for preparingcompounds of general formula (I) from compounds of the general formula (II).
Alternatively, R4 and/or R5 may be introduced after ether coupling (see Scheme 2).Compounds of general formula (I) may be prepared from compounds of general formula 15 (la), i.e. compounds of general formula (I) where R4 and R5 are hydrogen. Compounds of general formula (la) may be prepared from (lia) in an analogous fashion to thepréparation of (I) from (II) (see Scheme 1), while compounds of general formula (lia)may be prepared from (IV) and (Ilia) in an analogous fashion to the préparation of (II)(see Scheme 1). 20 012372 14
SCHEME2
Thus according to a further aspect, the invention provides a process for preparingcompounds of general formula (I) from compounds of the general formula (la). Méthodologies for introducing R4 and/or R5 into compounds of formula (la) include: i) Where R4/R5 are halogen, by reaction of (la) with a suitable halogenating agent inan inert solvent which does not adversely affect the reaction. Suitablehalogenating agents include trifluoromethanesulfonic acid and /V-iodosuccinimideand suitable inert solvents include dichloromethane. ii) Where R4ZR5 are -NO2, by reaction of (la) with a suitable nitrating agent, such asan alkali métal nitrate, in a solvent which does not adversely affect the reactionat, or below, room température. Suitable nitrating agents include trifluoromethanesulfonic acid/ potassium nitrate and suitable solvents includetrifluoroacetic acid. iii) Where R4/R5 is -SO2NR6R7 by reaction of an intermediate sulfonyl chloride withthe requisite amine of formula HNR6R7 in a suitable solvent. Suitable solventsinclude a mixture of water and dichloromethane and the reactions are generallyperformed at or below room température. The intermediate sulfonyl chloridesmay be prepared from compounds of formula (la) by reaction with chlorosulfonicacid under low température conditions in the presence of a solvent which doesnot adversely affect the reaction, either with or without subséquent treatment witha chlorinating agent such as phosphores oxychloride, phosphores pentachloride, 01237 2 15 oxalyl chloride or thionyl chloride in a solvent which does not adversely affect theréaction. Suitable solvents for the reaction with chlorosulfonic acid includetrifluoroacetic acid and a typical reaction température is 0 °C. Suitable solventsfor the reaction with chlorinating agents include acetonitrile and suitable 5 conditions include at reflux, as illustrated in Example 12 herein.
For example, compounds of formula (Iq), where R5 is -SO2NR6R7, may beprepared via the intermediate sulfonyl chlorides (XVIII) from compounds offormula (la) by reaction of (la) with chlorosulfonic acid, either with or without 10 subséquent treatment with a chlorinating agent such as phosphorus oxychloride, phosphorus pentachloride, oxalyl chloride or thionyl chloride, followed by reactionwith HNR6R7 (see scheme 2a). Reaction conditions typically comprise lowtempérature. The reaction can take place either neat, i.e. in the absence ofsolvent, or in the presence of an inert solvent which does not adversely affect the 15 reaction. The intermediate sulfonyl chloride (XVII) may be isolated, purified and then reacted with HNR6R7, alternatively it may be generated in situ, withoutisolation, and then reacted with HNR6R7. SCHEME 2a
Z Z 2 (|a> (XVltt) (Iq) 20
Thus according to a further aspect, the invention provides a process for preparingcompounds of general formula (I) from compounds of the general formula (II). In apreferred embodiment, there is provided a process for preparing compounds of formula(Iq) by reacting compounds of formula (la) in a suitable solvent, with chlorosulfonic acid, 25 either with or without subséquent treatment with a chlorinating agent such as phosphorus oxychloride, phosphorus pentachloride, oxalyl chloride or thionyl chloride, togive compounds of formula (XVlil) followed by reaction with HNR6R7 to give Compounds 012372 16 of formula (Iq). Preferably compounds of formula (XVIII) are generated in situ andreacted with HNR6R7 without isolation. *»
Alternative^, compounds of general formula (I) having a particular R4/R5 substituent maybe converted into other compounds of formula (I) using known techniques. For example: i) When R4/R5 is halogen such as chloro, bromo or iodo, it may be converted tocyano via reaction with a cyanide sait in the presence of a Pd(0) or (ll)catalyst ina high boiling solvent at elevated températures. Suitable Pd catalysts includepalladium tetrakis(triphenylphosphine), suitable cyanide saits include Zn(CN)2and suitable high boiling solvents which do not adversely affect the reactioninclude dimethylformamide as exempiified by Example 78 herein; ii) When R4ZRS is halogen such as chloro, bromo or iodo, it may be converted to thecorresponding ester -CO2R by treatment with carbon monoxide at high pressurewith a Pd(0) or (II) catalyst, in an alcohol solvent (ROH wherein R is - C4alkyl), in the presence of a base at elevated températures. For example thereaction may be carried out at pressures in the région of about 100 p.s.i, whilstsuitable Pd catalysts include dichlorobis(triphenylphosphine) palladium (II),suitable bases include triethylamine and suitable alcohol solvents includemethanol as exempiified by Préparation 50 herein; iii) When R4/R5 is nitro, it may be reduced to the corresponding -NH2 group viatreatment with a reducing agent in a protic solvent at, or above, roomtempérature. Suitable reducing agents include iron powder / calcium chloride,suitable protic solvents include aqueous éthanol and a typical reactiontempérature is from about 70°C to about 100°C, preferably about 90°C, asexempiified by Example 103 herein; iv) When R4/R5 is -NH2, it may be converted to the corresponding -NHSO2R9 groupby reaction with a sulfonylating agent in the presence of a base in an inert solventwhich does not adversely affect the reaction at, or below, room température.Suitable sulfonylating agents include methanesulfonyl chloride, suitable basesinclude triethylamine and suitable inert solvents include dichloromethane asexempiified by Example 128 herein; 012372 v) When R4/R5 is a -NHSO2R9 group, it may be converted to the corresponding -NR8SO2R9 group via treatment with an alkylating agent and a base in a suitableinert solvent. Examples of suitable alkylating agents include methyl iodide, 5 suitable bases include potassium carbonate and suitable inert solvents include acetonitrile, as exemplified by Préparation 88 herein; vi) When R4/R5 is a nitrile -CN, it may be converted to the corresponding -C(O)NH2group by hydrolysis under basic, oxidative or acid conditions. Basic hydrolysis is 10 preferably conducted with a hydroxide sait such as potassium hydroxide in a protic solvent such as f-butanol at elevated températures, as exemplified inExample 79 herein. vii) When R4/Rs is an ester -CO2R, it may be reduced to the corresponding alcohol 15 group -CH2OH via treatment with a hydride reducing agent, such as lithium aluminium hydride, as exemplified by Préparation 69 herein; viii) When R4/R5 is an ester -CO2R, it may be converted to the corresponding acid -COZH by treatment with a suitable hydroxide sait in the presence of water and a 20 suitable co-solvent. Suitable hydroxide salts include lithium hydroxide and suitable co-solvents include tetrahydrofuran, as exemplified by Préparation 55herein; ix) When R4/R5 is an acid -CO2H, it may be converted to the corresponding amide - 25 CONR6R7 by treatment with a coupling agent, a base and an amine HNR6R7 in a suitable inert solvent which does not adversely affect the reaction. Suitablecoupling agents include 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride in the presence of 1-hydroxybenzotriazole, suitable bases includetriethylamine and suitable solvents include dichloromethane, as exemplified by 30 Préparation 59 herein; x) When R4/R5 is halogen such as chlore, bromo or iodo, it may be converted to anα,β-unsaturated amide, by treatment with acrylamide, a Pd(0) or (II) catalyst anda suitable base, in an inert solvent which does not adversely affect the reaction, 35 at elevated températures. Suitable Pd catalysts include palladium (II) acetate in 012372 18 the presence of tri(o-tolyl)phosphine, suitable bases include triethylamine andsuitable inert solvents include acetonitrile as exemplified by Example 50 herein; • xi) When R4/R5 is an α,β-unsaturated amide, it may be converted to -CH2CH2CO2NH2, by treatment with a suitable reducing agent at an appropriatetempérature, in a suitable solvent which does not adversely affect the reaction.Suitable reducing agents include samarium diiodide at room température andsuitable solvents include tetrahydrofuran containing a small amount of water, asexemplified by Example 51 herein; xii) When R4/R5 is -CH2OH, it may be converted to -CH2NR8SO2R9 by means of aMitsunobu reaction at an appropriate température, in a suitable solvent whichdoes not adversely affect the reaction. Suitable reagents include diethylazodicarboxylate, triphenylphosphine and ferf-butyl methylsulfonylcarbamate, 0°C is a suitable reaction température and tetrahydrofuran is a suitable solventas exemplified by Préparation 72 herein;
Alternatively, compounds of general formula (I) having a particular NR1R2 group may beconverted into other compounds of general formula (I) having a different NR1R2 group.
For example: i) Compounds of formula (Ib) wherein either R1 or R2 is hydrogen, can be convertedinto a compound of formula (le) wherein neither R1 nor R2 are hydrogen, byreaction of the compound of formula (Ib) with an aldéhyde and a hydridereducing agent. Suitable aldéhydes include formaldéhyde, suitable reducingagents include sodium tri(acetoxy)borohydride and the reaction is preferablyconducted in a solvent which does not interfère with the reaction, such asdichloromethane at or below room température, as exemplified by Example 12herein. ii) Compounds of formula (Ib) wherein R1 or R2 is hydrogen, can be converted into acompound of formula (le) wherein R1 or R2 is methyl, by reaction of thecompound of formula (Ib) with a formylating agent in a suitable solvent, followedby subséquent réduction of the intermediate W-formy, compound with a hydridereducing agent in an inert solvent, preferably at elevated température. Suitable 012372 19 formylating agents include pentafluorophenyl formate (formed from formic acid,pentafluorophenol and dicyclohexylcarbodiimide) and suitable solvents for theformylation include dichloromethane. Suitable reducing agents include borane-tetrahydrofuran complex and suitable inert solvents for the réduction includetetrahydrofuran as exemplified by Example 110 herein.
Alternatively, compounds of general formula (I) may be prepared from compounds offormula V (see Scheme 3) wherein L is as defined for Scheme 1 and T is a group whichcan be converted into CH2NR1R2. Examples of suitable T substitutents include: -CO2R10,-CN and -C(O)NR1R2.
SCHEME 3
Méthodologies for converting compounds of formula (V) to (I), include: i) Where T is -CO2R10 and R10 = methyl or ethyl, by reaction with an amine ofgeneral formula NHR’R2 to form an amide, followed by réduction to provide anamine. ii) Where T = -CN, by réduction to its corresponding amine of formula -CH2NH2. iii) Where T = -C(O)NR1R2, by réduction to provide an amine.
Compounds of general formula (V) may be prepared in turn by the coupling ofcompounds of general formula (VI) and compounds of the general formula (IV).Reagents and conditions for such coupling reactions are as previously defined for thecoupling of compounds of general formulae (IV) and (III) in Scheme 1.
Compounds of general formula (VI) may be prepared in turn from compounds of generalformula (VII) (see Scheme 4). 012372 20 SCHEME4
Compounds of formula (VI) may be prepared by aromatic electrophilic substitution oîcompounds of formula (VII) to give compounds of formula (VI) directly. Alternativelycompounds of formula (VI) may be prepared in two or more steps; aromatic electrophilicsubstitution of compounds of formula (Vil) to give intermediate compounds which thenundergo further reaction to give compounds of formula (VI). The intermediatecompounds may be isolated or generated in situ without isolation. A preferred route isshown in Scheme 5. (Vil) SCHEME S .
Compounds of formula (VII) are reacted with sulfonyl chloride to give compounds of _formula (VIII) followed by reaction with NHR6R7 to give compounds of formula (Via).
According to further aspects, the invention provides compounds of formulae (II), (lia)and (V) as defined above.
Compounds of formulae (III), (Ilia), (IV), (VI) or (VII) are either known and available fromcommercial sources or are available from commercially available materials using knowntechniques (see Exemples hereinafter).
It will be apparent to those skilled in the art that sensitive functional groups may need to beprotected and deprotected during synthesis of a compound of formula I. This may beachieved by conventional techniques, for example as described in ‘Protective Groups inOrganic Synthesis’, 3rd édition, by T W Greene and PGM Wuts, John Wiley and Sons 012372 21
Inc, 1999. Example 35 provides one example of a protecting group strategy employed inthe synthesis of a compound of the présent invention.
The skilled chemist will appreciate that diaryl ethers may be prepared using a number ofsynthetic méthodologies. For a review of méthodologies see J S Sawyer, Tetrahedron, 56 (2000) 5045-5065, incorporated herein by reference.
The compounds of the invention are useful because they hâve pharmacological activityin mammals, including humans. More particularly, they are useful in the treatment orprévention of a disorder in which the régulation of monoamine transporter function isimplicated. Disease States that may be mentioned include hypertension, dépréssion(e.g. dépréssion in cancer patients, dépréssion in Parkinson's patients, postmyocardialinfarction dépréssion, subsyndromal symptomatic dépréssion, dépréssion in infertilewomen, paediatric dépréssion, major dépréssion, single épisode dépression, récurrentdépression, child abuse induced dépression, post partum dépréssion and grumpy oldman syndrome), generaiized anxiety disorder, phobias (e.g. agoraphobia, social phobiaand simple phobias), posttraumatic stress syndrome, avoidant personality disorder,prématuré éjaculation, eating disorders (e.g. anorexia nervosa and bulimia nervosa),obesity, Chemical dependencies (e.g. addictions to alcohol, cocaïne, heroin,phénobarbital, nicotine and benzodiazépines), cluster headache, migraine, pain,Alzheimer's disease, obsessive-compulsive disorder, panic disorder, memory disorders(e.g. dementia, amnestic disorders, and age-related cognitive décliné (ARCD)),Parkinson's diseases (e.g. dementia in Parkinson's disease, neuroleptic-inducedparkinsonism and tardive dyskinesias), endocrine disorders (e.g. hyperprolactinaemia),vasospasm (particularly in the cérébral vasculature), cerebellar ataxia, gastrointestinaltract disorders (involving changes in motility and sécrétion), négative symptoms ofschizophrenia, premenstrual syndrome, fibromyalgia syndrome, stress incontinence,Tourette’s syndrome, trichotillomania, kleptomanie, male impotence, attention déficithyperactivity disorder (ADHD), chronic paroxysmal hemicrania, headache (associatedwith vascular disorders), emotional lability, pathological crying, sleeping disorder (cataplexy) and shock.
Disorders of particular interest include dépression, attention déficit hyperactivity disorder,obsessive-compulsive disorder, post-traumatic stress disorder, substance abusedisorders and sexual dysfunction including (in particular) prématuré éjaculation. P12372 22;
Prématuré éjaculation may be defined as persistent or récurrent éjaculation before, upon * or shortly after penile pénétration of a sexual partner. It may also be defined aséjaculation occurring before the individual wishes [see 'The Merck Manual', 16,h édition, .p 1576, published by Merck Research Laboratories, 1992].
Thus, according to further aspects, the invention provides: i) a compound of the invention for use as a pharmaceutical; ii) the use of a compound of the invention in the manufacture of a médicament forthe treatment or prévention of a disorder in which the régulation of monoaminetransporter function is implicated, for example dépression, attention déficithyperactivity disorder, obsessive-compulsive disorder, post-traumatic stressdisorder, substance abuse disorders or sexual dysfunction including prématurééjaculation; iii) the use of a compound of the invention in the manufacture of a médicament forthe treatment or prévention of prématuré éjaculation; iv) a method of treatment or prévention of dépréssion, attention déficit hyperactivitydisorder, obsessive-compulsive disorder, post-traumatic stress disorder,substance abuse disorders or sexual dysfunction including prématuré éjaculation,which comprises administering a therapeuticaily effective amount of a compoundof the invention to a patient ih need of such treatment or prévention; v) a method of increasing ejaculatory latency which comprises the administration ofan effective amount of a compound of the invention to a male desiring increasedejaculatory latency; and vi) a compound of the invention for the treatment or prévention of a disorder inwhich the régulation of monoamine transporter function is implicated, for exampiedépression, attention déficit hyperactivity disorder, obsessive-compulsivedisorder, post-traumatic stress disorder, substance abuse disorders or sexualdysfunction including prématuré éjaculation. 012372 23 vii) a compound of the invention for treating prématuré éjaculation.
It is to be appreciated that ali référencés herein to treatment include curative, palliativeand prophylactic treatment.
The compounds of the invention may be administered atone or as part of a combinationtherapy. If a combination of active agents are administered, then they may beadministered simultaneousiy, separately or sequentially. In particular, the compounds ofthe invention may be combined with the following preferably for the treatment of PE: i) Alpha-blockers (e.g. phentolamine, doxazasim, tamsulosin, terazasin, prazasinand Example 19 of W09830560. A possible rationale for alpha-blockers treatingprématuré éjaculation is as follows. Muscular activity of the ejaculatory smoothmuscles (vas deferens, séminal vesicles and urethra) are controlled by thesympathetic nervous System through the release of noradrenalin. Noradrenalinacts on the alpha 1 adrenoreceptors, stimulating muscle contractions, leading toséminal émission and subsequently éjaculation. Blocking these receptors willtherefore inhibit éjaculation. ii) Apomorphine - teachings on the use of apomorphine as a pharmaceutical maybe found in US-A-5945117. iii) Dopamine D2 agonists (e.g. Premiprixal, Pharmacia Upjohn compound numberPNU95666). iv) Melanocortin receptor agonists (e.g. Melanotan II). v) PGE1 receptor agonists (e.g. alprostadil). vi) Mono amine transport inhibitors, particularly Noradrenaline Re-uptake Inhibitors(NRIs) (e.g. Reboxetine), other Serotonin Re-uptake Inhibitors (SRIs) (e.g.paroxetine) or Dopamine Re-uptake Inhibitors (DRIs). vii) 5-HT3 antagoniste (e.g. ondansetron and granisetron). A possible rationale for 5HT3 antagoniste treating prématuré éjaculation is as follows. 5-HT3 receptors, 012372 24 présent in the lumen of the posterior portion of the urethra, are stimulated by 5-HT in the semen during séminal émission, leading to a sensitisation of the spinalrelex pathway which leads to éjaculation. Therefore, an antagonist would prevent *this sensitisation and thus delay éjaculation. viii) PDE inhibitors such as PDE2 (e.g. erythro-9-(2-hydroxyl-3-nonyl)-adenine) andExampie 100 of EP 0771799-incorporated herein by reference) and in particular aPDE5 inhibitor (e.g. sildenafil, 1-{[3-(3,4-dihydro-5-methyl-4-oxo-7- propylimidazo[5,1 -f]-as-trazin-2-yl)-4-ethoxyphenyljsulfonyl}-4-ethylpiperazine i.e.vardenafil I Bayer BA 38-9456 or IC351 (see structure below, Icos Lilly)). Apossible rationale for PDE inhibitors treating prématuré éjaculation is as follows. cAMP and CGMP leveis in the ejaculatory smooth muscles regulate muscle toneof these ejaculatory muscles and so delay éjaculation. o
1C351 (Icos Ully) ix) Potassium channel openers. x) P2X purinergic receptor antagonists. xi) Endothelin receptor antagonists
For human use the compounds of the invention can be administered alone but in humantherapy will generally be administered in admixture with a suitable pharmaceuticalexcipient, diluent or carrier selected with regard to the intended route of administrationand standard pharmaceutical practice.
For example, the compounds of the invention, can be administered orally, buccally orsublingually in the form of tablets, capsules (including soft gel capsules), ovules, élixirs,solutions or suspensions, which may contain flavouring or colouring agents, for 012372 25 » immédiate-, delayed-, modified-, sustained-, dual-, controlled-release or pulsatile delivery applications. The compounds of the invention may also be administered viaintracavernosal injection. The compounds of the invention may also be administered viafast dispersing or fast dissolving dosage forms. 5
Such tablets may contain excipients such as microcrystalline cellulose, lactose, sodiumcitrate, calcium carbonate, dibasic calcium phosphate, glycine, and starch (preferablycorn, potato or tapioca starch), disintegrants such as sodium starch glycollate,croscarmellose sodium and certain complex silicates, and granulation binders such as 10 polyvinylpyrroiidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricating agents such as magnésiumstéarate, stearic acid, glyceryl behenate and talc may be included.
Solid compositions of a similar type may also be employed as filiers in gelatin capsules. 15 Preferred excipients in this regard include lactose, starch, a cellulose, milk sugar or highmolecular weight polyethylene glycols. For aqueous suspensions and/or élixirs, thecompounds of the invention, and their pharmaceutically acceptable salts, may becombined with various sweetening or flavouring agents, colouring matter or dyes, withemulsifying and/or suspending agents and with diluents such as water, éthanol, 20 propylene giycoi and glycerin, and combinations thereof.
Modified release and pulsatile release dosage forms may contain excipients such asthose detailed for immédiate release dosage forms together with additional excipientsthat act as release rate modifiers, these being coated on and/or included in the body of 25 the device. Release rate modifiers include, but are not exclusively limited to, hydroxypropylmethyl cellulose, methyl cellulose, sodium carboxymethylcellulose, ethylcellulose, cellulose acetate, polyethylene oxide, Xanthan gum, Carbomer, ammoniométhacrylate copolymer, hydrogenated castor oil, carnauba wax, paraffin wax, celluloseacetate phthalate, hydroxypropylmethyl cellulose phthalate, methacrylic acid copolymer 30 and mixtures thereof. Modified release and pulsatile release dosage forms may containone or a combination of release rate modifying excipients. Release rate modifyingexcipients may be présent both within the dosage form i.e. within the matrix, and/or onthe dosage form, i.e. upon the surface or coating. 012372 26
Fast dispersing or dissolving dosage formulations (FDDFs) may contain the followingingrédients: aspartame, acesulfame potassium, citric acid, croscarmellose sodium,crospovidone, diascorbic acid, ethyl acryiate, ethyl cellulose, gelatin, hydroxypropylmethyl cellulose, magnésium stéarate, mannitol, methyl méthacrylate, mintflavouring, polyethylene glycol, fumed silica, Silicon dioxide, sodium starch glycolate,sodium stearyl fumarate, sorbitol, xylitol. The terms dispersing or dissolving as usedherein to describe FDDFs are dépendent upon the solubility of the drug substance used i.e. where the drug substance is insoluble a fast dispersing dosage form can beprepared and where the drug substance is soluble a fast dissolving dosage form can beprepared.
The compounds of the invention can also be administered parenterally, for example,intravenously, intra-arterially, intraperitoneally, intrathecally, intraventricularly,intraurethrally, intrastemally, intracranially, intramuscularly or subcutaneously, or theymay be administered by infusion techniques. For such parentéral administration theyare best used in the form of a stérile aqueous solution which may contain othersubs 3nces, for example, enough salts or glucose to make the solution isotonie withblood. The aqueous solutions should be suitably buffered (preferably to a pH of from 3to 9), if necessary. The préparation of suitable parentéral formulations under stérileconditions is readily accomplished by standard pharmaceutical techniques well known tothose skilled in the art.
The following dosage levels and other dosage levels herein are for the average humansubject having a weight range of about 65 to 70 kg. The skilled person will readily beable to détermine the dosage levels required for a subject whose weight falls outside thisrange, such as children and the elderly.
For oral and parentéral administration to human patients, the daily dosage level of thecompounds of the invention or salts or solvatés thereof will usually be from 10 to 500 mg(in single or divided doses).
Thus, for example, tablets or capsules of the compounds of the invention may containfrom 5 mg to 250 mg of active compound for administration singly or two or more at atime, as appropriate. The physician in any event will détermine the actual dosage whichwill be most suitable for any individual patient and it will vary with the âge, weight and 012372 27 response of the particular patient. The above dosages are exemplary of the averagecase. There can, of course, be individual instances where higher or lower dosageranges are merited and such are within the scope of this invention. The skilled personwill also appreciate that, in the treatment of certain conditions (including PE),compounds of the invention may be taken as a single dose on an “as required” basis(i.e. as needed or desired).
Example Tablet Formulation
In general a tablet formulation could typically contain between about 0.01mg and 500mgof a compound of the invention whilst tablet fill weights may range from 50mg to1000mg. An example formulation for a 1Qmg tablet is illustrated:
Ingrédient %w/w
Compound of the invention 10.000*
Lactose 64.125
Starch 21.375
Croscarmellose Sodium 3.000
Magnésium Stéarate 1.500 * This quantity is typically adjusted in accordance with drug activity.
The compounds of the invention can also be administered intranasally or by inhalationand are conveniently delivered in the form of a dry powder inhaler or an aérosol sprayprésentation from a pressurised container, pump, spray or nebulizer with the use of asuitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetra-fluoro-ethane, a hydrofluoroalkane such as 1,1,1,2-tetrafluoroethane (HFA 134A [trademark]) or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA [trade mark]), carbon dioxide orother suitable gas. In the case of a pressurised aérosol, the dosage unit may bedetermined by providing a valve to deliver a metered amount. The pressurisedcontainer, pump, spray or nebulizer may contain a solution or suspension of the activecompound, e.g. using a mixture of éthanol and the propellant as the solvent, which mayadditionally contain a lubricant, e.g. sorbitan trioleate. Capsules and cartridges (made,for example, from gelatin) for use in an inhaler or insufflator may be formulated tocontain a powder mix of a compound of the invention and a suitable powder base suchas lactose or starch. 012372 Aérosol or dry powder formulations are preferably arranged so that each metered doseor “puff” contains from 1 to 50 mg of a compound of the invention for delivery to thepatient. The overall daîly dose with an aérosol will be in the range of from 1 to 50 mgwhich may be administered in a single dose or, more usually, in divided dosesthroughout the day.
The compounds of the invention may also be formulated for delivery via an atomiser.Formulations for atomiser devices may contain the following ingrédients as solubilisers,emulsifiers or suspending agents: water, éthanol, glycerol, propylene glycol, lowmolecular weight polyethylene glycols, sodium chloride, fluorocarbons, polyethyleneglycol ethers, sorbitan trioleate, oleic acid.
Alternatively, the compounds of the invention can be administered in the form of asuppository or pessary, or they may be applied topically in the form of a gel, hydrogel,lotion, solution, cream, ointment or dusting powder. The compounds of the inventionmay also be dermally or transdermaily administered, for example, by the use of a skinpatch. They may also be administered by the ocular, pulmonary or rectal routes.
For ophthalmic use, the compounds can be formulated as micronized suspensions inisotonie, pH adjusted, stérile saline, or, preferably, as solutions in isotonie, pH adjusted,stérile saline, optionally in combination with a preservative such as a benzylalkonium^chloride. Alternatively, they may be formulated in an ointment such as petrolatum.
For application topically to the skin, the compounds of the invention can be formulatedas a suitable ointment containing the active compound suspended or dissolved in, forexample, a mixture with one or more of the following: minerai oil, liquid petrolatum, whitepetrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifyingwax and water. Alternatively, they can be formulated as a suitable lotion or cream,suspended or dissolved in, for example, a mixture of one or more of the following:minerai oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60,cetyl esters, wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
The compounds of the invention may also be used in combination with a cyclodextrin.Cyclodextrins are known to form inclusion and non-inclusion complexes with drug 012372 29 molécules. Formation of a drug-cyclodextrin complex may modify the solubility,dissolution rate, bioavailability and/or stability property of a drug molécule. Drug-cyclodextrin complexes are generally useful for most dosage forms and administrationroutes. As an alternative to direct complexation with the drug the cyclodextrin may beused as an auxiliary additive, e.g. as a carrier, diluent or solubiliser. Alpha-, beta- andgamma-cyclodextrins are most commonly used and suitable examples are described inWO-A-91/11172, WO-A-94/02518 and WO-A-98/55148.
For oral or parentéral administration to human patients the daily dosage levels ofcompounds of the invention will be from 0.01 to 30 mg/kg (in single or divided doses)and preferably will be in the range 0.01 to 5 mg/kg. Thus tablets will contain 1mg to 0.4gof compound for administration singly or two or more at a time, as appropriate. Thephysician will in any event détermine the actual dosage which will be most suitable forany particular patient and it will vary with the âge, weight and response of the particularpatient. The above dosages are, of course only exemplary of the average case andthere may be instances where higher or lower dosés are merited, and such are withinthe scope of the invention.
Oral administration is preferred. Preferably, administration takes place shortiy before aneffect is required.
For veterinary use, a compound of the invention is administered as a suitably acceptableformulation in accordance with normal veterinary practice and the veterinary surgeon willdétermine the dosing regimen and route of administration which will be most appropriatefor a particular animal.
Thus according to a further aspect, the invention provides a pharmaceutical formulationcontaining a compound of the invention and a pharmaceutically acceptable adjuvant,diluent or carrier.
The invention is illustrated by the following non-limiting examples in which the followingabbreviations and définitions are used:
Arbocel® filter agent br broad 012372
Boc
CDI δ d Δ
DCCI
DCM
DMF
DMSO ES+ ES"
Ex h HOBt
HPLC m/z min
MS
NMR
Prec
Prep q s t
Tf
TFA
THF
TLC TS+
WSCDI ferf-butoxycarbonyl carbonyldiimidazole
Chemical shift doublet heat dicyclohexylcarbodiimide dichloromethane N, W-dimethylformamide dimethylsulfoxide electrospray ionisation positive scan electrospray ionisation négative scan
Example hours 1 -hydroxybenzotriazole high pressure liquid chromatography mass spectrum peak minutes mass spectrum nuclear magnetic résonance precursor préparation quartet singlet triplet trifluoromethanesulfonyl trifluoroacetic acid tetrahydrofuran thin layer chromatography thermospray ionisation positive scan 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride 1H Nuclear magnetic résonance (NMR) spectra were in ail cases consistent with theproposed structures. Characteristic Chemical shifts (δ) are given in parts-per-milliondownfield from tetramethylsilane using conventional abbreviations for désignation of 5 major peaks: e.g. s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. 012372 31
The following abbreviations hâve been used for common solvents: CDCI3,deuterochloroform; DMSO, dimethylsulfoxide. The abbreviation psi means pounds persquare inch and LRMS means low resolution mass spectrometry. Where thin layerchromatography (TLC) has been used it refers to silica gel TLC using silica gel 60 F254 5 plates, R, is the distance travelled by a compound divided by the distance travelled bythe solvent front on a TLC plate. Melting points were determined using a Perkin ElmerDSC7 at a heating rate of 20°C/minute).
Where indicated, compounds were characterised as their hydrochloride salts. A typical 10 procedure for formation of hydrochloride salts is given in Example 12. The procedurecan be carried out with other solvents e.g. diethyl ether or DCM.
Commercial starting matériels were obtained from Aldrich Chemical Co, LancasterSynthesis Ltd or Acros Organics. 15 EXAMPLE 1 3-f(Methvlamino)methyn-4-F3-methvl-4-methvlsulfanvl)phenoxvl-benzenesulfonamide o o
The amide of Préparation 8 (760 mg, 2.07 mmol) was slurried in THF (10 mL) and the 20 resulting suspension was treated with borane.tetrahydrofuran complex (1M solution inTHF, 6.22 mL, 6.22 mmol) at room température. The resulting solution was heated atreflux for 5 hours under an atmosphère of dry nitrogen. The réaction was cooled to roomtempérature and treated cautiousiy with 6M HCl solution (6 mL). The resulting mixturewas heated at reflux for 30 min. After cooling to room température the mixture was 25 diluted with water (10 mL) and basified by cautious addition of potassium carbonatesolid. The aqueous layer was extracted with EtOAc (20 mL) which gave a precipitate inthe organic layer, and the aqueous layer was further extracted with DCM (2 x 20 mL).The EtOAc fraction was washed with 2M NaOH (20 mL) giving a clear two-phaseséparation and the basic layer was extracted with DCM (4 x 25 mL). Ail the organic 30 fractions were combined and washed with brine (20 mL), dried (MgSO4) and evaporated 012372 32 to a colourless oil. Purification by flash chromatography [SiO2; 95:5:0.5 to 90:10:1(EtOAc/ MeOH/ 880 NH3)J afforded a white powder of the desired amine (646 mg, 89%).δΗ (300 MHz, de-DMSO) 2.26 (3H, d), 2.32 (3H, d), 2.45 (3H, d), 3.75 (2H, d), 6.90 (3H,m), 7.25 (3H, br), 7.67 (1H, t) 7.98 (1H, d); MS m/z (TS+) 353 (MH+). 5
Compounds of formula Id, i.e. compounds of general formula I where R1 is methyl, R2 ishydrogen and R5 is -SO2NH2, shown in Table 1 were prepared in an analogous fashionto Example 1 from the precursors indicated.
Table 1
Example Precursor data 2 Prep 9 HCl sait: δΗ (CD3OD, 400 MHz) 2.80 (3H, s),3.42 (2H, m), 4.41 (2H, s), 6.86-7.00 (2H,m), 7.09 (1H, s), 7.23 (1H, d), 7.90 (1H, d), -8.05 (1H, s); MS m/z (TS+) 351 (MH+) 3 Prep 12 SMe HCl sait: δΗ (CD3OD, 300 MHz) 2.54 (3H, s),2.82 (3H, s), 4.43 (2H, s), 7.00 (1H, d), 7.20(1H, d), 7.34 (1H, s), 7.42 (1H, d), 7.95 (1H,d), 8.11 (1H, s); MS m/z (TS+) 373 (MH+) 4 Prep 11 SMe HCl sait: δΗ (CD3OD, 400 MHz) 2.45 (3H, s),2.73 (3H, s), 5.44 (2H, s), 6.97 (3H, m), 7.42(1 H, m), 7.89 (1H, m), 8.03 (1H, s); MS m/z(ES+) 357 (MH+) 5 Prep 10 HCl sait: δΗ (CD3OD, 400 MHz) 2.79 (3H, s),3.18 (2H, m), 4.38 (2H, s), 4.41 (2H, m), 6.68 (2H, m), 6.97 (1H, d), 7.13 (1H, d), 7.91 (1H, d), 8.03 (1H, s); MS m/z (TS+) 367(MH+) 6 Prep 13 HCl sait: ÔH (CD3OD, 400 MHz) 2.78 (3H, s),3.15 (2H, m), 4.38 (4H, m), 6.79 (1H, d), 6.85 (3H, m), 7.84 (1H, d), 8.00 (1H, s); MSm/z (ES+) 367 (MH+) 012372 33
Exemple Precursor Z data 7 Prep 14 HCl sait: ÔH (CD3OD, 400 MHz) 2.81 (3H, s),4.43 (2H, s), 5.09 (4H, s), 6.93 (1H, d), 7.12(2H, s+d), 7.40 (1H, d), 7.90 (1H, d), 8.08(1H, s); MS m/z (TS+) 335 (MH+) 8 Prep 15 HCl sait: δΗ (CD3OD, 400 MHz) 2.16 (2H,m), 2.80 (3H, s), 2.92 (4H, t), 4.40 (2H, s), 6.86 (1H, d), 6.94 (1H, d), 7.03 (1H, s), 7.30(1H, d), 7.88 (1H, d), 8.03 (1H, s); MS m/z(TS+) 333 (MH+) 9 Prep 16 Ψ,.. Me HCl sait: δΗ (CD3OD, 400 MHz) 2.32 (3H, s),2.43 (3H, s), 2.81 (3H, s), 4.41 (2H, s), 6.84(1H, d), 6.91 (1H, d), 7.06 (1H, s), 7.24 (1H,d), 7.89 (1H, d), 8.05 (1H, s); MS m/z (ES+)352 (MH+) 10 Prep 17 HCl sait: δΗ (CD3OD, 400 MHz) 2.78 (3H, s),4.21 (4H, s), 4.39 (2H, s), 6.89 (1H, d), 7.01(1H, d), 7.08 (1H, s), 7.38 (1H, d), 7.85 (1H,d), 8.02 (1H, s); MS m/z (TS*) 351 (MH+) 11 Prep 18 δΗ (CD3OD, 400 MHz) 2.76 (3H, s), 3.30(2H, m), 3.42 (2H, m), 4.33 (2H, s), 6.90(1H, d), 6.94 (1H, d), 7.00 (1H, s), 7.29 (2H,d), 7.89 (1H, d), 8.04 (1H, s); MS m/z (ES+)351 (MH+), (ES‘) 349 <M-H+) EXAMPLES 12 and 13 3-f(Dimethvlamino)methvll-4-f3-methvl-4-(methylsulfanvl)phenoxvl-benzenesulfonamide (Example 12) and 3-Î(dimethvlamino)methvll-A(-methvl-4-f3-methvl-4- 5 (methvlsulfanvl)phenoxvlbenzenesulfonamide (Example 13)
Formaldéhyde (37% aq. solution, 282 gL, 3.76 mmol) was added to a suspension of thesecondary amine from Example 1 (409 mg, 1.16 mmol) in DCM (20 mL) at roomtempérature under nitrogen. The resulting mixture was stirred for 15 minutes before the 10 addition of sodium triacetoxyborohydride (984 mg, 4.64 mmol). The resulting reactionmixture was stirred for 5 hours before being basified with saturated NaHCO3 solution (10mL) and extracted with DCM (3x20 mL). The organic iayers were washed with brine (10 012372 34 mL), dried (MgSO4) and evaporated to a yellow oil. This was purified by HPLC(Phenomonex Luna C1B 75 χ 4.6 mm column, CH3CN, H2O, TFA). Fractions containingthe major product were evaporated and the residue was treated with sat. NaHCO3 ·solution (5 mL), and extracted with DCM (3x30 mL). The combined organic fractionswere washed with brine (30 mL), dried (MgSO4) and evaporated to give a white foam(155 mg, 36%) of Example 12; δΗ (300 MHz, CDCI3) 2.30 (6H, s), 2.35 (3H, s), 2.48 (3H,s), 3.60 (2H, s), 6.83 (3H, m), 7.20 (1H, m), 7.28 (2H, s), 7.74 (1H, d), 8.08 (1H, s); MSm/z (TS+) 367 (MH+). A minor product was also obtained after HPLC purification. The relevant fractions wereevaporated and the residue was treated with sat. NaHCO3 solution (5 mL), and extractedwith DCM (2x30 mL). The combined organic fractions were washed with brine (30 mL),dried (MgSO4) and evaporated to a gum. This was taken up in DCM (5 mL), treated with1M ethereal HCl (2 mL) and evaporated to give a white powder (39 mg, 9%) of Example13; HCl sait: ÔH (CDCI3, 300 MHz) 2.30 (6H, s), 2.35 (3H, s), 2.48 (3H, s), 3.60 (2H, s),6.83 (3H, m), 7.20 (1H, m), 7.28 (2H, s), 7.74 (1H, d), 8.08 (1H, s); MS m/z (TS+) 381(MH+).
In a repeat reaction, using 1 équivalent of formaldéhyde to the amine of Example 1,Example 12 was obtained in 78% yield after column chromatography [SiO2; 95:5:0.5 to90:10:1 (EtOAc/ MeOH/ 880 NH3)j. This was taken up in EtOAc and converted to theHCl sait by the addition of 1M ethereal HCl. The resulting precipitate was filtered anddried in vacuo to give Example 12 HCl sait; m.p. 188°C.
Alternatively, Example 12 can also be formed from the amine of Example 1 by themethod of Example 110.
Example 12 was also prepared as follows. A solution of the hydrochloride sait from Example 94 (20 g) in trifluoroacetic acid (100mL) was slowly added to a solution of chlorosulfonic acid (72 g) keeping the températurebetween 0 and 5 °C. After 1 h the reaction mixture was quenched slowly into water (200mL), at 0-20 °C. The mixture was then extracted with dichloromethane (200 mL) andseparated. The aqueous layer was then extracted with dichloromethane (60 mL) andseparated. The combined organic layers were washed with water (200 mL). The layers 072372 35 were separated and the dichloromethane removed in vacuo to give a solid. Acetonitrile(240 mL) was added and to this slurry was added phosphorus oxychloride (28.8 mL).
The solution was then heated at reflux overnight. The reaction mixture was cooled toroom température and quenched into a stirred mixture of ammonia (90 mL),dichloromethane (240 mL) and water (100 mL), keeping the température between 0 °Cand 10 °C. The mixture was adjusted with ammonia (if necessary) to greater than pH8.After 15 mins the reaction mixture was allowed to warm to room température and thelayers separated. The organic layer was concentrated in vacuo to give a thick brown oil.This was dissolved in acetone (100 mL) and slurried with carbon (Norit SX plus, 50%w/w) filtered and treated with another charge of carbon (Norit SX plus, 50%w/w). Thismixture was again filtered and the solution concentrated, replacing with water (200 mL).The slurry was granulated, filtered and vacuum dried overnight to give the title productas a creamy white solid (yield 40%). EXAMPLES 14 and 15 4-(2.3-Dihvdro-1.4-benzoxathiin-7-vloxv)-3-f(dimethvlamino)methvn-benzenesulfonamide and 4-(2,3-dihvdro-1.4-benzoxathiin-7-yloxv)-3-f(dimethvlamino)methvn-<V- methvlbenzenesulfonamide
These compounds were formed in an analogous fashion to Examples 12 and 13 startingfrom the secondary amine of Example 5. EXAMPLE 14. HCl sait: δΗ (CD3OD, 400 MHz) 2.97 (6H, s), 3.18 (2H, m), 4.42 (2H, m),4.52 (2H, s), 6.68 (2H, d), 6.99 (1H, d), 7.14 (1H, d), 7.94 (1H, d), 8.07 (1 H, s); MS m/z(ES+) 381 (MH+). EXAMPLE 15. HCl sait: δΗ (CD3OD, 400 MHz) 2.56 (3H, s), 2.80 (6H, s), 3.17 (2H, m),4.35 (2H, s), 4.41 (2H, m), 6.68 (2H, m), 6.98 (1H, d), 7.13 (1H, d), 7.81 (1H, d), 8.00(1H, s); MS m/z (ES+) 395 (MH+).
Compounds of formula le, i.e. compounds of general formula I where R1 and R2 aremethyl and R5 is -SO2NH2) shown in Table 2 were prepared according to Example 12 012372 36 from îhe precursors indicated. The /V-methyl sulfonamides analogous to Example 13were not isolated in these reactions and HPLC purification was not required.
V
H2NZ (le)
Table 2
Example Precursor data 16 Example 2 HCl sait: δΗ (CD3OD, 400 MHz) 2.98 (6H, s), 3.41(2H, m), 4.58 (2H, s), 6.95 (2H, m), 7.08 (1H, s), 7.25 (1 H, d), 7.95 (1H, d), 8.05 (1H, s); MS m/z(ES+) 365 (MH+) 17 Example 3 SMe HCl sait: δΗ (CD3OD, 300 MHz) 2.54 (3H, s), 2.98(6H, s), 4.53 (2H, s), 7.01 (1H, d), 7.20 (1H, dd), 7.33 (1H, s), 7.42 (1H, d), 7.99 (1H, d), 8.04 (1 H, s);MS m/z (TS+) 387 (MH+) 18 Example 4 SMe HCl sait: δΗ (CD3OD, 400 MHz) 2.43 (3H, s), 2.88(6H, s), 4.42 (2H, s), 6.99 (3H, m), 7.42 (1H, t), 7.92(1H, d), 8.06 (1H, s); MS m/z (ES*) 371 (MH*) 19 Example 6 θ·^ HCl sait: δΗ (CD3OD, 400 MHz) 2.89 (3H, s), 3.17(2H, m), 4.39 (2H, m), 4.47 (2H, s), 6.78 (1H, d), * 6.87 (3H, m), 7.89 (1 H, d), 8.01 (1H, s); MS m/z(TS+) 367 (MH*) 20 Example 7 TFA sait: δΗ (CDCI3, 400 MHz) 2.22 (6H, s), 3.60(2H, t), 5.05 (4H, d), 6.75-6.90 (3H, m), 7.20 (1H, d),7.60 (1H, m), 8.00 (1H, m); MS m/z 349 (MH*) 21 Example 8 HCl sait: δΗ (CD3OD, 400 MHz) 2.10 (2H, m), 2.85-3.00 (10H, m), 4.30 (1H, brs), 4.50 (2H, s), 6.80-6.95 (2H, m), 7.05 (1H, s), 7.25 (1H, d), 7.80 (1H,d), 8.10 (1H, s); MS m/z (ES*) 347 (MH*) 22 Example 10 HCl sait: δΗ (CD3OD, 400 MHz) 2.93 (6H, s), 4.21(4H, s), 4.50 (2H, s), 6.91 (1H, d), 7.02 (1H, d), 7.09(1H, s), 7.37 (1H, d), 7.91 (1 H, d), 8.05 (1H, s); MSm/z (TS*) 365 (MH*) 012372 37
Example Precursor il Z data 23 Example ' 11 * HCl sait: δΗ (DMSO-d6, 400 MHz) 2.76 (6H, s), 3.21(2H, t), 3.38 (2H, t), 4.39 (2H, s), 6.80 (1H, d), 6.86(1H, d), 7.10 (1H, s), 7.28 (3H, m), 7.80 (1H, d), 8.06 (1H, s), 10.23 (1H, br); MS m/z (TS+) 365(MH+) EXAMPLE 24 3-f(Dimethvlamino)methvn-4-f4-methvl-3-(methylsulfanvl)phenoxv1-benzenesulfonamide
5 The title compound was prepared from the secondary amine of Example 9 by the method of Example 110; δΗ (CD3OD, 400 MHz) 2.27 (3H, s), 2.41 (3H, s), 2.61 (6H, s),4.19 (2H, s), 6.76 (1H, d), 6.88-6.93 (2H, m), 7.20 (1H, d), 7.82 (1H, d), 8.03 (1H, d); MSm/z (TS+) 367 (MH+). 10 EXAMPLE 25 /V-(5-Methoxy-2-f3-methyl-4-(methvlsulfanvl)phenoxvlbenzvn-/V,A/-dimethvlamine
Dimethylamine hydrochloride (424 mg, 5.2 mmol), Et3N (725 pL, 5.2 mmol), AcOH (298pL, 5.2 mmol) and sodium triacetoxyborohydride (1.10 g, 5.2 mmol) were added to a 15 solution of the aldéhyde from Préparation 24 (1.00 g, 3.47 mmol) in THF (15 mL) andDCM (15 mL) and the mixture was stirred at room température for 16 h. After removingthe solvent in vacuo the residue was taken up in 2M HCl (20 mL) and washed with ether(2x15 mL). The aqueous layer was basified with NaOH pellets and extracted with DCM(4x20 mL). The combined DCM extracts were washed with brine, dried (MgSO4) and
20 evaporated. The residue was taken up in a small amount of DCM and treated with 1M 012372 3θ ethereal HCl to precipitate the HCl sait. This was filtered, washed with ether and dried togive a white solid (936 mg) contaminated with triethylamine hydrochloride. This wasdissolved in 1M NaOH (10 mL) and extracted with EtOAc (3x15 mL). The organic *extracts were washed with brine (10 mL), dried (MgSO4) and evaporated before being 5 re-dissolved in EtOAc and evaporated again. The residue was taken up in DCM andtreated with 1M ethereal HCl to precipitate the HCl sait, which was filtered, washed withether and dried to give a white solid (635 mg, 52%); δΗ (CDCI3, 300 MHz) 2.35 (3H, s), 2.45 (3H, s), 2.79 (6H, s), 3.90 (3H, s), 4.21 (2H, s), 6.70 (1H, d), 6.73 (1H, s), 6.90 (2H,m), 7.18 (1H, d), 7.65 (1H, s), 12.83 (1H, brs); MS m/z (TS+) 318 (MH+). 0
Compounds of formula If, i.e. compounds of general formula i where R1 and R2 aremethyl, shown in Table 3 were prepared according to Example 25 from the precursorsindicated.
(if) 15 Table 3
Example Precursor R4 Rs 9-· 2 data 26 Prep 25 H F HCl sait: δΗ (CDCI3, 300 MHz) 2.23(6H, s), 3.41 (2H, s), 6.98 (2H, m),7.34 (2H, m), 7.48 (1H, dd), 7.98(1H, d), 8.08 (1H, d), 8.80(1 H, s); MS m/z (TS+) 297 (MH+) 27 Prep 39 H -no2 0,. SMe δΗ (CDCI3, 300 MHz) 2.32 (6H, s),2.36 (3H, s), 2.47 (3H, s), 3.60 (2H,s), 6.80 (1H, d), 6.87 (2H, d), 7.19(1H, d), 8.03 (1H, d), 8.40 (1H, d); MS m/z (ES*) 333 (MH+) 28 Prep 38 H -no2 Taken on crude at ~75% purity; δΗ(CDCt3, 400 MHz) 2.33 (6H, s), 3.24 (2H, m), 3.38 (2H, m), 3.66(2H, s), 6.76 (2H, m), 6.86 (1H, m),7.17 (1H,d), 8.00 (1H, dd), 8.37(1H, d) 012372 39
Example Precursor R4 R5 A data 2 29 Prep 26 H H δΗ (CDCI3, 300 MHz) 2.28 (6H, s), 3.50 (2H, s), 7.03 (2H, m), 7.20-7.40 (3H, m), 7.52 (2H, m), 7.98(1H, d), 8.09 (1H, d), 8.81 (1H, m); MS m/z (TS+) 279 (MH+) 30 Prep 27 H H HCl sait: δΗ (d6-DMSO, 300 MHz) 2.77 (6H, d), 4.38 (2H, d), 7.08 (1H,d), 7.36 (1H, t), 7.52 (1H, t), 7.62(1H, s), 7.80 (1H, d), 7.91 (1H, dd),8.10 (1H, d), 9.25 (1H, s), 9.52 (1H,s); MS m/z (TS+) 280 (MH+) 31 Prep 29 H H N s— Maleate sait: δΗ (d6-DMSO, 300 MHz) 2.77 (6H, s), 4.33 (2H, s), 5.98 (2H, s), 6.87 (1H, d), 7.21 (1H,dt), 7.30(1 H, dd), 7.41 (1H, dt), 7.58 (1H, dd), 7.88 (1H, d), 8.11(1H, d), 9.32 (1H, s); MS m/z 285(MH+) 32 Prep 33 H Br HCl sait: δΗ (DMSO-d6, 400 MHz) 2.77 (6H, d), 3.23 (3H, m), 3.39(2H, m), 4.32 (2H, d), 6.75 (2H, m),7.03 (1H, s), 7.26 (1H, d), 7.57 (1H,dd), 7.87 (1H, s), 10.06 (1H, br, s);MS m/z (ES+) 366 (MH+) 33 Prep 32 Br H SMe δΗ (CDCI3,400 MHz) 2.22 (6H, s),2.30 (3H, s), 2.41 (3H, s), 3.41 (2H,s), 6.76 (2H, m), 6.94 (1H, s), 7.18(1H, s), 7.21 (1H, obs), 7.30 (1H,d); MS m/z (TS+) 366/368 (MH+) EXAMPLE 34 3-r(Dimethvlamino)methvll-/V-methvl-4-(6-quinolinvloxy)benzenesulfonamide
5 Chlorosulfonic acid (106 gL, 1.6 mmol) was added to a solution of Example 29 (50 mg, 0.16 mmol) in DCM (2 mL) and the mixture was stirred for 3 h at room température.Water (2 mL) was added, the mixture was adjusted to pH 6 with sat aq NaHCO3 andextracted with DCM (2x5 mL). The organic extracts were dried (MgSO4) and filtered and 4 -- 012372 40 8M methylamine in EtOH (0.3 mL) was added. After standing for 1 h the solvent wasremoved in vacuo and the residue was purified by column chromatography [SiO2;95:5:0.5 (DCM/ MeOH/ 880 NH3)]. The product was taken up in EtOAc and converted tothe HCl sait by the addition of ethereal HCl. This gave the desired product as a 5 hygroscopic solid (3 mg, 5%); δΗ (CD3OD, 300 MHz) 2.60 (3H, s), 2.99 (6H, s), 4.60 (2H,s), 7.21 (1H, d), 7.96 (1H, d), 8.04 (3H, m), 8.19 (1H, s), 8.38 (1H, d), 9.03 (1H, d), 9.18(1H, d); MS m/z (TS+) 371 (MH+). EXAMPLE 35 10 3-f(Methvlamino)methvn-4-(6-quinolinvloxv)benzenesulfonamide
Trifluoroacetic anhydride (0.96 mL, 6.8 mmol) was added to a solution of the amine ofExample 48 (900 mg, 3.4 mmol) and triethyiamine (1.9 mL, 13.6 mmol) in CH2Cl2 (15mL) at 0°C and the mixture was stirred for 5 min. The solvent was removed in vacuo and 15 the residue was partitioned between CH2CI2 and water. The organic layer was washedwith brine, dried (MgSO4) and evaporated to give a yellow oil, which was used withoutfurther purification. This crude oil was taken up in CH2CI2 (20 mL), cooled to 0°C and -CISO3H (2.4 mL, 36.1 mmol) was added dropwise. The mixture was allowed to warm toroom température and stirred for 4 h before being poured into ice water. The mixture 20 was extracted with CH2CI2 (50 mL) and the organic layer was treated with a saturatedsolution of NH3 in MeOH (10 mL). After stirring for 4 h 1M LiOH (20 mL) was added andstirring was continued overnight. Tic analysis indicated reaction was incomplète sofurther 1M LiOH (50 mL) was added and the mixture was stirred for 2 h. The mixturewas acidified to pH 8 with 2M HCl and extracted with CH2CI2 (3x200 mL). The combined 25 organic extracts were dried (MgSO4) and evaporated and the residue was triturated withether to give the title compound (500 mg, 43%) as a yellow solid; δΗ (CDCI3, 400 MHz)2.46 (3H, s), 3.87 (2H, s), 6.93 (1H, d), 7.25 (1H, s), 7.39 (1H, t), 7.42 (1H, d), 7.78 (1H,d), 8.00-8.08 (2H, m), 8.12 (1H, d), 8.86 (1H, s); MS m/z (ES+) 344 (MH+). 012372 EXAMPLE 36 /VT5-Bromo-2-(2,3-dihvdro-1-benzothien-5-vloxy)benzvn-A/-methvlamine 41
The aldéhyde of Préparation 19 (1.10 g, 3.28 mmol) was dissolved in 8M methylamine in 5 EtOH (4.1 mL, 32.8 mmol) and stirred for 5 h before the portionwise addition of NaBH4(372 mg, 9.83 mmol) over 30 min. EtOH (100 mL) was added and the reaction wasstirred for 16 h before being concentrated in vacuo. The residue was quenched with 6MHCl until pH 1 and the precipitated HCl sait was collected by filtration, washed with water(100 mL) and dried in vacuo to give a crystalline solid (1.04 g, 82%); δΗ (CDCI3l 400 10 MHz) 2.62 (3H, s), 3.26 (2H, t), 3.41 (2H, t), 4.18 (2H, s), 6.66 (1H, d), 6.90 (1H, d), 7.03(1H, s), 7.19 (1H, d), 7.39 (1H, d), 7.80 (1H, s); MS m/z (ES+) 350, 352 (MH+).
Compounds of formula Ig, i.e. compounds of general formula I where R1 and R4 arehydrogen and R2 is methyl, shown in Table 4 were prepared according to Example 36 15 from the precursors indicated. For those compounds which were isolated as the freebase the reaction mixture was partitioned between 2M HCl and ether after removal ofthe réaction solvent in vacuo. The aqueous layer was then basified and extracted withDCM, the DCM layer being dried (MgSO4) and evaporated to give the desired secondaryamine.
20 012372 42,
Table 4
Example Precursor R5 Z data 37 Prep 20 Br (Γί SMe HCl sait: δΗ (d6-DMSO, 300 MHz) 2.48(3H, s), 2.59 (3H, s), 4.18 (2H, s), 6.88(1H, d), 7.01 (1H, d), 7.16 (1H, d), 7.45(1H, t), 7.59 (1H, d), 7.91 (1H, s); MSm/z (TS+) 356, 358 (MH+) 38 Prep 21 Br U δΗ (CDCÏa, 400 MHz) 2.43 (3H, s), 3.11 (2H, t), 3.78 (2H, s), 4.41 (2H, t), 6.44(1 H, s), 6.51 (1H, d), 6.77 (1H, d), 6.98(1H, d), 7.31 (1H, d), 7.55 (1H, s); MSm/z (ES+) 366, 368 (MH+) 39 Prep 22 Br (Γί SMe δΗ (CDCIa, 400 MHz) 2.41 (3H, s), 2.45(3H, s), 3.72 (2H, s), 6.77 (1H d), 6.85(1H, d), 6.99 (1H, s), 7.18 (1H, d), 7.36(1 H, d), 7.59 (1H, s); MS m/z (TS+) 372,374 (MH+) 40 Prep 38 -no2 δΗ (CDCl3, 300 MHz) 2.55 (3H, s), 3.30(2H, m), 3.43 (2H, m), 3.95 (2H, s), 6.80(2H, m), 6.91 (1H, s), 7.22 (1H, d), 8.05(1H, d), 8.40 (1H, s); MS m/z (ES+) 317(MH+) 41 Prep 36 -no2 ôk δΗ (CDCI3, 400 MHz) 2.45 (3H, S), 3.10(2H, m), 3.86 (2H, s), 4.40 (2H, m), 6.53(2H, m), 6.80 (1H, d), 7.01 (1H, d), 8.00(1H, d), 8.27 (1H, s); MS m/z (TS+) 333(MH+) 42 Prep 40 -no2 δΗ (CDCI3, 400 MHz) 2.14 (2H, m), 2.52(3H, s), 2.93 (4H, t), 3.92 (2H, s), 6.78 '(1H, d), 6.81 (1H, d), 6.91 (1H, s), 7.22(1H, d), 8.02 (1H, dd), 8.29 (1H, s); MSm/z (TS+) 299 (MH+) 43 Prep 24 -OMe SMe HCl sait: δΗ (CDCI3, 300 MHz) 2.35 (3H,s), 2.45 (3H, s), 2.60 (3H, s), 3.84 (3H,s), 4.17 (2H, s), 6.80 (1H, d), 6.82 (1H,s), 6.88 (2H, s), 7.15 (1 H, d), 7.42 (1H,s), 9.85 (2H, brs); MS m/z (TS+) 304(MH+) 44 Prep 23 Br SMe δκ (CDCI3, 300 MHz) 2.35 (3H, s), 2.45(6H, s), 3.77 (2H, s), 6.73 (2H, m), 6.80(1H, s), 7.19 (1H, d), 7.32 (1H, d), 7.57(1H, s); MS m/z (TS+) 352, 354 (MH+) 45 Prep 30 H î. SMe HCl sait: δΗ (d6-DMSO, 400 MHz) 2.22(3H, s), 2.42 (3H, s), 2.58 (3H, s), 4.18(2H, s), 6.78 (1H, d), 6.96 (1H, d), 6.99(1H, s), 7.18 (1H, t), 7.25 (1H, d), 7.38(1H, t), 7.60 (1H, d); MS m/z (ES+) 274(MH+) 012372 43 Éxample Precursor R5 tÇXY Z data 46 Pcep 31 H HCl sait: δΗ (CDCI3, 400 MHz) 2.55 (3H,brs), 3.21 (2H, t), 3.32 (2H, m), 4.17(2H, s), 6.76 (1H, d), 6.84 (1H, d), 6.99(1H, s), 7.04 (1H, m), 7.12 (1H, d), 7.28(1H, obs), 7.61 (1H, d); MS m/z (ES+)272 (MH+) 47 Prep 28 H Maîeate sait: δΗ (DMSO-d6, 400 MHz) 2.60 (3H, s), 4.19 (2H, s), 5.99 (2H, s),7.03 (1H, d), 7.29 (1H, m), 7.37 (1H, s),7.45 (3H, m), 7.60 (1H, d), 8.06 (1H, d),8.37 (1H, d), 8.74 (2H, br), 8.83 (1H,dd); MS m/z 264 (MH+) 48 Prep 26 H δΗ (CDCI3, 300 MHz) 2.64 (3H, s), 4.25(2H, s), 6.89 (1H, d), 7.19 (1H, t), 7.30-7.41 (2H, m), 7.45 (1H, s), 7.49 (1H, d),7.69 (1H, d), 8.08 (1H, d), 8.16 (1H, d),8.87 (1H, d); MS m/z (ES+) 529 (2M+H+) 49 Prep 34 -CN HCl sait: δΗ (CD3OD, 400 MHz) 2.81(3H, s), 3.30 (1H, br), 4.42 (2H, s), 7.17(1H, br), 7.82 (1H, br), 8.06 (1H, br), 8.11 (3H, br), 8.39 (1H, br), 9.18 (1H,br), 9.21 (1H, br); MS m/z (ES+) 290(MH+) 3 - 2M Methylamine in MeOH (2 equiv.) and TKO’Pr^ (2 equiv.) in EtOH (~0.1 M soin of aldéhyde) were used in place of methylamine in EtOH. After isolation of the free base itwas converted to the maleate sait by standard methods. 5 EXAMPLE 50 (2g)-3-{4-(2.3-Dihvdro-1-benzothien-6-vloxv)-3-((dimethylamino)methvnphenvl)-2- prooenamide
A mixture of the bromide of Example 32 (400 mg, 1.10 mmol), acrylamide (156 mg, 2.1910 mmoi), triethylamine (0.38 mL, 2.74 mmol), palladium II acetate (12.5 mg, 0.06 mmol) and tri-o-tolylphosphine (33.4 mg, 0.11 mmol) in acetonitrile (15 mL) was heated atreflux for 72 h. After cooling to room température the solvent was removed in vacuo and 012372 44 the residue was partitiôned between EtOAc (50 mL) and 2M HCl (50 mL). The aqueous »phase was basified with 2M NaOH and extracted with EtOAc (3x50 mL). The combinedbasic extracts were dried (MgSO4) and evaporated. The residue was purified by column *chromatography [SiO2; 96:4:0.5 (DCM/ MeOH/ 880 NH3) increasing polarity to 90:10:1] 5 to give the title compound (196 mg, 50%) as a beige foam; δΗ (CDCI3, 400 MHz) 2.28(6H, s), 3.24 (2H, t), 3.38 (2H, t), 3.51 (2H, s), 5.73 (2H, br), 6.42 (1H, d), 6.59 (1H, dd), 6.82 (2H, m), 7.10 (1 H. d), 7.32 (1H, d), 7.60 (1H, d), 7.69 (1H, s); MS m/z (ES+) 355 (MH+). 10 EXAMPLE 51 3-(4-(2.3-Dihvdro-1-benzothien-6-yloxv)-3-[(dimethvlamino)methvnphenvl)propanamide o A solution of Sml2 in THF (0.1 M, 21.9 mL, 2.19 mmol) was added to a solution of thealkene of Example 50 (194 mg, 0.55 mmol) in THF (5 mL) under nitrogen followed by 15 water (1 mL). After stirring at room température for 10 min the reaction was quenchedwith 6M NaOH (10 mL) and stirred for 30 min. The organic phase was separated and theaqueous phase was extracted with EtOAc (2x20 mL). The combined organic layers wéredried (MgSO4) and evaporated to an oil, which was purified by column chromatography[SiO2; 93:7:1 (DCM/ MeOH/ 880 NH3) increasing polarity to 90:10:1] to give the title 20 compound (90 mg, 46%); δΗ (CDCI3, 400 MHz) 2.25 (6H, s), 2.54 (2H, t), 2.97 (2H, t),3.22 (2H, t), 3.36 (2H, t), 3.42 (2H, s), 5.20-5.46 (2H, br), 6.54 (1H, d), 6.73 (1H, s), 6.81(1H, d), 7.05 (2H, m), 7.31 (1H, s); MS m/z (TS+) 357 (MH+).
Compounds of formula If, i.e. compounds of general formula I where R1 and R2 are 25 methyl, shown in Table 5 were prepared according to Préparation 50 from theprecursors indicated. 012372 45
(If)
Table 5
Example Precursor R4 R5 data 52 Example 32 H -CO2Me δΗ (CDCI3, 400 MHz) 2.29 (6H,s), 3.26 (3H, m), 3.39 (2H, m),3.54 (2H, s), 3.89 (3H, s), 6.62(1H, d), 6.84 (2H, m) 7.13 (1H,d),.7.86 (1H,d), 8.12 (1H, s); MS m/z (TS+) 344 (MH+) 53 Example 33 -CO2Me H ά. SMe δΗ (CDCI3, 400 MHz) 2.24 (6H,s), 2.33 (3H, s), 2.42 (3H, s),3.48 (2H, s), 3.82 (3H, s), 6.73(2H, m), 7.14(1 H, d), 7.50(1H, s), 7.55 (1H, d), 7.78 (1H,d); MS m/z (TS+) 346 (MH+) 5 Compounds of formula If, i.e. compounds of general formula I where R1 and R2 aremethyl, shown in Table 6 were prepared according to Préparation 55 from theprecursors indicated.
Table 6
Example Precursor R4 R5 Z data 54 Example 52 H -CO2H δΗ (CD3OD, 400 MHz) 2.95 (6H, s),3.29 (2H, m), 3.42 (2H, m), 4.52 (2H,s), 6.80 (1H, d), 6.89 (1H, d), 7.03(1H, s), 7.29 (1H, d), 8.06 (1H, d), 8.23 (1H, s); MS m/z (TS+) 330 (MH+) 55 (-80% purity) Example 55 -CO2H H SMe δΗ (CD3OD, 400 MHz) 2.27 (3H, s),2.42 (3H, s), 2.88 (6H, s), 4.43 (2H,s), 6.95 (2H, m), 7.26 (1H, m), 7.42(2H, m), 7.72(1 H, m) 012372 46
Compounds of formula If, i.e. compounds of general formula I where R1 and R2 aremethyl, shown in Table 7 were prepared according to Préparation 59 from theprecursors indicated. 5 Table 7
Example Precursor R4 R5 il z data 56 Example 54 H -conh2 SH (CDCI3, 400 MHz) 2.27 (6H, s),3.25 (2H, m), 3.38 (2H, m), 3.54(2H, s), 5.90-6.38 (2H, br), 6.59(1H,d), 6.80 (1H, s), 6.86 (1H,d),7.11 (1H, d), 7.71 (1H, d), 7.92 (1H;s); MS m/z (TS+) 329 (MH+) 57 Example 55 -conh2 H SMe HCI sait: δΗ (CD3OD, 400 MHz) 2.32 (3H, s), 2.43 (3H, s), 2.94 (6H,s), 4.47 (2H, s), 6.98 (2H, br), 7.27(1H, br), 7.36(1 H, br), 7.62 (1H,br); MS m/z (TS+) 331 (MH+)
Compounds of formula If, i.e. compounds of general formula I where R1 and R2 aremethyl, shown in Table 8 were prepared according to Préparation 69 from theprecursors indicated
Table8
Example Precursor R4 R5 y-· Z data J 58 Example 52 H -CH2OH HCl sait: δΗ (DMSO-d6, 400 MHz)2.76 (6H, s), 3.22 (2H, m), 3.40(2H, m), 4.30 (2H, s), 4.49 (2H, s),5.27 (1 H, br, s), 6.68 (1H, d), 6.83(1H, d), 6.97 (1H, s), 7.25 (1H, d),7.37 (1H, d), 7.60 (1H, s), 10.07(1H, br); MS m/z (TS+) 316 (MH+) 59 Exampie 53 -CH2OH H SMe HCl sait: δΗ (CD3OD, 400 MHz) 2.34 (3H, s), 2.46 (3H, s), 2.90 (6H,s), 4.40 (2H, s), 4.55 (2H, s), 6.89(1H, s), 6.95 (2H, m), 7.18 (1H, d),7.28 (1H, d), 7.50 (1H, d); MS m/z(TS+) 318 (MH+) 012372 47 4-(2,3-Dihvdro-1-benzothien-5-yloxv)-3-i(methvlamino')methvnbenzamide EXAMPLE 60
The protected amine of Préparation 59 (317 mg, 0.76 mmoi) was dissolved in a 5 saturated solution of HCl in DCM (25 mL) at 0°C and left for 1 h before being neutralisedby the addition of 10% aq K2CO3 (25 mL). Water (50 mL) was added and the layers wereseparated. The aqueous layerwas extracted with DCM (25 mL) and the combinedorganic layers were dried (MgSO4) and evaporated. The resulting oil was dissolved inEtOAc (10 mL) and treated with 1M ethereal HCl (1 mL). The white precipitate was 10 collected by filtration and dried in vacuo to give the desired product (211 mg, 77%); δΗ(CD3OD, 400 MHz) 2.77 (3H, s), 3.35 (2H, obs), 3.39 (2H, t), 4.34 (2H, s), 6.79 (1H, d),6.90 (1H, dd), 7.02 (1H, s), 7.21 (1H, d), 7.83 (1 H, d), 8.00 (1H, s); MS m/z (TS+) 315(MH+). 15 Compounds of formula Ig, i.e. compounds of general formula I where R1 and R4 arehydrogen and R2 is methyl, shown in Table 9 were prepared according to Example 60from the precursors indicated.
Y 01237 2 48 ,
Table 9
Ex Prec R5 data 61 Prep 61 „A S OMe HCl sait: δΗ (CDC13, 400 MHz) 2.77 (3H, d),3.35 (2H, obs), 3.36 (3H, s), 3.39 (2H, t), 3.51 (4H, s), 4.35 (2H, S), 6.80 (1H, d), 6.90 (1H, dd), 7.01 (1H, s), 7.21 (1H, d), 7.79 (1H, d), 7.96 (1H, s); MS m/z (TS+) 373 (MH+) 62 Prep 60 Me % HCl sait: δΗ (CD3OD, 400 MHz) 2.77 (3H, s) , 2.88 (3H, s), 3.35 (2H, obs), 3.39 (2H, t) , 4.35 (2H, s), 6.79 (1H, d), 6.90 (1H, dd),7.01 (1H, s), 7.20 (1H, d), 7.78 (1H, d), 7.96 (1H, s); MS m/z (TS+) 329 (MH+) 63 Prep 62 rÇA n HCl sait: δΗ (d6-DMSO, 300 MHz) 2.52 (3H,obs), 2.61 (3H, s), 4.21 (3H, s), 6.90 (1H,d), 7.07 (1H, d), 7.19 (1H, d), 7.40 (1H,brs), 7.48 (1H, t), 7.92 (1H, d), 7.96 (1H,s), 8.21 (1H, s); MS m/z (TS+) 321 (MNH4+) 64 Prep 63 Me SMe HCl sait: δΗ (d6-DMSO, 300 MHz) 2.52 (3H,obs), 2.60 (3H, s), 2.79 (3H, d), 4.21 (2H,s), 6.89 (1H, d), 7.07 (1H, d), 7.19 (1H, d), 7.48 (1H, t), 7.85 (1H, d), 8.19 (1H, s), 8.48 (1H, d); MS m/z (TS+) 335 (MH+) 65 Prep 64 0 S OMe HCl sait: δΗ (d6-DMSO, 300 MHz) 2.52 (3H,obs), 2.60 (3H, s), 3.27 (3H, s), 3.46 (4H,m), 4.22 (2H, s), 6.91 (1H, d), 7.08 (1H, d),7.20 (1H, d), 7.50 (1H, t), 7.89 (1H, d), 8.10 (1H, s), 8.58 (1H, brs); MS m/z (TS+)379 (MH+) 66 Prep 65 „A SMe HCI sait: δΗ (d6-DMSO, 300 MHz) 2.52 (3H,obs), 2.60 (3H, t), 4.11 (2H, s+H2O), 6.82(1H, d), 7.21 (1H, d), 7.40 (3H, s+d), 7.88(1H, d), 7.96 (1H, brs), 8.21 (1H, s); MSm/z (ES*) 337 (MH*) 67 Prep 66 Me SMe HCl sait: δΗ (d6-DMSO, 300 MHz) 2.52 (3H,obs), 2.60 (3H, t), 2.79 (3H, d), 4.22 (2H,t), 6.94 (1H, d), 7.22 (1H, d), 7.40 (2H,s+d), 7.83 (1H, d), 8.19 (1H, d), 8.46 (1H,d); MS m/z (ES*) 351 (MH*) 68 Prep 67 0 <A δΗ (CDCIs, 400 MHz) 2.41 (3H, s), 3.08(2H, m), 3.80 (2H, s), 4.37 (2H, m), 5.94-6.36 (2H, brd), 6.46 (1H, s), 6.49 (1H, d),6.81 (1H, d), 6.96 (1H, d), 7.65 (1H, d), 7.86 (1H, s); MS m/z (TS*) 331 (MH*) 012372 49-
Ex 3rec R5 data 69 Prep 68 OMe ιΓί HCl sait: δΗ (CDCI3, 400 MHz) 2.42 (3H, s),3.08 (2H, m), 3.44-3.50 (4H, m), 3.80 (2H,s), 4.40 (2H, m), 6.45 (1H, s), 6.49 (1H, d), 6.62 (1H, brs), 6.83 (1H, d), 6.96 (1H, d), 7.62 (1H, d), 7.78 (1 H, s); MS m/z (TS*) 390 (MH+) 70 Prep 70 HO'''”''*. C^X.F SMe HCl sait: ÔH (d6-DMSO, 300 MHz) 2.48 (3H,s), 2.58 (3H, s), 4.12 (2H, s), 4.50 (2H, d), 5.32 (1H, t), 6.92 (2H, m), 7.03 (1H, dd), 7.39 (1H, dd), 7.46 (1H, d), 7.60 (1H, s); MS m/z (TS+) 308 (MH+) 71 Prep 69 HO'^X ιΓί SMe HCl sait: δΗ (d6-DMSO, 300 MHz) 2,52 (3H,obs), 2.58 (3H, t), 4.10 (2H, s+H2O), 4.48(2H, s), 6.94 (1H, d), 7.11 (1H, d), 7.21(1H, s), 7.25 (2H, m), 7.57 (1H, s); MS m/z(ES+) 324 (MH+) 72 Prep 49 -C=N A SMe HCl sait: δΗ (d6-DMSO, 300 MHz) 2.52 (3H,s), 2.60 (3H, s), 4.24 (2H, s), 6.94 (1H, d),7.04 (1H, d), 7.28 (1H, d), 7.50 (1H, t), 7.86 (1H, d), 8.08 (1H, s); MS m/z (TS+) 303 (MH+) 73 Prep 73 oo s Me" H SMe HCl sait: δΗ (CDCI3, 300 MHz) 2.48 (3H, s),2.64 (3H, s), 2.99 (3H, s), 4.23 (2H, s), 4.30 (2H, d), 6.40 (1 H, br), 6.81-6.89 (3H,m), 7.26-7.35 (2H, obs), 7.92 (1H, s); MSm/z (ES+) 385 (MH+), (ES') 383 (M-H+) 74 Prep 71 HO SMe HCl sait: δΗ (CD3OD, 400 MHz) 2.30 (3H,s), 2.44 (3H, s), 2.73 (3H, s), 4.25 (2H, s),4.59 (2H, s), 6.81 (1H, d), 6.88-6.92 (2H,m), 7.24 (1H, d), 7.37 (1H, d), 7.46 (1H, s);MS m/z (ES+) 304 (MH+) 75 Prep 72 0 O H ^^"Me SMe HCl sait: δΗ (CD3OD, 300 MHz) 2.37 (3H,s), 2.48 (3H, s), 2.78 (3H, s), 2.96 (3H,s),4.27 (2H, s), 4.31 (2H, s), 6.85 (1H, d),6.92-7.00 (2H, m), &amp;.31 (1H, d), 7.41 (1H,d), 7.57 (1H, s); MS m/z (ES+) 381 (MH+),(ES') 379 (M-H+) 76 Prep 75 P Wz CFixS''Nx^N3 H ^^^Me SMe HCl sait: δΗ (CD3OD, 400 MHz) 2.29 (3H,s), 2.41 (3H, s), 2.43 (3H, s), 3.76 (2H, s),4.30 (2H, s). 6.72-6.79 (3H, m), 7.12 (1H,br), 7.27 (2H, obs); MS m/z (ES*) 435(MH+), (ES’) 433 (M-H+) 012372 50 EXAMPLE 77 /V-{4-f(Dimethvlamino)methvn-3-i3-methvl-4- (methvlsulfanyl)phenoxv1benzvl}methanesulfonamide
5 Example 77 was prepared from the Boc protected sulfonamide of Préparation 74 by themethod of Example 60 ;HCI sait: δΗ (CD3OD, 400 MHz) 2.29 (3H, s), 2.42 (3H, s), 2.82(3H, s), 2.89 (6H, s), 4.17 (2H, s), 4.39 (2H, s), 6.39 (3H, m), 7.19 (1H, d), 7.24 (1H, d),7.48 (1H, d); MS m/z (TS+) 395 (MH+). 10 EXAMPLE 78 3-KMethvlamino)methvn-4-f3-methvl-4-(methvlsulfanvl)phenoxv1benzonitrile
Zn(CN)2 (700 mg, 5.96 mmol) and Pd(PPh3)4 (1.97 g, 1.7 mmol) were added to asolution of the bromide of Example 44 (3.0 g, 8.52 mmol) in DMF (20 mL) and the 15 mixture was heated at 100°C for 17 h. The reaction was cooled to room température,diluted with water (100 mL) and extracted with ether (2x100 mL then 3x50 mL). Thecombined organic layers were washed with water (3x50 mL), dried (MgSO4) andevaporated to a yellow oil. Initial purification by column chromatography [SiO2; 95:5:0.5(DCM/ MeOH/ 880 NH3)] was unsuccessful so the material was re-chromatographed 20 [SiO2; 50% pentane in 95:5:0.5 (DCM/ MeOH/ 880 NH3) increasing polarity to 0% pentane] to give the product (1.275 g, 50%) as a pale yellow oil. A sample was taken upin DCM (5 mL) and treated with 1M ethereal HCl to give the HCl sait as a white powderwhich was collected by filtration; δΗ (CDCI3, 300 MHz) 2.35 (3H, s), 2.47 (6H, s), 3.88(2H, s), 6.79 (1H, d), 6.87 (2H, m), 7.20 (1H, d), 7.46 (1H, d), 7.72 (1H, s); MS m/z (TS+) 25 299 (MH+). 012372 51 EXAMPLE 79 3-i(Methvlamino1methvn-4-f3-methvl-4-(rnethvisulfanvbphenoxv1benzamide o
^Me
Me SMe A mixture of the nitrile of Example 78 (404 mg, 1.35 mmol) and KOH (304 mg, 5.42 5 mmol) in tezï-butanol (10 mL) was heated at reflux for 1 h under N2. After cooling to roomtempérature the solvent was removed in vacuo and the residue was partitioned betweenwater (10 mL) and DCM (10 mL). The aqueous layer was extracted with DCM (4 χ 20mL) and the combined organic layers were washed with brine, dried (MgSO4) andevaporated. The residue was purified by column chromatography [SiO2; 93:7:1 (DCM/ 10 MeOH/ 880 NH3)] to give the desired product (376 mg, 88%) as a white foam; δΗ (CDCI3l300 MHz) 2.35 (3H, s), 2.47 (3H, s), 2.49 (3H, s), 3.88 (2H, s), 5.90-6.30 (2H, brs), 6.82(3H, m), 7.19 (1 H, d), 7.70 <1 H, d), 7.90 (1H, s); MS m/z (TS+) 317 (MH*).
Compounds of formula Ih, i.e. compounds of general formula l where R1 and R2 are 15 methyl and R4 is hydrogen, shown in Table 10 where prepared according to Example 12from the precursors indicated. R· NMe. (Ih) 52 012372
Table 10
Example Precursor Rs φ, Z data 80 Example 60 A δΗ (CD3OD, 400 MHz) 2.91 (6H, s), 3.35 (2H, obs), 3.38 (2H, t), 4.45(2H, s), 6.81 (1H, d), 6.90 (1H, d), 7.03 (1H, s), 7.21 (1H, d), 7.86 (1H,d), 8.03 (1H, s); MS m/z (TS+) 329(MH+) 81 Example 62 0 MeHN/^'*· δΗ (CD3OD, 400 MHz) 2.90-2.99 (9H,m), 3.35 (2H, obs), 3.43 (2H, t), 4.50(2H, s), 6.88 (1 H, d), 6.97 (1H, d), 7.07 (1H, s), 7.28 (1H, d), 7.85 (1H,d), 8.03 (1H, s); MS m/z (TS+) 343(MH+) 82 Example 61 „A ^Me ÔH (CDCI3i 400 MHz) 2.90 (6H, brm),3.35 (2H, obs), 3.37 (2H, brm), 3.51(4H, brm), 4.43 (2H, brs), 6.80-6.94(2H, brd), 7.01 (1H, brs), 7.20 (1H,brs), 7.82 (1H, brs), 7.98 (1H, brs); MS m/z (TS+) 387 (MH+) 83 Example 63 „A SMe δΗ (CDCI3i 300 MHz) 2.29 (6H, s), 2.47 (3H, s), 3.51 (2H, s), 6.73 (2H,s), 6.97 (1H, d), 7.30 (1H, t), 7.79(1H, d), 7.97 (1H, s); MS m/z (TS+) 335 (MNH?) 84 Example 64 A Me φ. SMe δΗ (CDCI3, 300 MHz) 2.29 (6H, s), 2.46 (3H, s), 3.02 (3H, d), 3.54 (2H,s), 6.20 (1H, brs), 6.69 (2H, m), 6.97(1 H, d), 7.30(1 H, t), 7.75(1 H, d), - 7.91 (1H, s); MS m/z (TS+) 349(MH+) 85 Example 65 A OMe SMe HCl sait: δΗ (CDCI3, 300 MHz) 2.49(3H, s), 2.94 (6H, s), 3.42 (3H, s), 3.65 (4H, m), 4.33 (2H, s), 6.79 (2H,d), 6.96(1 H, d), 7.35 (1H, t), 7.39(1H, brs), 7.98 (1H, d), 8.68 (1H, s); MS m/z (TS+) 393 (MH+) 86 Example 66 „A SMe δΗ (CDCI3, 400 MHz) 2.38 (6H, s), 2,47 (3H, s), 3.53 (2H, s), 6.88 (2H,d), 7.03(1 H, s), 7.19 (1H, d), 7.77(1H, d), 7.95 (1H, s); MS m/z (ES+) 351 (MH+) 87 Example 67 A I Me SMe δΗ (CDCI3, 400 MHz) 2.27 (6H, s), 2.46 (3H, s), 3.01 (3H, d), 3.50 (2H,s), 6.19 (1H, brs), 6.88 (2H, m), 7.00(1H, s), 7.19(1 H, d), 7.72 (1 H, d), 7.85 (1H, s); MS m/z (ES+) 365(MH+) 012372 53
Example Precursor R5 Z data 88 Example 68 0 ιΓί HCl sait: δΗ (CDCI3, 400 MHz) 2.25(6H, s), 3.07 (2H, s), 3.49 (2H, s), 4.37 (2H, m), 5.47-6.22 (2H, brd), 6.44 (1H, s), 6.49 (1H, d), 6.86 (1H,d), 6.95 (1H, d), 7.68 (1H, d), 7.87(1H, s); MS m/z (TS+) 346 (MH*) 89 Example 69 0 OMe HCl sait: δΗ (CD3OD, 400 MHz) 2.91(6H, s), 3.13 (2H, s), 3.27 (3H, s), 4.39 (2H, s), 4.46 (2H, s), 6.64 (2H,s+d), 6.87 (1 H, d), 7.08 (1H, d), 7.95(1H, d), 8.00 (1H, s); MS m/z (TS*) 403 (MH*) 90 Example 70 SMe HCl sait: ÔH ’(d6-DMSO, 300 MHz) 2.46 (3H, s), 2.74 (6H, s), 4.29 (2H,s), 4.51 (2H, s), 5.32 (1H, brs), 6.93(2H, d), 7.08 (1H, d), 7.41 (2H, m), 7.63 (1H, s); MS m/z (TS+) 322(MH*) 91 Example 71 ά. SMe HCl sait: δΗ (d6-DMSO, 400 MHz) 2.52 (3H, obs), 2.76 (6H, s), 4.09(2H, s), 4.49 (2H, s), 5.32 (1H, brs), 6.87 (1H, d), 7.08 (1H, d), 7.26 (1H,s), 7.38 (2H, m), 7.60 (1H, s); MSm/z (ES*) 338 (MH*) 92 Example 78 -C=N SMe HCl sait: δΗ (CDCI3, 400 MHz) 2.35(3H, s), 2.48 (3H, s), 2.87 (6H, d), 4.39 (2H, d), 6.85 (1H, d), 6.90 (1H,d), 6.93 (1H, dd), 7.21 (1H, d), 7.60(1H, d), 8.17 (1H, s); MS m/z (TS*) 313 (MH*) 93 Example 72 -C=N SMe HCl sait: δΗ (d6-DMSO, 300 MHz) 2.49 (3H, obs), 2.79 (6H, s), 4.41(2H, s), 6.97 (1H, d), 7.14 (1H, d), 7.32 (1H, d), 7.49 (1H, t), 7.87 (1H,d), 8.22 (1H, s); MS m/z (TS*) 317(MH*) 94 Example 45 H SMe HCl sait: δΗ (d6-DMSO, 400 MHz) 2.23 (3H, s), 2.42 (3H, s), 2.76 (6H,s), 4.34 (2H, s), 6.80 (1H, d), 7.97(1H, dd), 7.00 (1H, s), 7.19 (1H, t), 7.24 (1H, d), 7.40 (1H, t), 7.67 (1H,d); MS m/z (ES*) 288 (MH*) 95 Example 46 H HCl sait: δΗ (CDCI3, 400 MHz) 2.74(6H, s), 3.22 (2H, m), 3.38 (2H, m),4.26 (2H, s), 6.71 (1H, d), 6.80 (2H,brm), 7.15 (2H, brm), 7.32 (1H, d),7.79 (2H, d); MS m/z (ES*) 286(MH*) 012372 54
Example Precursor R5 data 96 Example 73 V H ά, SMe HCl sait: δΗ (CD3OD, 300 MHz) 2.46(3H, s), 3.93 (6H, s), 3.97 (3H, s), 4.24 (2H, s), 4.42 (2H, s), 6.91-7.00(3H, m), 7.41-7.54 (2H, m), 7.61 (1H,s); MS m/z (TS+) 399 (MH+), (ES') 397 (M-H+) 97 Example 75 0 0 Me''S''N'X*XK H SMe HCl sait: δΗ (CD3OD, 400 MHz) 2.31(3H, s), 2.43 (3H, s), 2.86-2.94 (9H,m), 4.22 (2H, s), 4.39 (2H, s), 6.83(1H, d) 6.89-6.94 (2H, m), 7.26 (1H,d), 7.40 (1H, d), 7.54 (1H, s); MS m/z(ES’) 393 (M-H+) 98 Example 74 ΗΟ'^'-χ SMe HCl sait: δΗ (CD3OD, 300 MHz) 2.36(3H, s), 2.47 (3H, s), 2.98 (6H, s), 4.43 (2H, s), 4.63 (2H, s), 6.89 (1H,d), 6.91-7.00 (2H, m), 7.30 (1 H, d), 7.43 (1H, d), 7.55 (1H, s); MS m/z(ES*) 318 (MH*) 99 Example 76 °o SMe HCl sait: δΗ (CD3OD, 300 MHz) 2.39(3H, s), 2.47 (3H, s), 2.85 (6H, s), 4.32 (2H, s), 4.44 (2H, s), 6.80-6.86(3H, m), 7.21 (1H, d), 7.35 (1H, d), 8.08 (1H, s); MS m/z (ES*) 449(MH*), (ES’) 447 (M-H*) 100 Example 102 0 δΗ (CD3OD, 400 MHz) 2.26 (6H, s),3.58 (2H, s), 6.97 (1H, d), 7.35 (1H,d), 7.46 (1H, dd), 7.54 (1H, d), 7.80(1 H, d), 8.03 (2H, m), 8.20 (1 H, d), ,8.74 (1H, d); MS m/z (TS*) 322(MH*)
Example 94 was also prepared as follows. A solution of the productfrom Préparation 30 (200 g, 0.78 mol) in DCM (1.4 L) was 5 added to THF (1.4 L). To this mixture was added dimethylamine hydrochloride (69.5 g,0.85 mol) and triethylamine (235 g, 2.33 moi) successively. The température wasadjusted to 20 °C and after 3 h sodium triacetoxyborohydride (246 g, 1.16 mol) wasadded (After 20 h, if the reaction has completed, continue with work up; otherwise seenote below). Dichloromethane (2 L) was added and a solution of 8% sodium bicarbonate 10 (0.9 L) was added over 0.5 h. The layers were separated and the organic layer washed with water (1 L). The layers were again separated and the organic layer wasconcentrated. Ethyl acetate (0.27 L) was added and the solvent removed replacing with 012372 55 fresh ethyl acetate (800 mi). The solution was then cooled to below 5 °C and 7.02 MHCI/IPA (0.117 L, 0.82 mol) added whist the température was maintained below 10 °C.After stirring for 1 h at below 5 °C, the slurry was filtered, washed with ethyl acetate (3 x0.2 L) and dried in a vacuum oven at 50 °C overnight to give the desired product as a 5 powdery solid (141.5 g, 56%). [Note: if reaction hasn’t completed after 20h. Add anotherportion of dimethylamine hydrochloride (13g, 0.16mol) and triethylamine (43.4g,0.43mol) successively. After 2h at room température add sodium triacetoxyborohydride(46g, 0.22mol). Leave for a further 20h and then work up as above]. 10 Compounds of formula li, i.e. compounds of general formula I where R2 is methyl, R4 ishydrogen and R5 is -C(=O)NH2, shown in Table 11 were prepared according to Example
15 Table 11
Example Precursor R1 data 101 Example 92 Me SMe δΗ (CDCI3, 300 MHz) 2.30 (6H, s), 2.35(3H, s), 2.46 (3H, s), 3.58 (2H, s), 5.60-5.80 (1H, brs), 6.00-6.20 (1H, brs), 6.32(3H, m), 7.19 (1H, m), 7.71 (1H, d), 7.90(1H, s); MS m/z (TS+) 331 (MH+) 102 Example 49 H δΗ (CDCI3, 400 MHz) 2.43 (3H, s), 3.84(2H, s), 6.94 (1H, d), 7.20 (1H, d), 7.34-7.39 (1 H, m), 7.43 (1 H, dd), 7.70 (1 H, d),7.91 (1H, s), 7.99 (1H, d), 8.09 (1H, d), 8.82 (1H, d); MS m/z (ES+) 309 (MH+) 012372 56 EXAMPLE 103 /V-(5-Amino-2-r3-methvl-4-(methvlsulfanvl)phenoxv1benzvl)-A/.A/-dimethvlamine
A mixture of the nitro compound of Example 27 (2.0 g, 6 mmol), Fe powder (2.51 g, 44.95 mmol) and CaCI2 (300 mg, 2.7 mmol) in EtOH (20 mL) and water (4 mL) was heated at reflux for 20 h. After cooling to room température the solvent was removed in vacuo andthe residue was partitioned between brine (100 mL) and ether (100 mL). The aqueouslayer was extracted with ether (50 mL) and the combined organic layers were dried(MgSO4) and evaporated to give the product (1.47 g, 81%) as an orange oil; δΗ (CDCI3, 10 300 MHz) 2.22 (6H, s), 2.32 (3H, s), 2.40 (3H, s), 3.33 (2H, s), 6.59 (1H, dd), 6.60-6.75 (2H, m), 6.78 (1H, dd), 6.94 (1H, s), 7.10-7.20 (3H, m); MS m/z (ES+) 303 (MH+). EXAMPLE 104 A/-f5-Amino-2-(2,3-dihvdro-1-benzothien-5-vloxv)benzvl1-/V,/V-dimethylamine
The title compound was prepared from the nitro compound of Example 28 by the methodof Example 103; δΗ (CDCl3) 400 MHz) 2.20 (6H, s), 3.16 (2H, t), 3.30 (4H, m), 3.54 (2H,br), 6.53 (1H, dd), 6.60 (1H, d), 6.71 (2H, m), 6.79 (1H, d), 7.01 (1H, d); MS m/z (ES+)301 (MH+). 20 012372 57 EXAMPLE 105 /V-|'3-(Aminomethyl)-4-(2,3-dihvdro-1.4-benzoxathiin-6-vloxv)phenvn- methanesulfonamide
The nitrile of Préparation 95 (720 mg, 1.99 mmol) was dissolved in a 1M solution ofBH3.THF in THF (10 mL, 10 mmol) and the mixture was heated at reflux for 3 h. Aftercooling to room température the reaction was quenched by the cautious addition ofMeOH (10 mL). The solvent was evaporated, the residue was treated with 6M HCl (10 10 mL) and heated at reflux for 1 h. After cooling, the mixture was basified with 2M NaOHand the pH was adjusted to 7 with sat aq NH4CI. The mixture was extracted with EtOAc(3x50 mL) and DCM (2x50 mL) and the combined organic layers were dried (MgSO4)and evaporated to give a beige foam (685 mg, 94%) which was used witbout furtherpurification; δΗ (CDCI3, 400 MHz) 3.00 (3H, s), 3.13 (2H, m), 3.87 (2H, s), 4.40 (2H, m), 15 6.62 (1H, d), 6.67 (1H, s), 6.79 (2H, d), 7.08 (1H, d), 7.25 (1H, d); MS m/z (TS+) 367 (MH+).
Compounds of formula Ij, i.e. compounds of general formula l where R1, R2 and R4 arehydrogen and R5 is -NRB-SO2Me, shown in Table 12 were prepared according to 20 Example 105 from the precursors indicated
z 012372 53
Table 12
Example Precursor R8 data 106 Prep 96 φ-α SMe H δΗ (CDCI3, 300 MHz) 2.47 (3H, s), 3.02 (3H, s),3.08 (3H, br), 3.85 (2H, s), 6.87 (2H, m), 6.99(1H, d), 7.15 (1H, dd), 7.20 (1H, d), 7.30 (1H,d); MS m/z (ES’) 371 (M-H+) 107 Prep 97 il SMe H Used crude in a subséquent step: δΗ (CD3OD, 400 MHz) 2.37 (3H, s), 2.95 (3H, s), 3.75 (2H,s), 6.58 (1H, d), 6.71 (2H, m), 6.89 (1H, d), 7.15(1H, dd), 7.28(1 H, obs) 108 Prep 100 SMe Me Used crude in a subséquent step: δΗ (CDCI3) 300 MHz) 2.36 (3H, s), 2.46 3H, s), 2.90 (3H,s), 3.36 (3H, s), 3.93 (2H, s), 6.83 (3H, m), 7.20(2H, m), 7.42 (1H, d). 109 Prep 99 ^SMe Me H δΗ (CD3OD, 400 MHz) 2.24 (3H, s), 2.40 (3H, s),2.97 (3H, s), 3.80 (2H, s), 6.60 (1H, d), 6.81-6.87 (2H, m), 7.08-7.17 (2H, m), 7.29 (1H, d); MS m/z (ES+) 353 (MH+), (ES’) 351 (M-H+) EXAMPLE 110 5 A/-{4-(2,3-Dihvdro-1.4-benzoxathiin-6-vloxv)-3-r(methvlamino)methvnphenvl)- methanesulfonamide
Dicyclohexylcarbodiimide (460 mg, 2.23 mmol) was added to a solution ofpentafluorophenol (413 mg, 2.24 mmol) in ether (10 mL) followed by formic acid (95 pL, 10 2.5 mmol). The mixture was stirred for 2 h and then filtered, washing the residue with ether. The filtrate was concentrated to ~5 mL and a solution of the prîmary amine ofExample 105 (411 mg, 1.1 mmol) in DCM (10 mL) was added. The mixture was stirredfor 16 h then concentrated to an oily residue. This crude oil was taken up in a solution ofBH3.THF in THF (1M, 20 mL, 20 mmol) and heated at reflux for 1.5 h under N2. After
15 cooling to room température the reaction was quenched by the cautious addition ofMeOH (10 mL) and then concentrated in vacuo. The oily residue was treated with 6M 012372 59 HCl and heated at reflux for 30 min. After cooling to room température the mixture wasbasified with aq K2CO3 and extracted with DCM (3x). The combined organic extractswere dried (MgSO4) and evaporated. The residue was purified by columnchromatography [SiO2; 90:10:1 (DCM/ MeOH/ 880 NH3)] to give a colourless oil which 5 was taken up in EtOAc (20 mL) and treated with 1M ethereal HCl (2 mL). After stirringfor 1.5 h the solid was collected by filtration to give the title product (282 mg, 60%); δΗ(CD3OD, 400 MHz) 2.78 (3H, s), 2.98 (3H, s), 3.18 (2H, m), 4.29 (2H, s), 4.39 (2H, m),,6.74 (1H, d), 6.80-6.90 (3H, m), 7.22 (1H, d), 7.44 (1H, s); MS m/z (TS+) 381 (MH+). 10 Compounds of formula Ik, i.e. compounds of general formula I where R1 and R4 arehydrogen, R2 is methyl and R5 is -NHSO2Me, shown in Table 13 were preparedaccordïng to Example 110 from the precursors indicated.
15 Table 13
Example Precursor Z data 111 Example 107 C^iX.F δΗ (CDCIa, 400 MHz) 2.40 (6H, s), 2.99 (3H, s),3.70 (2H, s), 6.64 (2H, t), 6.88 (1H, d), 7.15 (1H,d), 7.25 (2H, s); MS m/z (TS+) 371 (MH+) 11.2 Example 106 SMe HCl sait: δΗ (CD3OD, 400 MHz) 2.55 (3H, s), 3.82 (3H, s), 3.04 (3H, s), 4.32 (2H, s), 6.97(1H, d), 7.11 (1H, d), 7.23 (1H, s), 7.30 (1H, d),7.39 (1H, d), 7.56 (1H, s); MS m/z (TS+) 387(MH+) 113 Example 109 A Me HCl sait: δΗ (CD3OD, 400 MHz) 2.24 (3H, s), 2.39 (3H, s), 2.76 (3H, s), 2.93 (3H, s), 4.25(2H, s), 6.69 (1H, d), 6.82 (1H, d), 6.93 (1H, s),7.17 (1H, d), 7.21 (1H, d), 7.43 (1H, s); MS m/z(ES+) 367 (MH+), (ES') 365 (M-H+) 012372 60
Compounds of formula Im, i.e. compounds of general formula 1 where R1 and R4 arehydrogen, R2 is methyl and R5 is -NR8SO2Me, shown in Table 14 were preparedaccording to Example 110 from the precursors indicated.
Table 14
Example Precursor R8 2 data 114 Prep 85 H HCl sait δΗ (CDCIs, 400 MHz) 2.09 (2H,m), 2.73 (3H, s), 2.88 (4H, t), 3.00 (3H, s),4.21 (2H, s), 6.80 (2H, m), 6.88 (1H, s), 7.19 (1H, d), 7.34 (1H, d), 7.75 (1H, s); MS m/z (TS+) 347 (MH+) 115 Prep 84 H SMe HCl sait: δΗ (d6-DMSO, 400 MHz) 2.20(3H, s), 2.40 (3H, s), 2.55 (3H, s), 2.97(3H, s), 4.08 (2H, s), 6.80 (1H, d), 6.87(1H, d), 6.91 (1H, S), 7.14 (1H, d), 7.20(1H, d), 7.39 (1H, s); MS m/z (TS+) 367(MH+) 116a Prep 88 Me SMe δΗ (CDCI3> 300 MHz) 2.17 (3H, s), 2,37(3H, s), 2.48 (3H, s), 2.62 (3H, s), 2.97(3H, s), 3.34 (3H, s), 4.23 (2H, s), 6.79(1H, d), 6.94 (2H, s), 7.35 (2H, m), 7.81(1H, s); MS m/z (TS+) 381 (MH+) 117 Prep 89 OH SMe HCl sait: δΗ (CDCI3, 400 MHz) 2.29 (3H,s), 2.39 (3H, s), 2.42 (3H, s), 2.94 (3H, s),3.60 (2H, t), 3.74 (2H, t), 3.79 (2H, s), 6.78 (3H, m), 7.14 (2H, m), 7.41 (1H, s); MS m/z (TS+) 410 (MH+) 118 Prep 87 H \—O δΗ (CDCI3, 400 MHz) 2.42 (3H, s), 2.58-2.79 (2H, br), 2.94 (3H, s), 3.08 (2H, m),3.71 (2H, s), 4.38 (2H, m), 6.39 (1H, s), 6.47 (1H, d), 6.82 (1 H, d), 6.94 (1H, d), 7.07 (1H, d), 7.18 (1H, s); MS m/z (TS+) 381 (MH+) 012372 61
Example Precursor R8 Z data 119 Prep 86 H δΗ (CD3OD, 400 MHz) 2.80 (3H, s), 3.00(3H, s), 3.27 (2H, m), 3.40 (2H, m), 4.28(2H, m), 6.85 (2H, m), 7.00 (1H, s), 7.20(1H, d), 7.24 (1H, dd), 7.47 (1H, d); MSm/z (TS+) 365 (MH+) a - Also made from Example 10 8 by the method of Example 110.
Compounds of formula In, i.e. compounds of general formula I where R1 and R2 aremethyl, R4 is hydrogen, and Rs is -NR8SO2Me, shown in Table 15 were prepared 5 according to Example 12 from the precursors indicated.
Table 15
Example Precursor R8 9, Z Data 120 Example 111 H SMe HCl sait: δΗ (CD3OD, 400 MHz) 2.42 (3H,s), 2.89 (6H, s), 2.98 (3H, s), 4.37 (2H, s), 6.88 (2H, m), 6.97 (1H, d), 7.28 (1H, d), 7.39 (1H, t), 7.48 (1H, s); MS m/z (TS+) 385(MH+) 121 (from primary amine) Example 105 H δΗ (CDCI3, 400 MHz) 3.00 (3H, s), 3.13 (2H,m), 3.87 (2H, s), 4.40 (2H, m), 6.62 (1H, d),6.67 (1H, s), 6.79 (2H, d), 7.08 (1H, d), 7.25(1H, d); MS m/z (TS+) 367 (MH+) 122 (from primary amine) Example 106 H ίΊ SMe HCl sait: δΗ (CD3OD, 400 MHz) 2.49 (3H,s), 2.93 (6H, s), 3.00 (3H, s), 4.41 (2H, s),6.95 (1 H, d), 7.07 (1H, d), 7.21 (1H, s), 7.33(2H, m), 7.54 (1H, s); MS m/z (TS+) 395(MH+) 012372 62
Example Precursor R8 Data « 123 Example 114 H HCl sait: δΗ (CDCI3, 400 MHz) 2.12 (2H, m), 2.81 (6H, s), 2.91 (4H, t), 3.13 (3H, s), 4.25(2H, s), 6.73 (1H, d), 6.83 (2H, m), 7.10(1H, d), 7.39 (1H, d), 7.90 (1H, s); MS m/z(TS+) 360 (MH+) 124 Example 118 H δΗ (CDCI3, 400 MHz) 2.22 (6H, s), 2.98 (3H, s), 3.07 (2H, m), 3.41 (2H, s), 4.38 (2H, m),6.36 (1H, s), 6.45 (1H, d), 6.86 (1H, d), 6.92(1H, d), 7.12 (1H, d), 7.27 (1H, s); MS m/z(TS+) 395 (MH+) 125 Example 117 OH i1 SMe HCl sait: δΗ (CDCI3, 300 MHz) 2.38 (3H, s),2.48 (3H, s), 2.86 (6H, brs), 3.15 (3H, s), 3.73 (2H, brs), 3.87 (2H, brs), 4.35 (2H,brs), 6.82 (3H, brs), 7.20 (2H, m), 7.41 (1H, 1d); MS m/z (TS+) 425 (MH*) 126 (from primary amine) Example 108 Me SM© HCl sait: δΗ (CD3OD, 400 MHz) 2.29 (3H,s), 2.43 (3H, s), 2.89 (3H, s), 2.91 (6H, s),3.26 (3H, s), 4.42 (2H, s), 6.84 (1H, d), 6.97(2H, m), 7.27 (1H, d), 7.47 (1H, dd), 7.60(1H, d); MS m/z (TS+) 395 (MH+) 127 (from primary amine) Example 109 H A y^SMe Me HCl sait: δΗ (CD3OD, 400 MHz) 2.27 (3H,s), 2.42 (3H, s), 2.94 (6H, s), 2.99 (3H, s),4.42 (2H, s), 6.77 (1H, d), 6.89 (1H, d), 6.99(1H, s), 7.19 (1H, d), 7.28 (1H, dd), 7.50(1H, s); MS m/z (TS+) 381 (MH+), (ES+) 381(MH+), (ES’) 379 (M-H+) EXAMPLE 128 /V-{3-f(Dimethvlamino)methvn-4-[3-methvl-4-(methvlsulfanyl)phenoxv1- phenvDmethanesulfonamide
Methanesulfonyl chloride (371 pL, 4.79 mmol) was added to a solution of the aniline ofExample 103 (725 mg, 2.4 mmol) and Et3N (1 mL, 7.17 mmol) in DCM (10 mL) at 0°C.After stirring at 0°C for 1 h the reaction was allowed to warm to room température beforethe solvent was removed in vacuo. 2M NaOH (10 mL) was added to the residue and the 10 mixture was stirred overnight. The resulting clear solution was neutralised by the addition 012372 63 » of sat aq NH4CI and extracted with DCM (2x30 mL). The combined organic layers were dried (MgSO4) and evaporated to give an oil. This was taken up in EtOAc (10 mL), the * HCl sait was precipitated by the addition of 1M ethereal HCl and the product (669 mg, 67%) was collected by filtration; δΗ (d6-DMSO, 400 MHz) 2.23 (3H, s), 2.42 (3H, s), 2.75 5 (6H, s), 3.04 (3H, s), 4.38 (2H, s), 6.84 (1H, d), 6.93 (1H, d), 6.98 (1H, s), 7.17-7.25 (2H, m), 7.50 (1H, s); MS m/z (ES+) 381 (MH+).
Compounds of formula Ip, i.e. compounds of general formula I where R1 and R2 aremethyl, R4 is hydrogen, and R5 is -NHSO2R9, shown in Table 16 were prepared 10 according to Example 128 from the precursors indicated.
Table 16
Example Precursor R9 data 129 Example 104 Me HCI sait; ÔH (CD3OD, 400 MHz) 2.92 (6H,s), 2.99 (3H, s), 3.26 (2H, t), 3.40 (2H, t), 4.41 (2H, s), 6.88 (2H, d), 7.00 (1H, s), 7.10(1H, d), 7.27 (1H, d), 7.50 (1H, s); MS m/z(TS+) 381 (MH+) 130 Example 103 • Et SMe HCl sait; δΗ (d6-DMSO, 400 MHz) 1.21 (3H,t), 2.23 (3H, s), 2.42 (3H, s), 2.74 (6H, s), 3.16 (2H, q), 4.26 (2H, s), 6.92 (1H, d), 6.92(1H, d), 6.98 (1H, s), 7.18-7.25 (2H, m), 7.51 (1H, s); MS m/z (ES+) 395 (MH+) 9 012372 64‘
PREPARATIONS PREPARATION 1 5-(Aminosulfonvn-2-fluoro-/\/-methvlbenzamide
To a solution of 5-(aminosulfonyl)-2-fluorobenzoic acid [prepared according to Chem.Pharm. Bull. 1995, 43, 582-7] (22.98 g, 105 mmol) in THF (500 mL) at room températureunder nitrogen was added carbonyldiimidazole (17 g, 105 mmol). After stirring for 2.25 ha solution of methylamine in THF (2M, 70 mL, 140 mmol) was added dropwise and the 10 reaction was allowed to stir for 18 h. The crude reaction mixture was concentrated to alow volume and EtOAc (150 mL) was added to the resulting thick oil. This mixture wasstirred and a granular precipitate formed which was collected by filtration. This crudeproduct, contaminated with imidazole, was suspended in DCM (300 mL) and heated atreflux for 5 h. After cooling to room température the mixture was filtered to give the 15 desired product (19.8 g, 81%) containing <2% w/w imidazole; 1H NMR δΗ (300 MHz, d4-MeOH) 2.97 (3H, s), 7.40 (1H, t), 8.05 (1H, m), 8.29 (1H, d); MS m/z (TS+) 250 (MNH4+). PREPARATION 23-Chloro-4-(methylsulfanvl)phenoi
OH
SMe (i) Préparation of 2-chloro-1-(methvlsulfanvl)-4-nitrobenzeneTo a solution of 4-fluoro-3-chloronitrobenzene (27 g, 156 mmol) in DMF (150 mL) atroom température was added 5-tert-butyl-4-hydroxy-2-methylphenyl sulfide (100 mg)followed by sodium thiomethoxide (NaSMe) (10 g, 143 mmol) and the reaction was 25 stirred for 6h. The DMF was removed in vacuo and the residue was partitioned betweenether (1 L) and water (1 L). The ether layer was washed with water (1 L) and brine (1 L),dried (MgSO4) and the solvent was removed under reduced pressure. The residue waspurified by column chromatography (SiOz; DCM: pentane 1:5 increasing polarity to 3:7) 012372 65 to give the title compound (15.22 g, 49%) as a yellow solid; δΗ (400 MHz, CDCI3) 2.53(3H, s), 7.20 (1H, d), 8.09 (1H, dd), 8.20 (1H, d). (ii) Préparation of 3-chloro-4-(methvlsulfanyl)aniline
To a mixture of the above compound (14.08 g, 69 mmol) in acetic acid (300 mL) andwater (60 mL) was added Fe powder (23 g, 412 mmol) and the reaction mixture wasswirled until ail the starting material had dissolved. The mixture was leftto stand for 1.5 hand the acetic acid was then removed under reduced pressure. The residue was takenup in sat NaHCO3 (aq) (500 mL) and EtOAc (500 mL) and filtered through Arbocel®. Thelayers were separated, the aqueous phase was extracted with EtOAc (300 mL) and thecombined organics were washed with brine, dried (MgSO4) and the solvent was removedin vacuo to give the title compound (11.52 g, 96%) as a beige solid; δΗ (400 MHz, CDCI3)2.38 (3H, s), 3.66 (2H, br), 6.53 (1H, dd), 6.70 (1H, d), 7.12 (1H, d); MS m/z (ES+) 174(MH+). (iii) Préparation of 3-chloro-4-(methylsulfanyl)phenol
The above aniline (11.5 g, 66.2 mmol) was dissolved in the minimum THF (~15 mL) andwater (500 mL) was added with vigorous stirring, followed by conc H2SO4 (25 mL). Themixture was cooled in an ice-water bath and a solution of NaNO2 (5.0 g, 72.5 mmol) iniced water (10 mL), was added via pipette under the surface of the reaction mixture. Thereaction was stirred at 0°C for 1.5 h and the resulting yellow/brown solution wasdecanted from the remaining solid into a dropping funnel containing ice (~200 g). Thissolution was added at a steady rate over 7 min to a vigorously stirred mixture ofCu(NO3)2 (230 g, 0.99 mol) and Cu2O (8.52 g, 67.4 mmol) in water (1 L) at roomtempérature. After the addition was complété the mixture was stirred for a further 15 minbefore being extracted with ether (500 mL). The residual red/brown solid in the reactionflask was taken up in MeOH (100 mL) and diluted with ether (300 mL) before beingpoured into the aqueous layer from above. The ether layer was separated and thecombined organic layers were extracted with 1M NaOH (3 x 100 mL). The aqueousextracts were acidified with conc. HCl and then extracted with ether (2 x 150 mL). Theether layers were then washed with brine, dried (MgSO4) and the solvent was removedin vacuo to give the phénol (5.465 g, 47%) as a brown crystalline solid; δΗ (400 MHz,CDCI3) 2.44 (3H, s), 5.08 (1H, br), 6.77 (1H, d), 6.93 (1H, d), 7.18 (1H, d); MS m/z (ES")173 (M-H+). 012372 66 PREPARATION 3 3-Fluoro-4-(methylsulfanvl)phenol
SMe
This compound was prepared using a similar method to that described above for5 Préparation 2 starting from commercialiy available 3,4-difluoronitroben2ene; δΗ (CDCI3i 300 MHz) 2.40 (3H, s), 5.03 (1H, br), 6.60 (2H, m), 7.27 (1H, m obscured); MS m/z (ES')157 (M-H+). PREPARATION 4 10 2,3-Dihvdro-1,4-benzoxathiin-6-ol
1,2-Dibromoethane (2.3 mL, 26.7 mmol) and K2CO3 (8.21 g, 59.4 mmol) were slurried inacetone (250 mL) and a solution of 2-sulfanyl-1,4-benzenediol (prepared according to J.Org. Chem. 1990, 55, 2736) (4.22 g, 29.7 mmol) in acetone (50 mL) was added over 4 h 15 to the stirred mixture. Once the addition was complété stirring was continued for a further 10 h before the solvent was removed in vacuo. The residue was partitioned -between water (50 mL) and EtOAc (50 mL), the aqueous layer was extracted with EtOAc(50 mL) and the combined organic layers were dried (MgSO4) and evaporated.Purification of the residue by column chromatography [SiO2; 9:1 (pentane/EtOAc)] gave 20 the title compound (2.48 g, 55%) as a pale orange oil; δΗ (CDCI3, 400 MHz) 3.08 (2H, m), 4.31 (2H, m), 4.44 (1H, s), 6.42 (1 H, d), 6.49 (1H, s), 6.66 (1H, d); MS m/z (ES") 167(M-H+). PREPARATION 5 2,3-Dihvdro-1,4-benzoxathiin-7-ol 25
012372 67
The title compound was prepared in a similar manner to the compound of Préparation 4starting from 4-sulfanyl-1,3-benzenediol (prepared accordingto J. Org. Chem. 1979, 26,4971-4973); δΗ (CDCI3, 400 MHz) 3.05 (2H, t), 4.37 (2H, t), 6.32 (1H, s), 6.35 (1H, d),6.84 (1H, d); MS m/z (TS+) 169 (MH+). PREPARATION 6 1,3-Dihydro-2-benzofuran-5-ol
1.3- Dihydro-2-benzofuran-5-amine (prepared according to US4000286) (2.7 g, 20 mmol)
10 was dissolved in a mixture of water (300 mL) and conc. H2SO4 (21 mL), cooled to 0°C and NaNO2 (1.43 g, 20.7 mmol) in water (10 mL) was added over 15 min. After stirring at0°C for 1 h the mixture was allowed to stir at 10°C for 30 min and urea was added until anégative test with starch/KI paper was observed. The solution was then poured over 2min into a mixture of water (180 mL) and conc. H2SO4 (12.6 mL) at 90°C and stirred at 15 this température for 1.5 h. The hot mixture was filtered then allowed to cool to roomtempérature. The aqueous mixture was extracted with EtOAc (2 χ 100 mL) and thecombined organic layers were dried (MgSO4) and evaporated to give the title phénol(974 mg, 36%) as a cream solid; δΗ (CDCI3,400 MHz) 5.03 (4H, s), 6.71 (2H, m), 7.08(1H, d). 20 PREPARATION 7 2.3- Dihydro-1-benzothiophen-6-ol
Ci) Préparation of 2,3-dihvdro-1-benzothiophen-6-ol 1,1-dioxide25 A suspension of 2,3-dihydro-1-benzothiophen-6-amine 1,1-dioxide [prepared according to J. Am. Chem. Soc. 1955, 77, 5939] (15.73 g, 85.8 mmol) in water (500 mL) and conc.H2SO4 (35 mL) was warmed until solution was achieved. The mixture was cooled to 0°Cand a solution of NaNO2 (6.22 g, 90 mmol) in water (15 mL) was then added over 5 min.The réaction was stirred at 0°C for 1 h then urea was added, to remove excess nitrite, 012372 68 until a négative test with starch/Kl paper was obtained. The mixture was allowed towarm to room température then added with stirring to a mixture of conc. H2SO4 (55 mL)and water (750 mL) at 90°C. The reaction was re-heated to 90°C and stirred at this *température for 30 min. The hot reaction mixture was filtered through Arbocel® then 5 stirred at room température overnight. The aqueous mixture was extracted with ether(2.5 L) and then EtOAc (5 χ 500 mL) and the combined organic layers were dried(MgSO4) and evaporated to give the desired phénol (12.7 g, 80%) which was usedwithout further purification; δΗ (CDCI3, 400 MHz) 3.30 (2H, m), 3.50 (2H, m), 7.05 (1H,m), 7.14 (1H, s), 7.23 (1H, m); MS m/z (ES') 183 (M-H+). 10 (ii) Préparation of 2.3-dihvdro-1-benzothiophen-6-ol A solution of the sulfone from stage (i) (4.84 g, 26.3 mmol) in toluene (100 mL) and THF(70 mL) was added to a solution of DIBAL in toluene (1M, 100 mL, 100 mmol) and themixture was then heated at reflux for 16 h. After cooling to room température EtOH (75mL) was added cautiously followed by water (100 mL) with stirring. 6M HCl was added 15 to the resulting thick suspension and the organic layer was separated. The aqueouslayer was extracted with EtOAc (3 χ 150 mL) and the combined organic layers weredried (MgSO4) and evaporated to a beige solid. Purification by column chromatography[SiO2; DCM/ MeOH/ 880 NH3 (97:3:0.25) increasing polarity to (95:5:0.5)] afforded thedesired title phénol as a beige solid (1.85 g, 53%); ÔH (CD3OD, 400 MHz) 3.13 (2H, t), 20 3.30 (2H, m), 6.41 (1H, d), 6.60 (1H, s), 6.98 (1H, d); MS m/z (ES’) 151 (M-H+). PREPARATION 8 5-(Aminosulfonvl)-2-Î3-methvl-4-(methvlsulfanvl)phenoxv1-/\/-methvlbenzamide
25 The fluoroamide of Préparation 1 (732 mg, 3.15 mmol) was treated with 4-(methylthio)-m-cresol (commercially available) (535 mg, 3.47 mmol) and potassium carbonate (457mg, 3.31 mmol) in DMF (10 mL). The mixture was heated at 100 °C for 5 hours. Thesolvent was removed by évaporation under reduced pressure and the residue wastreated with 2M HCl (10 mL). The resulting suspension was extracted several times with 30 dichloromethane. The combined dichloromethane layers contained a suspension and 012372 69 « were evaporated to a solid residue. The residue was triturated with ether (5 mL) and the remaining solid was washed with ether (3x10 mL) to give an off-white solid (765 mg, * 66%). ÔH (300 MHz, d6-DMSO) 2.28 (3H, s), 2.48 (3H, s), 2.70 (3H, d), 6.90 (1H, d), 7.02 (1H, d), 7.03 (1H, s), 7.30 (1H, d), 7.35 (2H, s), 7.79 (1H, d), 8.10 (1H, d), 8.30 (1H, m); 5 MS m/z (TS+) 367 (MH+), 385 (MNH/). PREPARATIONS 9-18
Compounds of formula Va, i.e. compounds of general formula V where T is-C(=O)NHMe, R4 is hydrogen and R5 is -SO2NH2, shown in Table 17 were prepared 10 according to Préparation 8 using the sulfonamide of Préparation 1 and the phénolindicated.
Table 17
Préparation Precursor phénol data 9 Synth.Commun.1991, 21,959-964 δΗ (d6-DMSO,400 MHz) 2.80 (3H, d), 3.20 (2H,t), 3,40 (2H, t), 6.90 (1H, m), 7.05 (1H, s), 7.25(1H, d), 7.35 (1H, s), 7.80 (1H, m), 8.10 (1H, s),8.30 (1H, brs); MS m/z (TS+) 365 (MH+) 10 Prep 5 δΗ (CD3OD, 400 MHz) 2.92 (3H, s), 3.17 (2H,m), 4.41 (2H, m), 6.60-6.70 (2H, m), 6.97 (1H,d), 7.18 (1H, d), 7.90 (1H, d), 8.31 (1H, s); MSm/z (TS+) 381 (MH+) 11 Prep 3 SMe δΗ (CD3OD, 400 MHz) 2.43 (3H, s), 2.97 (1H, s),6.89 (2H, m), 7.00 (1H, d), 7.39 (1H, br), 7.88(1H, brd), 8.23 (1H, s); MS m/z (ES*) 371 (MH+) 12 Prep 2 SMe δΗ (CD3OD, 400 MHz) 2.85 (3H, s), 2.99 (3H, s),6.99 (1H, d), 7.09 (1H, d), 7.22 (1H, s), 7.37(1H, d), 7.92 (1H, d), 8.28 (1H, s); MS m/z (ES*)387 (MH+) 012372 70
Préparation Precursor phénol data * M 13 Prep 4 \—CO δΗ (CDgOD, 400 MHz) 2.87 (3H, brs), 3.13 (2H, brs), 4.37 (2H, brs), 6.73 (1H, brs), 6.82 (3H,m), 7.82 (1H, s), 8.28 (1H, brs); MS m/z (ES+) 381 (MH+) 14 Prep 6 δΗ (ds-DMSO, 400 MHz) 2.79 (3H, s), 4.98 (4H,brs), 6.92 (1H, d), 7.04 (1H, d), 7.09 (1H, s), 7.37 (3H, m), 7.79(1 H, m), 8.10(1 H, s), 8.30(1H, s); MS m/z (TS+) 349 (MH+) 15 Commercial 4 δΗ (CD3OD, 400 MHz) 2.08 (2H, m), 2.90 (7H, m), 6.84 (2H, m), 6.97 (1H, s), 7.23 (1H, d), 7.81 (1H, d), 8.31 (1H, s); MS m/z (TS+) 347(MH+) 16 Tetrahedron 1982, 38,2721 &amp;Synthesis1982, 475 ¢,. Me Product used without purification 17 Prep 101 δΗ (CD3OD, 400 MHz) 2.88 (3H, s), 4.20 (4H, s),6.89 (1H, d), 6.97 (1H, d), 7.01 (1H, s), 7.30(1H, d), 7.84 (1H, d), 8.28 (1H, s); MS m/z (TS+)382 (MNH4+) 18 Prep 7 δΗ (DMSO-d6, 400 MHz) 2.78 (3H, d), 3.23 (2H,m), 3.40 (2H, m), 6.75 (1H, dd), 6.90 (1H, d), 7.02 (1H, s), 7.27 (1H, d), 7.34 (1H, d), 7.80(1H, d), 8.10 (1H, s), 8.26 (1H, br, d); MS m/z(ES’) 363 (M-H+) PREPARATION 19 5-Bromo-2-(2.3-dihvdro-1-benzothien-5-vloxv)benzaldehyde
5 A mixture of 5-bromo-2-fluorobenzaldehyde (1.08 g, 5.32 mmol), 5-hydroxy-2,3- dihydrobenzothiophene (prepared as described in Synth. Commun. 1991, 21, 959-964)(808 mg, 5.31 mmol) and K2CO3 (1.47 g, 10.6 mmol) in DMF (5 mL) was heated at 90°Cfor 16 h. After cooling to room température the mixture was partitioned between water(50 mL) and ether (50 mL), the aqueous layer being extracted with ether (50 mL). The 10 combined organic extracts were washed with water (50 mL), dried (MgSO4) and evaporated. The residue was purified by column chromatography [SiO2; 9:1 012372 (pentane/EtOAc)], then triturated with ether, to give the product (1.1 g, 62%) as a paleyellow solid; δΗ (CDCI3,400 MHz) 3.28 (2H, t), 3.41 (2H, t), 6.78 (1H, d), 6.84 (1H, d),6.92 (1H, s), 7.20 (1H, d), 7.58 (1H, d), 8.00 (1H, s), 10.43 (1H, s). 5 Compounds of general formula II shown in Table 18 were prepared according to
Préparation 19 by reacting the phénol indicated with the required 2-fluorobenzaldehyde.In most cases the crude reaction product after aqueous work-up was used directly insubséquent steps without further purification.
10
Table 18
Préparation Precursor Phénol R4 R5 Z data 20 Prep 3 H Br ‘ ιΓί SMe δ„ (CDCI3, 300 MHz) 2.48 (3H, s), 6.81 (3H, m), 7.37 (1H, t), 7.64(1H, d), 8.06 (1H, s), 10.39 (1H, s);MS m/z (TS+) 358, 360 (MNH4*) 21 Prep 5 H Br U» M δΗ (CDCI3l 400 MHz) 3.13 (2H, m),4.42 (2H, m), 6.55 (1H, s), 6.59(1H, d), 6.81 (1H, d), 7.04 (1H, d),7.59 (1H, d), 8.01 (1H,s), 10.40(1H, s) 22 Prep 2 H Br SMe δΗ (CDCI3i 400 MHz) 2.43 (3H, s),6.78 (1H, d), 6.94(1 H, d), 7.08(1H, s), 7.19(1H, d), 7.59 (1H, d),8.00(1 H, s) 23 commercial H Br SMe δΗ (CDCi3) 300 MHz) 2.35 (3H, s),2.49 (3H,s), 6.78 (1H,d), 6.90(2H, s), 7.22 (1H, d), 7.59 (1H, d),8.05 (1H, s), 10.45 (1H, s); MS m/z(TS+) 356, 354 (MNH?) 24 commercial H MeO SMe ÔH (CDCI3, 300 MHz) 2.35 (3H, s),2.45 (3H, s), 3.87 (3H, s), 6.82(1H, d), 6.83 (1H, s), 6.92 (1H, d),7.13(1 H, dd), 7.19(1 H, d), 7.40(1H, d), 10.40 (1H, s); MS m/z(TS+) 389 (MH*) 012372 72
Préparation Precursor Phénol R4 R5 Îl z data » « 25 commercial H F U δΗ (CDCi3, 300 MHz) 7.02 (1H, dd),7.21 (1H, s), 7.30 (1H, m), 7.40(1H, m), 7.54 (1H, d), 7.66 (1H,dd), 8.01 (1H, d), 8.18 (1H,d), 8.88 (1H, d), 10.43 (1H, s); MS m/z(ES+) 268 (MH+) 26 commercial H H Ό δΗ (CDCI3, 400 MHz) 6.97 (1H, d),7.21-7.27 (2H, m), 7.38 (1H, dd),7.49-7.58 (2H, m), 7.92-8.01 (2H,m), 8.11 (1H, d), 8.83 (1H, d), 10.50 (1H, s); MS m/z (ES+) 272(MNa+), (ES’) 248 (M-H+) 27 J. Chem.Soc. 1952,4985-4993 H H δΗ (CDCI3, 300 MHz) 7.08 (1H, d),7.36 (2H, m), 7.65 (1H, m), 7.79(1H,dd), 8.01 (1H, d), 8.13 (1H,d),9.29 (1H, d), 10.45 (1H, s); MS m/z(TS+) 251 (MH+) 28 commercial H H δΗ (CDCI3, 400 MHz) 7.09 (1H, d),7.28 (1H, m), 7.35 (1H, m), 7.40(1H, m), 7.50 (1H, br), 7.59 (1H,m), 7.86 (1H, dd), 7.99 (1H„ dt),8.15 (1H, d), 8.86 (1H, m), 10.46(1H, s); MS m/z 250 (MH+) 29 Chem. Pharm. Bull., 1978;26, 1443 H H a; nS-ÿ ÔH (CDCI3, 400 MHz) 6.91 (1H, d),7.25 (2H, m), 7.55 (2H, m), 7.96(1H, m), 8.12 (1H, d), 8.95 (1H, s),10.5 (1H, s); MS m/z 256 (MH+) 30 commercial H H SMe δΗ (CDCI3, 300 MHz) 2.35 (3±î, s), 3.44 (3H, s), 6.87 (3H, m), 7.17(2H, m), 7.50 (1H, t), 7.92 (1H, dd)10.52 (1H, s); MS m/z (TS+) 259(MH+) 31 Synth. Commun. 1991,21, 959-964 H H ÔH (CDCI3, 400 MHz) 3.26 (2H, t),3.39 (2H, m), 6.85 (2H, t), 6.92(1H, s), 7.18 (2H, m), 7.48 (1H, t),7.92 (1H, d), 10.51 (1H, s); MS m/z(TS+) 257 (MH+) 32 commercial Br H SMe δΗ (CDCI3, 400 MHz) 2.36 (3H, s),2.44 (3H, s), 6.88 (2H, m), 6.96(1H, s), 7.18-7.25 (2H, obs), 7.77(1H,d), 10.43 (1H,s) 33 Prep7 H Br δΗ (CDCI3, 400 MHz) 3.27 (2H, m),3.42 (2H, m), 6.67 (1H, d), 6.80(1H, d), 6.90 (1H,s),71.6(1H, d),7.58 (1H, d), 8.01 (1H, s), 10.41(1H, s); MS m/z (TS+) 354 (MNH?) 012372 73
Préparation Precursor Phénol R4 R5 2 data 34a commercial H CN δΗ (DMSO-d6, 300 MHz) 6.26 (1H,d), 6.43 (1H, d), 7.49 (1H, d), 7.65-7.71 (2H, m), 7.88 (1H, d), 8.07(1H, d), 8.17 (1H, s), 8.73 (1H, d),8.89 (1H, s); MS m/z (ES-) 273 (Μ-Η), (ES+) 275 (MH+) a - 4-Fluoro-3-formylbenzonitrile was synthesised according to Synth. Commun. 1997,27(7), 1199 and J. Org. Chem. 1961, 26, 2522.
The product from Préparation 30 was also prepared as foliows. 5
Potassium carbonate (334.1 g, 2.42 moi) and 4-(methylthio)-m-cresol (273.4 g, 1.77mol) were added successively to DMF (2 L). 2-Fluorobenzaldehyde (200 g, 1.61 mol)was then added to the slurry and the mixture heated in the range 100-110 °C. After 48 hthe reaction mixture was allowed to cool to room température and water (1.2 L) added. 10 The solution was cooled to below 10 °C and the pH adjusted to 5 with concentrated HCl(0.37 L), keeping the température below 10 °C. Water (0.15 L) and dichloromethane(0.9 L) were added and the mixture stirred. The layers were separated and the organiclayer was washed with water (4 x 0.75 L). The solvent was distilled to azeotropicallyremove the water. Fresh dichloromethane was added as required. The dry 15 dichloromethane solution was then concentrated in vacuo to give the crude product asan oil (422 g, 100%).
Compounds of formula IX shown in Table 19 were prepared according to Préparation19, using either 2-chloro-5-nitrobenzaldehyde or 2-chloro-5-nitrobenzonitrile with the 20 phénol indicated. For these reactions a shorter reaction time (ca. 2-3 h) was usuallysufficient to achieve good conversion. In most cases the crude reaction product afteraqueous work-up was used directly in subséquent steps without further purification.
(ix) 012372 74
Table 19
Préparation I Precursor W data ,î 35 Prep 3 -ON SMe δΗ (’CDCIa, 400 MHz) 2.48 (3H, s), 6.85-6.95 (3H, m), 7.28 (1H, t), 8.30(1H, d), 8.52(1 H, s) 36 Prep 5 0 δΗ (CDCl3,400 MHz) 3.14 (2H, d), 4.43(2H, d), 6.62 (2H, m), 6.92 (1H, d), 7.08 (1H, d), 8.27 (1H, d), 8.72 (1H, s),10.51 (1H, s); MS m/z (TS+) 318 (MH+) 37 Prep 2 -ON k SMe δΗ (CDCI3, 300 MHz) 2.55 (3H, s), 6.94(1H, d), 7.09 (1H, dd), 7.22 (1H, d), 7.27 (1H, d), 8.36 (1H, dd), 8.60 (1H,d); MS m/z (TS+) 338 (MNH?) 38 Synth.Commun.1991, 21,959-964 δΗ (CDCI3, 400 MHz) 3.29 (2H, m), 3.42 (2H, m), 6.88 (2H, m), 6.96 (1H,s), 7.23 (1H, d), 8.26 (1H, d), 8.75 (1H,s), 10.54 (1H, S) 39 commercial 0 k SMe δΗ (CDCI3, 400 MHz) 2.38 (3H, s), 2.50(3H, s), 6.92 (1H, d), 6.99 (2H, m), 7.24 (1H, d), 8.28 (1H, dd), 8.78 (1H,d), 10.57 (1 H, s) 40 commercial X δΗ (CDCI3, 400 MHz) 2.18 (2H, m), 2.95 (4H, t), 6.90 (2H, m), 7.29 (1H, d),8.27 (1H, d), 8.79 (1H, s), 10.59 (1Ή,s); MS m/z (TS+) 301 (MNH4+) 41 Prep 4 -C=N δΗ (CDCI3, 400 MHz) 3.18 (2H, t), 4.44(2H, t), 6.76 (1H, d), 6.86 (1H, s), 6.92(2H, d), 8.32 (1H, d), 8.57 (1H, s); MSm/z (TS+) 332 (MNH/) 42 commercial -ON SMe δΗ (CDCIa, 400 MHz) 2.32 (3H, s), 2.47(3H, s), 6.87 (1H, d), 6.94 (2H, m), 7.21 (1H, d), 8.26 (1H, dd), 8.51 (1H,d); MS m/z (TS+) 318 (MNH/) 43 Tetrahedron1982, 38,2721 &amp;Synthesis1982,475 -ON (S y^SMe Me δΗ (CDCI3i 400 MHz) 2.31 (3H, s), 2.41(3H, s), 6.76 (1H, dd), 6.85 (2H, m), 7.19 (1H, d), 8.24 (1H, dd), 8.53 (1H,d); MS m/z (TS+) 318 (MNH?) Ο 1237 2 PREPARATION 44 te/f-Butyl 5-bromo-2-(2,3-dihvdro-1-benzothien-5-yloxv)benzvl(methvl)carbamate 75
The hydrochloride sait of Example 36 (1.04 g, 2.7 mmol) was slurried in DCM (12 ml_) 5 and Et3N (750 μΙ_, 5.38 mmol) was added, followed by di-fe/i-butyl dicarbonate (766 mg,3.51 mmol). After stirring at room température for 20 min the reaction was quenched bythe addition of 0.2M HCl (20 mL). The well shaken mixture was separated and theaqueous layer was extracted with DCM (10 mL). The combined organic layers weredried (MgSO4) and evaporated to give the product (assumed quantitative yield) as a 10 colourless oil which was used without further purification; δΗ (CDCI3, 400 MHz) 1.56 (9H,s), 2.82-2.98 (3H, brd), 3.23 (2H, t), 3.40 (2H, t), 4.44 (2H, brd), 6.71 (2H, d), 6.79 (1H,s), 7.12 (1H, d), 7.29 (1H, d), 7.39 (1H, s).
Compounds of formula X shown in Table-20 were prepared according to Préparation 44 15 starting from the precursors indicated.
Table 20
Préparation Precursor ά. Z data 45 Example 38 δΗ (CDCI3i 400 MHz) 1.41 (9H, brs), 2.81 (3H, m),3.07 (2H, m), 4.36 (4H, m), 6.38 (1H, s), 6.43(1H, d), 6.71 (1H, d), 6.92 (1H, d), 7.26 (1H, d),7.34 (1 H, s); MS m/z (ES+) 468 (MH+) 012372 76
Préparation Precursor 2 data 46 Example 39 ^"Cl SMe δΗ (CDCI3, 400 MHz) 1.48 (9H, s), 2.41 (3H, s), 2,82 (3H, brd), 4.39 (2H, brd), 6.73 (1H, d), 6.80(1H, d), 6.93 (1H, s), 7.04 (1H, d), 7.32 (1H, d), 7.39 (1H, s); MS m/z (TS+) 474 (MH+) 47 Exampie 37 ï, SMe δΗ (CDCIa, 300 MHz) 1.46 (9H, brs), 2.46 (3H, s), 2.89 (3H, brs), 4.41 (2H, brs), 6.68 (2H, m), 6.82(1H, d), 7.27 (1H, obs), 7.40 (1H, d), 7.43 (1H, s);MS m/z (TS+) 458 (MH+) 48 Example 44 I SMe SH (CDCIa, 300 MHz) 1.45 (9H, br) 2.38 (3H, s), 2.44 (3H, s), 2.90 (3H, br), 4.47 (2H, br), 6.70-6.81 (3H, m) 7.20 (1H, d), 7.24-7.58 (2H, m) PREPARATION 49 tert-Butvl 5-cvano-2-f3-fluoro-4-(methvlsulfanvl)phenoxv1benzyl-(methvl)carbamate
5 The title compound was prepared from the bromide of Préparation 47 by the method ofExample 78 ;δΗ (CDCl3l 300 MHz) 1.48 (9H, brs), 2.50 (3H, s), 2.93 (3H, brs), 4.55 (2H,brs), 6.79 (2H, m), 6.88 (1H, d), 7.35 (1H, t), 7.53 (1H, d), 7.59 (1 H, s); MS m/z (TS*)403 (MH+). 10 PREPARATION 50
Methvl 3-{Î(terf-butoxvcarbonvl)(methvl)aminolmethyl)-4-(2.3-dihvdro-1-benzothien-5- vloxv)benzoate
A mixture of the bromide of Préparation 44 (1.22 g, 2.7 mmol), Et3N (1.13 mL, 8.11
15 mmol) and dichlorobis(triphenylphosphine)palladium (H) (190 mg, 0.27 mmol) in MeOH „012372 (14 mL) was heated at 80°C under 100 psi pressure of CO for 18 h. Analysis by tic indicated the reaction was not complété so a further portion of catalyst (190 mg, 0.27
mmol) was added and the mixture was heated at 100°C under 100 psi pressure of CO for 24 h. The mixture was diluted with EtOAc (20 mL) and filtered through a pad of silica 5 gel, eluting with excess EtOAc. The solvent was removed in vacuo and the residue waspartitioned between EtOAc (50 mL) and a 2:1 mixture of water:880 NH3 (50 mL). Theaqueous layer was extracted with EtOAc (25 mL) and the combined organic layers weredried (MgSO4) and evaporated. Purification by column chromatography [SiO2; 4:1(pentane/EtOAc)] gave the product (970 mg, 84%) as an oil; δΗ (CDCI3, 400 MHz) 1.42 10 (9H, s), 2.90 (3H, brs), 3.22 (2H, t), 3.38 (2H, t), 3.84 (3H, s), 4.50 (2H, brd), 6.74 (2H, d), 6.82 (1H, s), 7.13 (1H, d), 7.82 (1H, d), 7.93 (1H, brd); MS m/z (ES+) 430 (MH+).
Compounds of formula XI shown in Table 21 were prepared according to Préparation 50starting from the precursors indicated.
Table 21
Préparation I Precursor data 51 Prep 45 M δΗ (CDCla, 400 MHz) 1.42 (9H, s), 2.86 (2H, m), 3.07 (2H, m), 3.85 (3H, s), 4.37 (2H, m), 4.48(2H, m), 6.48 (2H, m), 6.79 (1H, d), 6.97 (1H, d),7.83 (1H, d), 7.95 (1H, s); MS m/z (ES+) 446(MH*) 52 Prep 46 SMe δΗ (CDCIs, 400 MHz) 1.43 (9H, brs), 2.47 (3H, s), 2.88 (3H, brd), 3.90 (3H, s), 4.51 (2H, brd), 6.81(1H, d), 6.91 (1H, d), 7.06 (1H, s), 7.20 (1H, d), 7.89 (1H, d), 7.98 (1H, brd); MS m/z (TS+) 469(MNH/) 53 Prep 47 SMe δΗ (CDCla, 300 MHz) 1.47 (9H, brs), 2.46 (3H, s),2.91 (3H, brs), 3.94 (3H, s), 4.52 (2H, brs), 6.78(2H, m), 6.91 (1H, d), 7.35 (1H, m), 7.92 (1 H, d),8.02 (1H, brs); MS m/z (TS+) 453 (MNH4+) 012372 78
Préparation Precursor data 54 Prep 48 k SMe δΗ (CDCI3, 300 MHz) 1.44 (9H, s), 2.37 (3H, s), 2.47 (3H, s), 2.94 (3H, br), 3.90 (3H, s), 4.73(2H, br), 6.79-6.87 (3H, m), 7.20 (1 H,d), 7.86(1H,d), 8.00 (1H, br); MS m/z (ES*) 454 (MNa*) PREPARATION 55 3-{î(terf-Butoxvcarbonyl)(methvl)amino1methvn-4-(2,3-dihvdro-1-benzothien-5- yloxy)benzoic acid
A solution of the ester of Préparation 50 (970 mg, 2.26 mmol) in THF (20 mL) and 1MLiOH (20 mL) was heated at reflux for 16 h. After cooling to room température the THFwas removed in vacuo, the residue was neutralised with sat aq NH4CI and the mixturewas extracted with DCM (100 mL) and then ether (100 mL). The combined organic 10 layers were dried (MgSO4) and evaporated to give a white foam (960 mg) which wasused without further purification; δΗ (CDCI3, 400 MHz) 1.30 (9H, s), 2.78 (3H, brs), 3.20(2H, brs), 3.38 (2H, t), 4.41 (2H, m), 6.62 (2H, m), 6.78 (1H, m), 7.10 (1H, m), 7.84 (1H,m), 7.99 (1 H, m); MS m/z (ES ) 414 (M-H). 15 Compounds of formula XII shown in Table 22 were prepared according to Préparation
(Xfl) 012372 79
Table 22
Préparation Precursor data 56 Prep 51 δΗ (CDCI3i 400 MHz) 1.26 (9H, s), 2.74 (3H,s), 3.02 (2H, m), 4.31 (4H, m), 6.38 (2H, m),6.64 (1H, d), 6.87 (1H, d), 7.68 (1H, brs), 7.78 (1H, brs); MS m/z (ES') 430 (M-H+) 57 Prep 52 SMe δΗ (CDCI3i 400 MHz) 1.44 (9H, brs), 2.49(3H, s), 2.92 (3H, brd), 4.57 (2H, brd), 6.82(1H, d), 6.94 (1H, d), 7.08 (1H, s), 7.21 (1H,d), 7.97 (1H, d), 8.04 (1H, brd); MS m/z (ES’)436 (M-H+) 58 Prep 53 X SMe δΗ (CDCI3i 300 MHz) 1.46 (9H, brs), 2.49(3H, s), 2.93 (3H, brs), 4.57 (2H, brs), 6.77(2H, m), 6.92 (1H, d), 7.32 (1H, t), 7.99 (1H,d), 8.08 (1H, brs); MS m/z (ES') 420 (M-H+) PREPARATION 59 ferf-Sutyl 5-(aminocarbonvl)-2-(2,3-dihvdro-1-benzothien-5-vloxy)benzvl- 5 (methyl)carbaroate
Et3N (267 μΙ_, 1.92 mmol), HOBt.H2O (129 mg, 0.84 mmol) and WSCDI (191 mg, 1.0mmoi) were added to a solution of the acid of Préparation 55 (318 mg, 0.77 mmol) inDCM (10 mL) and the mixture was stirred for 1 h before the addition of a saturated 10 solution of NH3 in THF (2 mL). After stirring for a further 16 h the reaction was dilutedwith water (50 mL), 0.2M HCl (20 mL) and DCM (25 mL). The organic layer wasseparated and the aqueous layer was extracted with DCM (25 mL). The combinedorganic layers were dried (MgSO4) and evaporated to give a white foam (assumedquantitative yield) which was used without further purification; δΗ (CDCl3, 400 MHz) 1.44 15 (9H, s), 2.91 (3H, br), 3.27 (2H, t), 3.40 (2H, t), 4.54 (2H, br), 6.75-6.88 (3H, m), 7.18 (1H, d), 7.68 (1H, d), 7.74 (1H, s).
Compounds of formula XIII shown in Table 23 were prepared according to Préparation 59 from the precursors indicated. 012372
Table 23
Préparation Precursor R5 I data 60 Prep 55 H δΗ (CDCI3,400 MHz) 1.43 (9H, s),2.83-3.00 (6H, m), 3.24 (2H, t), 3.39 (2H, t), 4.51 (2H, brs), 6.70-6.85 (3H, m), 7.15 (1H, d), 7.62(1H, d), 7.68(1 H, s) 61 Prep 55 X OMe ιΓί s—' δΗ (CDCl3, 400 MHz) 1.46 (9H, s),2.89 (3H, br), 3.24 (2H, t), 3.37-3.43 (5H, m), 3.56 (2H, t), 3.63(2H, m), 4.54 (2H, br), 6.46 (1H,br), 6.75-6.86 (3H, m), 7.16 (1H,d), 7.62 (1 H, d), 7.69 (1H, s) 62 Prep 58 0 SMe δΗ (de-DMSO, 400 MHz) 1.29 (9H,br), 2.40 (3H, s), 2.75 (3H, s), 4.39 (2H, s), 6.78 (1H, d), 6.91(2H, m), 7.23(1 H, br), 7.36(1 H,t), 7.78 (2H, m), 7.90 (1H, br); MSm/z (TS+) 438 (MNH4+) 63 Prep 58 0 “Άχ H C^LF SMe δΗ (CDCI3, 400 MHz) 1.41 (9H, s),2.40 (3H, s), 2.92 (3H, brs), 2.98(3H, d), 4.45 (2H, brs), 6.10 (1H,brs), 6.67 (2H, m), 6.88 (1H, d),7.27 (1H, obs), 7.63 (2H, m); MSm/z (TS+) 452 (MNH4+) 64 Prep 58 0 OMe C^L.p SMe δΗ (CDCl3,400 MHz) 1.40 (9H, s),2.40 (3H, s), 2.81 (3H, brs), 3.35(3H, s), 3.53 (2H, m), 3.61 (2H,m), 4.44 (2H, brs), 6.45 (1H, brs),6.66 (2H, m), 6.87 (1H, d), 7.29(1H,d), 7.64 (1H, d), 7.72 (1H, s);MS m/z (TS+) 479 (MH+) 012372 81
Préparation Precursor R5 Z data 65 Prep 57 O SMe δΗ (CDCI3, 400 MHz) 1.43 (9H,brs), 2.47 (3H, s), 2.90 (3H, brd),4.52 (2H, brs), 6.87 (1H, d), 6.91(1H, d), 7.03 (1H, s), 7.10 (1H, d),7.72 (1H, d), 7.78 (1H, s); MS m/z(ES') 435 (M-H+) 66 Prep 57 O H ιΓί SMe δΗ (CDCI3, 400 MHz) 1.42 (9H,brs), 2.47 (3H, s), 2.88 (3H, brd),3.00 (3H, d), 4.48 (2H, brs), 6.16(1H, brd), 6.85 (2H, m), 7.01 (1H,s), 7.19 (1H, d), 7.67 (2H, m); MSm/z (ES") 449 (M-H+) 67 Prep 56 δΗ (CDCI3, 400 MHz) 1.42 (9H, s),2.86 (3H, m), 3.08 (2H, m), 3.97(2H, m), 4.48 (2H, brs), 5.86-6.27(2H, brs), 6.45 (1H, s), 6.49 (1H,d), 6.82 (1H, d), 6.96 (1H, d), 7.64 (1H, d), 7.71 (1H, s); MS m/z(TS+) 331 (MH+-Boc) 68 Prep 56 O S OMe % δΗ (CDCI3, 400 MHz) 1.26 (9H, s),2.74 (3H, s), 3.02 (2H, m), 4.31 .(4H, m), 6.38 (2H, m), 6.64 (1H,d), 6.87 (1H, d), 7.68 (1H, brs), 7.78 (1H, brs); MS m/z (ES') 430(M-H+) PREPARATION 69 terf-Butyl 2-f3-chloro-4-(methvlsulfanvl)phenoxv1-5-(hvdroxvmethvl)benzvl- ( methvDcarbamate
A solution of LiAIH4 in THF (1M, 2 mL, 2 mmol) was added dropwise to a solution of theester of Préparation 52 (452 mg, 1 mmol) in THF (10 mL) under N2. Once the reactionwas judged complété by tic analysis, ether (10 mL) was added and the excess LiAIH4was quenched by the cautious addition of 2M NaOH. The organic layerwas separated, 10 washed with brine, dried (MgSO4) and evaporated. Purification of the residue by column chromatography [SiO2; 39:1 (DCM/MeOH)j gave the desired alcohoi (200 mg, 47%) as a 012372 82 gummy white solid; δΗ (CDCI3> 400 MHz) 1.41 (9H, brs), 1.80 (1H, brs), 2.43 (3H, s),2.81 (3H, brd), 4.42 (2H, brd), 4.66 (2H, s), 6.82 (1H, d), 6.88 (1H, d), 6.96 (1 H, s), 7.16(1H, d), 7.27 (2H, obs); MS m/z (ES+) 446 (MNa+). 5 Compounds of formula XIV shown in Table 24 were prepared according to Préparation69 starting from the precursors indicated.
Table 24
Préparation Precursor data 70 Prep 53 SMe δΗ (CDCIa, 400 MHz) 1.39 (9H, brs), 1.99(1H, brs), 2.39 (3H, s), 2.78 (3H, brd), 4.39(2H, brs), 4.62 (2H, d), 6.61 (2H, t), 6.88 (1H,d), 7.20-7.30 (3H, m+CHCI3); MS m/z (TS+) 408 (MH+) 71 Prep 54 à. SMe δΗ (CDCIa, 300 MHz) 1.45 (9H, s), 2.34 (3H,s), 2.46 (3H, s), 2.90 (3H, br), 4.49 (2H, s), 4.67 (2H, s), 6.72-6.81 (2H, m), 6.85 (1H, d), '7.18 (1H, d), 7.21-7.30 (2H, obs); MS m/z(TS+) 404 (MH+) PREPARATION 72 terf-Butyl 3-ffîferf-butoxvcarbonvl)(methvl)amino1methvl)-4-f3-methvl-4- (methylsulfanvl)phenoxv1benzvl(methvlsulfonyl)carbamate
A solution of diethyl azodicarboxylate (505 pL, 3.21 mmol) in THF (5 mL) was addeddropwise to a solution of terf-butyl methylsulfonylcarbamate (synthesised according to 012372 83
Tetrahedron Lett. 1994, 35, 379-380) (655 mg, 3.36 mmol), the alcohol of Préparation71 (1.226 g, 3.04 mmol) and triphenylphosphine (880 mg, 3.36 mmol) in THF (15 mL) at0°C. The réaction was stirred at 0°C for 2 h then diluted with EtOAc (80 mL) and washedwith 10% aq. K2CO3 (100 mL). The organic layer was washed with brine, dried (MgSO4)and evaporated. The residue was purified by column chromatography [SiO2; 1:4EtOAc’.pentane] to give the title compound (1.406 g, 80%) as a colourless oil; δΗ (CDCI3,300 MHz) 1.45 (9H, s), 1.52 (9H, s), 2.38 (3H, s), 2.44 (3H, s), 2.83 (3H, s), 3.22 (3H, s),4.49 (2H, s), 4.85 (2H, s), 6.74-6.83 (3H, m), 7.18-7.29 (3H, obs); MS m/z (TS+) 481(MH+-BOC). PREPARATION 73 terf-Butvl 3-(f(terf-butoxvcarbonyl)(methvl)amino]methvl)-4-f3-fluoro-4- (methvIsulfanvDphenoxvlbenzvKmethvIsulfonyQcarbamate
The title compound was prepared from the alcohol of Préparation 70 by the method ofPréparation 72; δΗ (CDCI3, 300 MHz) 1.44 (9H, s), 1.52 (9H, s), 2.44 (3H, s), 2.82 (3H,s), 3.23 (3H, s), 4.45 (2H, s), 4.87 (2H, s), 6.61-6.70 (2H, m), 6.90 (1H, d), 7.25-7.33(3H, m); MS m/z (ES+) 607 (MNa+). PREPARATION 74 fert-Butvl 4-f(dimethvlamino)methvn-3-f3-methvl-4- (methvlsulfanvl)phenoxvlbenzvl(methylsulfonvDcarbamate
The title compound was prepared from the alcohol of Example 59 by the method of
Préparation 72. The crude product was not purified by column chromatography but taken on directly to the next step; δΗ (CDCI3, 400 MHz) 1.39 (9H, s), 2.22 (6H, s), 2.28 (3H, s), 2.38 (3H, s), 3.07 (3H, s), 3.42 (2H, s), 4.76 (2H, s), 6.72 (2H, m), 6.79 1H, s), 7.07 (1 H, " d), 7.12 (1H, d), 7.40 (1H, obs). 012372 84 PREPARATION 75 fert-Butyl methvir2-f3-methvl-4-(methvlsulfanvl)phenoxvl-5- ({[(trifluoromethvhsulfonvHamino^methvDbenzvIlcarbaroate
The title compound was prepared from the alcohol of Préparation 71 by the method ofPréparation 72 using trifluoromethanesulfonamide instead of fert-butyl 10 methylsulfonylcarbamate. The desired product was contaminated with fert-butyl 5-({{3-{[(fe/Î-butoxycarbonyl)(methyl)amino]methyl)-4-(3-methyl-4-(methylsulfanyl)phenoxy]benzyl}[(trifluoromethyl)suÎfonyljamino}methyl)-2-[3-rnethyl-4-(methylsulfanyl)phenoxy]benzyl(methyl)carbannate and was taken on as a mixture; MSm/z (ES') 533 (M-H+). 15
Compounds of formula XV shown in Table 25 were prepared according to Préparation44 using the precursors indicated. 'Bu 012372 85
Table 25
Préparation Precursor Z data 76 Example 41 δΗ (CDCI3, 400 MHz) (major rotamer) 1.51(9H, s), 2.92 (3H, s), 3.10 (2H, m), 4.40(2H, m), 4.52 (2H, br), 6.53 (2H, m), 6.81(1H, m), 7.03 (1H, d), 7.97-8.21 (2H, m); MS m/z (TS+) 433 (MH+) 77 Example 40 δΗ (CDCI3, 300 MHz) 1.50 (9H, br), 2.99(3H, s), 3.29 (2H, m), 3.43 (2H, m), 4.60(2H, br), 6.81 (2H, m), 6.91 (1H, s), 7.22(1H, d), 8.04 (1H, d), 8.21 (1H, br) 78 Example 42 δΗ (CDCI3, 400 MHz) 1.56 (9H, s), 2.15(2H, m), 2.85-3.00 (7H, m), 4.60 (2H, brd),6.78 (2H, m), 6.87 (1H, s), 7.12 (1H, d), 8.03 (1H, d), 8.10 (1H, s); MS m/z (TS+) 399 (MH+) PREPARATION 79 terf-Butyl methvlf2-f3-methyl-4-(methvlsulfanyl)phenoxvl-5-nitrobenzvl)carbamate
/V-Methyl-A/-(2-[3-methvl-4-(methvlsulfanvl)phenoxvl-5-nitrobenzvl)amine and {2-T3- methvl-4-(methvlsulfanvl)phenoxv1-5-nitrophenvl)methanol.
To a suspension of the aldéhyde of Préparation 39 (21.0 g, 69.2 mmol) in EtOH (100mL) was added 8M methylamine in EtOH (86.5 ml, 692 mmol). A solution was given and 10 after stirring for a short time a precipitate was observed. This was re-dissolved by theaddition of THF (100 mL), the solution was cooled to 0°C and NaBH4 (7.85 g, 208 mmol)was then added. The réaction was allowed to warm slowly to room température andstirred overnight before the solvent was removed in vacuo. The residue was taken up inwater (150 mL) and ether (150 mL), and 2M HCl was added cautiously until pH 1. The 15 layers were separated and the aqueous layer was washed with ether (2x100 mL). The combined organic extracts were dried and evaporated to give {2-[3-methyl-4- (methylsulfanyl)phenoxy]-5-nitrophenyl}methanol (18.9 g, 89%) as a yellow solid; δΗ 012372 86 (CDCIa, 400 MHz) 2.35 (3H, s), 2.48 (3H, s), 4.90 (2H, s), 6.79 (1 H, d), 6.89 (1 H, s), 6.91 -(1H, d), 7.22 (1H, d), 8.07 (1H, dd), 8.41 (1H, d).
The aqueous layer from above was neutralised by pouring onto excess solid K2CO3. The *basic solution was extracted with ether (2x100 mL) and these ether extracts were dried(MgSO4) and evaporated to give A/-methyl-/V-{2-[3-methyl-4-(methylsulfanyl)phenoxy]-5-nitrobenzyl}amine (1.65 g, 7.5%) as an orange oil; MS m/z (ES+) 319 (MH+).A/-Methvl-/V-{2-f3-methvl-4-(methylsulfanvl)phenoxv1-5-nitrobenzvl)amine from (2-F3- methvl-4-(methylsulfanvl)phenoxv1-5-nitroohenvl}methanol.
Methanesulfonyl chloride (4.81 mL, 61.9 mmol) was added slowly to a solution of {2-[3-methyl-4-(methylsulfanyl)phenoxy]-5-nitrophenyl}methanol (18.9 g, 61.9 mmol) and Et3N(9.5 mL, 68.2 mmol) in DCM (60 mL). The mixture was stirred at room température for 3h then poured into water and extracted with DCM (3 times). The combined organicextracts were dried (MgSO4) and evaporated to give a dark, viscous oil. This oil wastaken up in DCM (50 mL) and 8M methylamine in EtOH (200 mL, 1.6 mol) was addedfollowed by Et3N (10 mL, 71.7 mmol). After stirring for 18 h the mixture was concentratedin vacuo to give crude amine which was used without further purification. tert-Butyl methvl(2-r3-methvl-4-(methvlsulfanvl)phenoxv1-5-nitrobenzvl)carbamate
The crude amine from above was dissolved in DCM (100 mL) at 0°C and Et3N (11.4 mL,81.8 mmol) was added, followed by di-ierf-butyl dicarbonate (15.0 g, 68.7 mmol). Theréaction was allowed to warm to room température and stirred for 16 h before beingconcentrated in vacuo. The residue was partitioned between EtOAc and water and theaqueous layer was extracted with EtOAc (2 times). The combined organic layers weredried (MgSO4) and evaporated. The residue was purified by column chromatography(SiO2; 1sl column - 3% MeOH in DCM; 2"d column EtOAcrpentane 1:3) to give the titlecompound (14.2 g, 54%) as a yellow oil; δΗ (CDCI3,400 MHz) 1.44 (9H, s), 2.32 (3H, s),2.44 (3H, s), 2.95 (3H, s), 4.56 (2H, br), 6.75 (1H, d), 6.84 (2H, m), 7.17 (1H, d), 8.00(1H, d), 8.18 (1H, br); MS m/z (TS+) 419 (MH+).
Compounds of formula XVI shown in Table 26 were prepared according to Example 103from the precursors indicated 01237 2
Table 26
Préparation Precursor Z data 80 Prep 77 δΗ (CDCI3, 300 MHz) 1.50 (9H, br), 2.80(3H, br), 3.20 (2H, m), 2.37 (2H, m), 3.60(2H, br), 4.40 (2H, s), 6.50-6.80 (5H, m), 7.05 (1H, d); MS m/z (ES+) 387 (MH+) 81 Prep 78 4 δΗ (CDCI3, 400 MHz) 1.42 (9H, s), 2.05 (2H,m), 2.80 (7H, m), 4.37 (2H, s), 6.50-6.65(3H, m), 6.69 (1H, s), 6.78 (1H, d), 7.08(1H, d); MS m/z (TS+) 369 (MH+) 82 Prep 76 δΗ (CDCI3, 400 MHz) 1.43 (9H, s), 2.88 (3H,br), 3.07 (2H, m), 3.59 (2H, br), 4.30 (2H,s), 4.36 (2H, m), 6.32 (1H, s), 6.40 (1H, d),6.49-6.65 (2H, m), 6.75 (1 H, d), 6.88 (1H,d); MS m/z (TS+) 403 (MH+) 83 Prep 79 Γί SMe δΗ (CDCI3, 300 MHz) 1.47 (9H, s), 2.33 (3H,s), 2.40 (3H, s), 2.82 (3H, br), 3.60 (2H, s),4.35 (2H, s), 6.50-6.77 (4H, m), 6.80 (1H,d), 7.16 (1H, d); MS m/z (TS+) 389 (MH+) 5 PREPARATION 84 tert-Butvl methvl{2-f3-methyl-4-(methvlsulfanvl)phenoxv1-5- f (methvlsulfonvl)arnino1benzvi)carbarnate
Methanesulfonyl chloride (4.16 mL, 53.7 mmol) was added dropwise to a solution of the 10 aniline of Préparation 83 (9.5 g, 24.5 mmol) and Et3N (7.5 mL, 53.8 mmol) in DCM (50 mL) at 0°C. After stirring at 0°C for 30 min the reaction was allowed to warm to room 012372 88 température before the solvent was removed in vacuo. 2M NaOH (50 mL) was added tothe residue and the mixture was stirred for 30 min. The mixture was extracted withEtOAc and the organic layer was washed with brine, dried (MgSO4) and evaporated togive an oil. Purification by column chromatography [SiO2; 97.5:2.5:0.25 5 (DCM/MeOH/880 NH3)] gave the product (9.0 g, 79%) as a brown foam; δΗ (CDCI3) 300MHz) 1.43 (9H, brs), 2.35 (3H, s), 2.42 (3H, s), 2.88 (3H, brs), 3.01 (3H, s), 4.46 (2H,brs), 6.76 (2H, d+s), 6.83 (1H, d), 7.16 (1 H, s), 7.20 (2H, brs); MS m/z (ES+) 467 (MH+).
Compounds of formula XVII shown in Table 27 were prepared according to Préparation
Table 27
Préparation Precursor (Jl. Z data 85 Prep 81 &amp; δΗ (CDCI3i 400 MHz) (rotamers) 1.44 and 1.48 (9H, 2xs), 2.10 (2H, quintet), 2.88 (7H,m), 3.00 (3H, s), 4.49 (2H, br), 6.23 (1H, br),6.72 (1H, d), 6.81 (1H, s), 6.83 (1H, d), 7.13(3H, m); MS m/z (TS+) 347 (MH+-Boc) 86 Prep 80 ιΓί 3—J Product used without purification. 87 Prep 82 δΗ (CDCI3> 400 MHz) (rotamers) 1.40 and 1.44 (9H, 2xs), 2.80 and 2.85 (3H, 2xs), 2.95(3H, s), 3.07 (2H, m), 4.38 (2H, m), 6.36 (1H,s), 6.44 (1H, d), 6.84 (1H, d), 6.92 (1 H, d), 7.12 (2H, m); MS m/z (TS+) 498 (MNH4+) 012372 89 terf-Butyl methvl{2-r3-methvl-4-(methvlsulfanyl)phenoxv1-5-fmethvl(methvl- sulfonvDaminolbenzvDcarbamate PREPARATION 88
SMe 5 Mel (1.07 mL, 17.2 mmol) was added dropwise to a mixture of the sulfonamide ofPréparation 84 (2.0 g, 4.3 mmol) and K2CO3 (592 mg, 4.3 mmol) in CH3CN (10 mL)under N2. The mixture was stirred for 16 h and then partitioned between EtOAc (50 mL)and 2M NaOH (50 mL). The organic layer was washed with brine, dried (MgSO4) andevaporated. The residue was purified by column chromatography [SiO2; 590:10:1 10 (DCM/MeOH/880 NH3)] to give the product (1.23 g, 60%) as a yellow oil; δΗ (CDCI3, 300MHz) 1.45 (9H, s), 2.34 (3H, s), 2.42 (3H, s), 2.86 (3H, s), 2.90 (3H, s), 3.28 (3H, s),4.49 (2H, s), 6.80 (3H, br), 7.18 (3H, m); MS m/z (TS+) 498 (MNH4+). PREPARATION 89 15 tetf-Butvl 5-f(2-hvdroxyethvl)(methvlsulfonvl)amino1-2-f3-methvl-4- (methylsulfanvl)phenoxv1benzyl(methvl)carbamate
2-Bromoethanol (1.34 mL, 18.9 mmol) was added to a mixture of the sulfonamide ofPréparation 84 (2.0 g, 4.3 mmol) and K2CO3 (2.605 g, 18.8 mmol) in CH3CN (10 mL) 20 under N2. The mixture was heated at reflux for 16 h, cooled and then partitioned between EtOAc (50 mL) and 2M NaOH (50 mL). The organic layer was washed with brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography [SiO2; 390:10:1 (DCM/MeOH/880 NH3)] to give the product (524 mg, 24%) as a pink foam; δΗ (CDC!3, 300 MHz) 1.42 (9H, s), 2.37 (3H, s), 2.43 (3H, s), 2.91 012372 (3H, s), 2.98 (3H, s), 3.68 (2H, brs), 3.79 (2H, d), 4.49 (2H, s), 6.81 (3H, m), 7.19 (3H, ‘ m); MS m/z (TS+) 528 (MNH4+). 90 PREPARATION 90 5-Amino-2-(2,3-dihvdro-1.4-benzoxathin-6-vloxv)benzonitrile
10 10
Fe powder (930 mg, 16.7 mmol) was added to the nitro compound of Préparation 41(740 mg, 2.38 mmol) in AcOH (5 mL) and water (1 mL) and the mixture was stirred atroom température for 16 h. The solvent was removed in vacuo, the residue was taken upin EtOAc (50 mL) and 10% aq K2CO3 (50 mL) and filtered through Arbocel®. Theorganic layer was separated and the aqueous layer was extracted with EtOAc (50 mL).The combined organic extracts were dried (MgSO4) and evaporated to a brown foam(670 mg, 99%) which was used without further purification; δΗ (CDCI3, 400 MHz) 3.18(2H, m), 4.36 (2H, m), 6.60-6.70 (2H, m), 6.70-6.80 (3H, m), 6.85 (1H, s); MS m/z (TS+)302 (MNH/).
Compounds of formula Vb, Le. compounds of formula V where T is cyano, R4 ishydrogen and Rs is amino, shown in Table 28 were prepared according to Préparation90 from the precursors indicated. 20 (Vb) 012372 91
Table 28
Préparation Precursor Z data 91 Prep 35 SMe δΗ (CDCI3, 400 MHz) 2.40 (3H, s), 6.62-6.72 (2H, m), 6.80-6.90 (3H, m), 7.28 (1H,d) 92 Prep 37 î. SMe δΗ (CDCI3, 300 MHz) 2.47 (3H, s), 3.83(2H, br), 6.83-6.94 (4H, m), 7.01 (1H, s),7.19 (1H, d); MS m/z (TS+) 308 (MNH4+) 93 Prep 42 SMe δΗ (CDCI3,400 MHz) 2.30 (3H, s), 2.40(3H, s), 3.84 (2H, br), 6.77 (4H, m), 6.85(1H, s), 7.13 (3H, d); MS m/z (TS+) 288(MNH4+) PREPARATION 94 5-Amino-2-r4-methvl-3-(methvlsulfanv0phenoxvlbenzonitrile
The title compound was prepared from the nitro compound of Préparation 43 by themethod of Example 103; δΗ (CDCI3, 400 MHz) 2.27 (3H, s), 2.41 (3H, s), 3.66 (2H, br),6.62 (1H, d), 6.79 (2H, s), 6.82 (1H, s), 6.89 (1H, s), 7,08 (1H, d); MS m/z (ES+) 293(MNa+), (ES') 269 (M-H+).
Compounds of formula Vc, i.e. compounds of formula V where T is cyano, R4 ishydrogen and R5 is -NHSO2Me, shown in Table 29 were prepared according toPréparation 84 from the precursors indicated.
15 012372 92
Table 29
Préparation Precursor data 95 Prep 90 4 δΗ (CDCI3, 400 MHz) 2.98 (3H, s), 3.10 (2H, m), 4.39 (2H, m), 6.67 (1H, dd), 6.76 (1H,s), 6.81 (1 H, d), 7.33 (1H, dd), 7.49 (1H, s);MS m/z (TS+) 380 (MNH/) 96 Prep 92 ά. SMe δΗ (CDCIa, 300 MHz) 2.51 (3H, s), 3.06 (3H,s), 6.52 (1H, br), 6.92 (1H, d), 7.02 (1H,dd), 7.14 (1H, d), 7.24 (1H, d), 7.41 (1H,dd), 7.57 (1H, d); MS m/z (ES+) 391 (MNa+) 97 Prep 91 δΗ (CDCI3i 400 MHz) 2.43 (3H, s), 3.02 (3h, S), 6.41 (1H, brs), 6.72-6.85 (2H, m), 6.92(1H, d), 7.28 (1H, t), 7.38 (1H, d), 7.51 (1H,s); MS m/z (ES+) 351 (MH+) 98 Prep 93 SMe δΗ (CDCI3, 400 MHz) 2.19 (3H, s), 2.42 (3H,s), 2.99 (3H, s), 6.81 (1H, d), 6.86 (2H, m),7.15 (1H, d), 7.33 (1H, d), 7.51 (1H, s); MSm/z (TS+) 366 (MNH/) 99 Prep 94 Me δΗ (CDCI3, 400 MHz) 2.31 (3H, s), 2.43 (3H,s), 3.02 (3H, s), 6.61 (1H, s), 6.72 (1H, dd),6.83 (1H, d), 6.88 (1H, s), 7.17 (1H, d), 7.37(1H, dd), 7.55 (1H, s); MS m/z (TS+) 366(MNH4+) PREPARATION 100 N-f3-Cvano-4-f3-methvl-4-(methvlsulfanvl)phenoxv1phenvl)-A/- 5 methvlmethanesulfonamide
The title compound was prepared from the sulfonamide of Préparation 98 by the methodof Préparation 88; δΗ (CDCI3,400 MHz) 2.31 (3H, s), 2.44 (3H, s), 2.83 (3H, s), 3.27 (3H,s), 6.79 (1H, d), 6.88 (2H, m), 7.17 (1H, d), 7.44 (1H, dd), 7.58 (1H, d); MS m/z (ES+) 10 385 (MNa+). P123/ 93 PREPARATION 101 1,3-Dihvdro-2-benzothiophen-5-ol
OK ’—s (i) Préparation of i4-(allvloxv)-2-(hvdroxymethvl)phenvnmethanol
Dimethyl 4-(allyloxy)phthalate [préparée! according to Inouye, M.; Tsuchiya, K.; Kitao, T.Angew. Chem. 1992, 104, 198-200 (See also Angew. Chem., Int. Ed. Engl., 1992, 204-205)J (θ·9 9. 38 mmol) was dissolved in THF (40 mL) and cooled to 0°C before thedropwise addition of lithium aluminium hydride (1M in THF, 77 mL, 77 mmol) over 10min. The mixture was then allowed to stir at room température for 3 h before beingquenched cautiously by the addition of water (1.4 mL) followed by 2M NaOH (1.4 mL).Excess MgSO4 was then added followed by water until a granular precipitate formed (ca. 5 mL). The mixture was then filtered and evaporated to a brown oil (7.1 g, ca. 95%). 1HNMR showed the material to be of ca. 85% purity. It was used directly in the next stagewithout.further purification; δΗ (CDCI3, 400 MHz) 2.63 (1H, brs), 2.91 (1H, brs), 4.52 (2H,m), 4.67 (4H, m), 5.26 (1H, dd), 5.38 (1H, dd), 5.97-6.09 (1H, m), 6.80 (1H, dd), 6.92(1H, d), 7.22(1 H, d). (ii) Préparation of 5-(allvloxv)-1,3-dihvdro-2-benzothiophene
Crude diol from stage (i) (3.5 g, 18 mmol) was dissolved in DCM (60 mL) and treatedwith Et3N (10 mL, 72 mmol) and the solution was cooled to 0°C. Methanesulfonylchloride (4.2 mL, 54 mmol) was added dropwise and the solution was stirred for 1 hbeing allowed to reach room température. The reaction was then quenched by theaddition of water followed by 2M HCl (50 mL). The DCM layer was separated and theaqueous layer was re-extracted with DCM (50 mL). The combined organic fractions werewashed with water (50 mL), dried (MgSO„) and concentrated to a volume of ca. 30 mL.Benzyltriéthylammonium chloride (1 g) was added followed by a solution of sodiumsulfide (5 g, 91 mmol) in water (50 mL). The mixture was stirred rapidly under a nitrogenatmosphère for 15 h. The organic layer was separated and the aqueous layer was re-extracted with DCM (50 mL). The combined organic layers were dried (MgSO4) andevaporated to a yellow oil. Flash chromatography afforded two fractions; the first waspure product and the second product contaminated with dimeric material. Trituration ofthe second fraction caused crystallisation of the dimeric material which was removed byfiltration. The filtrate was combined with the first chromatography fraction to afford the 012372 94 desired product (800 mg, 23%); δΗ (CDCI3, 400 MHz) 4.16 (2H, s), 4.19 (2H, s), 4.48(2H, m), 5.26 (1H, d), 5.37 (1 H, d), 5.95-6.06 (1H, m), 6.74 (2H, m), 7.09 (1H, d). (iii) Préparation of 1,3-dihvdro-2-benzothiophen-5-ol
The allyl ether from stage (ii) (800 mg, 4.16 mmol) was dissolved in THF (10 mL) andtreated with palladium tetrakis(triphenylphosphine) (481 mg, 0.42 mmol) followed bysodium borohydride (944 mg, 25 mmol). The mixture was then heated to 45 °C andstirred at this température for 15 h. After cooling to room température the THF wasevaporated and the residue partitioned between 2M NaOH solution (25 mL) and diethylether (25 mL). The aqueous layer was separated and the organic layer re-extracted with2M NaOH solution (25 mL). The combined aqueous layers were neutralised to pH 7-8with concentrated hydrochloric acid and extracted with EtOAc (2 x 25 mL). Thecombined organic extracts were dried (MgSO4) and evaporated to a clear oïl of the titlephénol which sotidified upon standing (540 mg, 85%); 4.14 (2H, s), 4.17 (2H, s), 6.63-6.68 (2H, m), 7.04 (1H, d).
Biological Activitv A number of compounds were tested for biological activity by their ability to inhibit theuptake of serotonin by human serotonin transportera as follows. (i) Cell Culture
Human embryonic kidney cells (HEK-293) stably transfected with either thehuman serotonin transporter (hSERT), noradrenaline transporter (hNET) or 'dopamine transporter (hDAT) were cultured under standard cell culturetechniques (cells were grown at 37°C and 5% CO2 in DMEM-culture media(supplemented with 10% dialysed foetal calf sérum (FCS), 2mM l-glutamine and250pg/ml geneticin)). Cells were harvested for the assay to yield a cellsuspension of 750,000 cells/ml. (i) Détermination of inhibitor potencv
Ail test compounds were dissolved in 100% DMSO and diluted down in assaybuffer to give appropriate test concentrations. Assays were carried out in 96-wellfilter bottom plates. Cells (7500 cells/assay well) were pre-incubated in standardassay buffer containing either test compound, standard inhibitor or compoundvehicle (1% DMSO) for 5 minutes. Reactions were started by addition of either3H-Serotonin, 3H-Noradrenaline or 3H-Dopamine substrates. Ail reactions were 012372 95 carried out at room température in a shaking incubator. Incubation times were 5 minutes for the hSERT and hDAT assays and 15 minutes for the hNET assay.
Reactions were terminated by removal of the reaction mixture using a vacuum manifold followed by rapid washing with ice cold assay buffer. The quantity of 3H- substrate incorporated into the cells was then quantified.
Assay plates were dried in a microwave oven, scintillation fiuid added, andradioactivity measured. Potency of test compounds was quantified as IC50 values(concentration of test compound required to inhibit the spécifie uptake ofradiolabelled substrate into the cells by 50%). (iii) Standard Assay Buffer Composition:
Trizma hydrochloride (26mM)
NaCI (124mM) KCl (4.5mM) KH2PO4 (1.2mM)
MgCI2.6H2O (1.3mM)
Ascorbic acid (1.136mM)
Glucose (5.55mM)pH 7.40CaCI2 (2.8mM)
Pargyline (100μΜ)
Note: The pH of the buffer was adjusted to 7.40 with 1M NaOH before additionof CaCl2 and pargyline. (iv) Sumroarv of Assay Parameters hSERT Assay hDAT Assay hNET Assay Cell concentration per assay well. 75,000 75,000 75,000 Substrate Concentration. 3H-5HT (50nM) 3H-Dopamine (200nM) 3H-Noradrenaline (200nM) Incubation time (minutes) 5 5 15 0)2372
Compounds having a serotonin re-uptake inhibition (SRI) IC50 value of less than or equal «* to 100nM include thetitle compounds of Examples 1-6, 8-23, 25, 26, 29-32, 34-36, 43,45-49,51,56-102,109-130.
Compounds having an serotonin re-uptake inhibition (SRI) IC50 value of less than orequal to 100nM and which are more than 10-fold as potent in the inhibition of serotoninre-uptake than in the inhibition of dopamine re-uptake or noradrenaline re-uptake includethe title compounds of Examples 1-6, 9-13,16-19, 21, 22, 25, 26, 29-32, 34-36, 43, 45,47-49, 51, 57-88, 90-102, 109-121, 123, 124, 127, 129.
Compounds having an serotonin re-uptake inhibition (SRI) IC50 value of less than orequal to 10OnM and which are more than 10O-fold as potent in the inhibition of serotoninre-uptake than in the inhibition of dopamine re-uptake or noradrenaline re-uptake includethe title compounds of Examples 1, 2, 4, 5, 9, 12, 13, 16-19, 21, 22, 25, 26, 29-32, 34-36, 43, 45, 48, 49, 58-80, 83-88, 90, 92-97, 99-102, 111-113, 115-118, 120, 123, 124,127.
Compounds having an serotonin re-uptake inhibition (SRI) IC50 value of less than orequal to 50nM and which are more than 100-fold as potent in the inhibition of serotoninre-uptake than in the inhibition of dopamine re-uptake and noradrenaline re-uptakeinclude the title compounds of Examples 1, 2, 4, 9, 12, 17,18, 26, 29, 30, 36, 43, 45,-48,49, 60-66, 68-75, 78, 79, 90, 92-94, 100, 102, 116, 118, 124.
In particular, the title compound of Example 16 had a serotonin re-uptake inhibition (SRI)ICS0 of 4.7 nM; the title compound of Example 29 had a serotonin re-uptake inhibition(SRI) ICsq of 2.0 nM; and the title compound of Example 62 had a serotonin re-uptakeinhibition (SRI) IC50 of 3.7 nM.

Claims (1)

012372 97 Claims A compound of general formula (I), pharmaceutically acceptable salts, solvatésor polymorphs thereof; NR1R2Claims A compound of general formula (I), pharmaceutically acceptable salts, solvatorti polymorphs thereof; NR1R2 10 15 20 wherein; R1 and R2, which may be the same or different, are H, Ci-C6alkyl or (CH2)d(C3-C6cycloalkyl) wherein d = 0, 1, 2 or 3; or R1and R2 togetherwiththe nitrogen to which they are attached form an azetidine ring; Z or Y is -SR3 and the other Z or Y is halogen or -R3; wherein R3 is independentlyC.,-C4 alkyi optionally substituted with fluorine; except that R3 is not CF3; or Z and Y are linked so that, togetherwith the interconnecting atoms, Z and Yform a fused 5 to 7-membered carbocyclic or heterocyclic ring which maybe saturated, unsaturated or aromatic, and wherein when Z and Y form aheterocyclic ring, in addition to carbon atoms, the iinkage contains one ortwo heteroatoms independently selected from oxygen, sulfur and nitrogen;with the proviso that when R5 is fluorine and R2 is methyl thsn the fusedring is not 1,3-dioxaiane and Z and Y together do not form a fused phenyiring; R4 and R5, which may be the same or different, are: A-X, wherein A = -CH=CH- or -(CH2)P- where p is 0, 1 or 2; X is hydrogen, F, Ci,Br, l, ÇONR6R7, SO2NR6R7, SO2NHC(=O)RE, OH, CMalkoxy, NR6SO2RS,NO2, NR6R11, CN, CO2R10, CHO, SR10, S(O)RS or SO2R10; R6, R7, R8 andR10 which may be the same or different, are hydrogen or C-j_ealkyioptionally substituted independently by one or more R12; Rs is Cv6 alkyioptionally substituted independently by one or more R12; R11 is hydrogen,0,.6 alkyi optionally substituted independently by one or more R12, C(O)R6,CO2R9, C(O)NHR6 or SO2NR6R7; R12 is F, OH, CO2H, C^cycioaikyi, NH2,CONHj, C^alkoxy, C^alkoxycarbonyi or a 5- or 6-membered heterocyclic 25 012372 98 ring containing 1, 2 or 3 heteroatoms selected from N, S and O optionallysubstituted independently by one or more R13; or R6 and R7, together withthe nitrogen to which they are attached, form a 4-, 5- or 6-memberedheterocyclic ring optionally substituted independently by one or more R13; 5 or 5- or 6-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selectedfrom N, S and O, optionally substituted independently by one or more R13; wherein R13 is hydroxy, C1-C4alkoxy, F, CrCgalkyl, haloalkyl, haloalkoxy, -NH2,-NH(CrCsalkyl) or -N(CrC6alkyl)2. 10 2 A compound according to claim 1, pharmaceutically acceptable salts, solvatés orpolymorphs thereof, wherein R1 and R2, which may be the same or different, are ihydrogen or CrC6alkyl. 15 3 A compound according to daims 1 or 2, pharmaceutically acceptable salts, solvatés or polymorphs thereof, wherein when Z or Y is -SR3, R3 is methyl orethyl. 4 A compound according to daims 1 or 2, pharmaceutically acceptable salis, 20 solvatés or polymorphs thereof, wherein when Z and Y are iinked to form a fused ring, the ring is a heterocyclic ring. 5 A compound according to daim 4, pharmaceutically acceptabie salts, solvatés orpolymorphs thereof, wherein in addition to carbon atoms, the linkage contains 25 one or two suifur atoms. 6 A compound according to any preceding daim, pharmaceutically acceptabiesalts, solvatés or polymorphs thereof, wherein R6 and R7, which may be the sameor different, are hydrogen, C^Csalkyl optionally substituted by hydroxy, -CONH2 30 or C1-C3alkoxy. 7 A compound according to any preceding claim, pharmaceutically acceptable salts, solvatés or polymorphs thereof, wherein R8 is hydrogen, hydroxyethyl ormethyl. 35 01237^ 99 8 A compound according to any preceding ciaim, pharmaceutically acceptablesalts, solvatés or polymorphs thereof, wherein R9 is methyl, ethyl, isopropyl,trifluoromethyl or methoxyethyl. 5 9 A compound according to any preceding daim, pharmaceutically acceptable salts, soivates or polymorphs thereof, wherein p is 1 or 0. 10 A compound according to any preceding daim, pharmaceutically acceptablesalts, soivates or polymorphs thereof, wherein R4 and R5, which may be the 10 same or different, are -(CH2)P-X, where p is û, 1 or 2; X is hydrogen, hydroxy, CONR6R7, SO2NR6R7,NR8SO2R9, SR10, SOR9 or SO2R10 wherein Re, R7, R8, R8 and R10 are asdefmed in daim 1, or 5- or 6-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected15 from N, S and O. 11 A compound according to any preceding daim, pharmaceutically acceptablesalts, soivates or polymorphs thereof, wherein R4 and R5, which may be thesame or different, are: 20 -(CH2)p-X, where p is 0 or 1; X is hydrogen, hydroxy, CONR6R7, SO2NR5R7 or NR8SO2R9; wherein R6 and R7, which may be the same or different, arehydrogen or CrC3alkyl optionaily substituted by hydroxy, -CONH2 or C·,-C3alkoxy (preferably methoxy); Ra is hydrogen, hydroxyethyl or methyl; orR9 is methyl, ethyl, isopropyl, trifluoromethyl or methoxyethyl; or 25 triazolyl, imidazolyl or pyrazoiyl. 12 A compound according to any preceding daim, pharmaceutically acceptable salts, soivates or polymorphs thereof, wherein R4 and R5 are not both hydrogen. 30 13 A compound according to any preceding daim, pharmaceutically acceptable t salts, soivates or polymorphs thereof, wherein R4 is hydrogen. 14 A compound according to cîaim 1, pharmaceutically acceptable salts, soivates orpolymorphs thereof, selected from the group: 012372 100 4-(2,3-dihydro-1-benzothien-5-yloxy)-3-[(methytamino)methyi]- benzenesuifonamide (Example 2); 3- [(dimetbylamino)methyl]-4-[3-methyl-4-(methyisulfanyl)phenoxy]-benzenesulfonamide (Example 12); 4- (2,3-dihydro-1-benzothien-5-yloxy)-3-[(dimethyiamino)methyl]-benzenesulfonamide (Example 16); 4-[3-chioro-4-(methylsulfanyl)phenoxy]-3-[(dimethylamino)methyl]-benzenesulfonamide (Example 17); 3-[(dimethylamino)methyl]-4-[3-fluoro-4-(tnethylsulfanyl)phenoxy]-benzenesuifonamide (Example 18); W,/V-dirnethyl-/V-[2-(6-quinoiinyloxy)benzyl]amine (Example 29); 3- [(methylamino)methyl]-4-(6-quinolinyloxy)benzenesulfonamide (Exampie 35); 4- (2,3-dihydro-1-benzothien-5-yioxy)-3-[(methyiamino)methylîbenzamide(Example 60); 4-(2,3-dihydro-1-benzothien-5-yioxy)-/\/-methyl-3-[(methylamino)methyi]-benzamide (Example 62); W-{3-[(methyiamino)methyl]-4-[3-methyl-4-(methylsuifanyl)phenoxy]benzyl}methanesuifonamide (Exampie 75); 3- [(methyiamino)methyi]-4-[3-methyi-4-(methylsu!fanyi)phenoxy3benzamide(Example 79); 4- (2,3-dihydro-1,4-benzoxathiin-7-yloxy)-3-[(dimethylamino)methyl]benzamide(Exampie 88); {3-[(dimethy!amino)methyl]-4-[3-fluoro-4-(methyisulfanyl)phenoxy]phenyl}-methanol (Example 90); 3-[(dimethyiamino)methyl]-4-(6-quinolinyioxy)benzamide (Example 100);3-[(methylamino)methyl}-4-(6-quinoiinyloxy)benzarnide (Example 102);W-methyl-W-{3-[(methylamino)methyl]-4-[3-methyl-4-(methylsulfany!)phenoxy]-phenyljmethanesulfonamide (Example 116) and A/-{4-(2,3-dihydro-1,4-benzoxathiin-7-yioxy)-3-[{dimethyiamino)methyi]phenyl}-methanesulfonamide (Exampie 124). 15 A compound as defined in any preceding claim, pharmaceuiically acceptable saits, soivates or polymorphe thereof, for use as a pharmaceuticai. 16 16 5 17 5 17 10 18 10 18 1915 20 012372 101 1915 20 A pharmaceutical formulation containing a compound as defined in any one ofdaims 1 to 14, or pharmaceuticatly acceptable salts, solvatés or polymorphsthereof, and a pharmaceutically acceptable adjuvant, diluent or carrier. The use of a compound as defined in any of daims 1 to 14, pharmaceuticallyacceptable salts, solvatés or polymorphs thereof, in the manufacture of amédicament for the treatment or prévention of a disorder in which the régulationof monoamine transporter fonction is implicated. The use according to claim 17 wherein the disorder is dépréssion, attentiondéficit hyperactivity disorder, obsessive-compulsive disorder, post-traumaticstress disorder, substance abuse disorders or sexual dysfonction. The use according to claim 18 wherein the disorder is prématuré éjaculation. Use of a compound as defined in any one of daims 1-14, pharmaceuticallyacceptable salts, solvatés or polymorphs thereof, in the manufacture of a substanceto increase ejaculatory latency. 20 21 20 21 A process for the préparation of a compound of general formula (I); 25 Z (I) 30 012372 102 wherein R1, R2, R4, R5, X and Z are as defmed in any one of ciaims 1 to 14comprising reacting a compound of general formula la NR1R210; R1 and R2, which may be the same or different, are H, C1-C6alkyl or (CH2) d (C3-C6cycloalkyl) d = 0, 1, 2 or 3; or R1and R2 togetherwiththe nitrogen to which they are attached form an azetidine ring; Z or Y is -SR3 and the other Z or Y is halogen or -R3; R3 is independently C., -C4 alkyl substituted with fluorine; except that R3 is not CF3; or Z and Y are linked together, with the interconnecting atoms, Z and Yform a fused 5 to 7-membered carbocyclic or heterocyclic ring which may be saturated, unsaturated or aromatic, and wherein Z and Y form aheterocyclic ring, in addition to carbon The invention also relates to the subject of the present invention, wherein the compounds are independently selected from oxygen, sulfur, and nitrogen, with the proviso that when R 5 is fluorine and R 2 is methyl, the fused ring is not 1,3-dioxane and Z and Y together do not form a fused phenyiring. ; R4 and R5, which may be the same or different, are: A-X, where A = -CH = CH- or - (CH2) P- where p is 0, 1 or 2; X is hydrogen, F, Cl, Br, 1, SOONR6R7, SO2NR6R7, SO2NHC (= O) RE, OH, CMalkoxy, NR6SO2RS, NO2, NR6R11, CN, CO2R10, CHO, SR10, S (O) RS or SO2R10; R6, R7, R8 and R10 which may be the same or different, are hydrogen or independently R12; Rs is Cv6 independently or independently R12; R11 is hydrogen, O, R12, C (O) R6, CO2R9, C (O) NHR6 or SO2NR6R7; R12 is F, OH, CO2H, C₁ cy cycycloalkyl, NH₂, CONH₁, C₁ alk alkoxy, C₁ alk alkoxycarbonyl or 5-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, S and O; optionallysubstituted independently by one or more R13; or R6 and R7, together withthe nitrogen to which they are attached, form 4-, 5- or 6-membered heterocyclic ring independently by R13; 5 or 5 or 6-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selectedfrom N, S and O, independently of one or more of R13; R13 is hydroxy, C1-C4alkoxy, F, CrCalkyl, haloalkyl, haloalkoxy, -NH2, -NH (CrCsalkyl) or -N (CrC6alkyl) 2. A compound according to claim 1, pharmaceutically acceptable salts, solvated orpolymorphs thereof, wherein R1 and R2, which may be the same or different, are hydrogen or CrC6alkyl. A compound according to 1 or 2, pharmaceutically acceptable salts, solvates or polymorphs thereof, wherein Z or Y is -SR3, R3 is methyl orethyl. A compound according to 1 or 2 suede, pharmaceutically acceptable salts, solvates or polymorphs thereof, wherein are provided in a heterocyclic ring. A compound according to suede 4, pharmaceutically acceptable salts, solvated orpolymorphs thereof, wherein in addition to carbon atoms, the linkage contains one or two sulfur atoms. 6. A compound according to any preceding suede, pharmaceutically acceptabiesalts, solvates or polymorphs thereof, wherein R6 and R7, which may be the sameor different, are hydrogen, C1-C3alkyl, substituted by hydroxy, -CONH2 or C1-C3alkoxy. 7 A compound according to the preceding claim, pharmaceutically acceptable salts, solvates or polymorphs thereof, R8 is hydrogen, hydroxyethyl ormethyl. A compound according to any preceding claim, pharmaceutically acceptable, solvated or polymorphous thereof, wherein R is methyl, ethyl, isopropyl, trifluoromethyl or methoxyethyl. A compound according to any preceding claim, wherein said compounds are or are polymorphs thereof, wherein one or more of said compounds, wherein said R4 and R5 are be the same or different, are - (CH 2) P x, where p is û, 1 or 2; X is hydrogen, hydroxy, CONR6R7, SO2NR6R7, NR8SO2R9, SR10, SOR9 or SO2R10 Re, R7, R8, R8 and R10 are asdefmed in suede 1, gold 5 or 6-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected15 from N, S and O. 11 A compound according to any preceding suede, pharmaceutically acceptablealts, orivates or polymorphs thereof, wherein R4 and R5, which may be thesame or different, are: - - (CH2) pX, where p is 0 or 1; X is hydrogen, hydroxy, CONR6R7, SO2NR5R7 or NR8SO2R9; R6 and R7, which may be the same or different, ishydrogen or CrC3alkyl optionally substituted by hydroxy, -CONH2 or C4-C3alkoxy (preferably methoxy); Ra is hydrogen, hydroxyethyl or methyl; orR9 is methyl, ethyl, isopropyl, trifluoromethyl or methoxyethyl; or triazolyl, imidazolyl or pyrazolyl. A compound according to any preceding suede, pharmaceutically acceptable salts, or polymeric oriviruses, R4 and R5 are not both hydrogen. A compound according to any preceding claim, wherein said R4 is hydrogen. A compound according to claim 1, pharmaceutically acceptable salts, orivolymorphs, selected from the group: 4- (2,3-dihydro-1-benzothien-5-yloxy) -3 - [(methytamino) methyi] - benzenesulfonamide (Example 2); 3- [(dimethylaminino) methyl] -4- [3-methyl-4- (methylsulfanyl) phenoxy] benzenesulfonamide (Example 12); 4- (2,3-dihydro-1-benzothien-5-yloxy) -3 - [(dimethylamino) methyl] benzenesulfonamide (Example 16); 4- [3-chloro-4- (methylsulfanyl) phenoxy] -3 - [(dimethylamino) methyl] benzenesulfonamide (Example 17); 3 - [(dimethylamino) methyl] -4- [3-fluoro-4- (methylsulfanyl) phenoxy] benzenesulfonamide (Example 18); N, N-dimethyl- / N- [2- (6-quinolinyloxy) benzyl] amine (Example 29); 3- [(methylamino) methyl] -4- (6-quinolinyloxy) benzenesulfonamide (Exampie 35); 4- (2,3-dihydro-1-benzothien-5-yloxy) -3 - [(methylamino) methyl) benzamide (Example 60); 4- (2,3-Dihydro-1-benzothien-5-yloxy) -N-methyl-3 - [(methylamino) methyl] benzamide (Example 62); W- {3 - [(methyiamino) methyl] -4- [3-methyl-4- (methylsulfanyl) phenoxy] benzyl} methanesulfonamide (Exampie 75); 3- [(Methylamino) methyl] -4- [3-methyl-4- (methylsulfanyl) phenoxy] benzamide (Example 79); 4- (2,3-dihydro-1,4-benzoxathiin-7-yloxy) -3 - [(dimethylamino) methyl] benzamide (Exampie 88); {3 - [(dimethylamino) methyl] -4- [3-fluoro-4- (methylsulfanyl) phenoxy] phenyl} methanol (Example 90); 3 - [(dimethylamino) methyl] -4- (6-quinolinyloxy) benzamide (Example 100); 3 - [(methylamino) methyl] -4- (6-quinolinyloxy) benzamide (Example 102); W-methyl-W- {3 - [(methylamino) methyl] -4- [3-methyl-4- (methylsulfanyl) phenoxy] -phenyl] methanesulfonamide (Example 116) and A / - {4- (2,3-dihydro-1,4-benzoxathiin) -7-yioxy) -3 - [(dimethylamino) methyl] phenyl} -methanesulfonamide (Exampie 124). A compound as defined in any preceding claim, pharmaceutically acceptable saits, or polymorphic esters thereof, for use as a pharmaceuticai. 16 16 5 17 5 17 10 18 10 18 1915 20 012372 101 1915 20 A pharmaceutical formulation containing a compound as defined in any one ofdaims 1 to 14, or pharmaceuticatly acceptable salts, solvated or polymorphsthereof, and a pharmaceutically acceptable adjuvant, diluent or carrier . The use of a compound containing 1 to 14 suicides, pharmaceutically acceptable salts, solvates or polymorphs thereof, in the manufacture of amedicine for the treatment or prevention of a disorder in which the regulation of monoamine transporter function is implicated. Deficiency, attention deficit Hyperactivity disorder, obsessive-compulsive disorder, post-traumatic stress disorder, substance abuse disorders or sexual dysfunction. The disorder is premature ejaculation. Use of a compound as defined in any one of suicides 1-14, pharmaceutically acceptable salts, solvates or polymorphs thereof, in the manufacture of a substanceto increase ejaculatory latency. A process for the preparation of a compound of general formula (I); R1, R2, R4, R5, X and Z are as defmed in any one of the compounds of the NR1R2. (la) 10 under suitable réaction conditions to form the compound of formula I, wherein thesuitable reaction conditions are: i) where R4/Rs are halogen, by réaction of (la) with a suitable haiogenatingagent in an inert solvent which does not adversely affect the reaction;- ii) where R4/R5 are -NO2, by reaction of (la) with a suitable nitrating agent inan inert solvent which does not adversely affect the reaction at, or below,room température; or ii) where R4/R5 is -SO2NR6R7 by reaction of an intermediate sulfonyl chloridewith the requisite amine of formula HNR6R7 in a suitable solvent. A process according.to cîaim 23 for preparing a compound of formula (iq), i.e. acompound of formuia I where R5 is -SO,NR6R7 and R4 is hydrogen, 15 22 012372 103R4 / Rs are halogen, by reaction of a suitable halogenating agent in a solvent which does not adversely affect the reaction of the compounds of formula (I) where R4 / R5 are -NO2, by reaction of (la) with a suitable nitrating agent inan inert solvent which does not adversely affect the reaction at, or below, room temperature; or ii) where R4 / R5 is -SO2NR6R7 by reaction of an intermediate sulfonyl chloride with the requisite amine of formula HNR6R7 in a suitable solvent. A process according to claim 23, wherein R5 is -SO, NR6R7 and R4 is hydrogen, wherein R5 is -SO, NR6R7 and R4 is hydrogen, comprising a) reacting a compound of formuia la, optionally in a suitable solvent, withchlorosulfonic acid to give a compound of formula XVIIIcomprising a compound of formula, optionally in a solvent, with chlorosulfonic acid to a compound of formula XVIII followed by b) reacting with HNR6R7 to give the compound of formula (iq>. 23 A process according to claim 22 wherein the compound of formula XVIII is 10 generated in situ and reacted with HNR6R7 without isolation. 24 A process according to any one of daims 21 to 23 which further comprises thestep of preparing compounds of formuia (ia), by reacting compounds of formula(Ha) 012372 104followed by b) reacting with HNR6R7 to give the compound of formula (Iq>. 23 A process according to claim 22 wherein the compound of formula XVIII is produced in situ and reacts with HNR6R7 without isolation. suede 21 to 23 which further comprises thestep of preparing compounds of formula (ia), by reacting compounds of formula (IIa) 012372 «· with a compound of formula HNR1R2, or with a suitable sait form thereof, togetherwith a hydride reducing agent in a suitable solvent, to form the compound offormula (la). 25 An intermediate compound of formula (lia) or (XVIII) as defined in daims 21 to24, with the proviso that (1 la) may not be 2 ( (31, 41 - Methylenedioxy) phenoxy)benzaldehyde.With a compound of formula HNR1R2, with a suitable form, together with a reducing agent in a suitable solvent, to form the compound offormula (la). An intermediate compound of formula (IIa) or (XVIII) as defined in suicides 21 to 24, with the proviso that (1 la) may not be 2 ((31, 41-methylenedioxy) phenoxy) benzaldehyde. wherein R1, R2, R4, R5, X and Z are as defined in any one of daims 1 to 14,comprising reacting compounds of formula IIR1, R2, R4, R5, X and Z are as defined in any one of suicides 1 to 14, comprising reacting compounds of formula II 15 (II) 012372 105 with a compound of formula HNR’R2 or with a suitable sait form thereof, together with a hydride reducing agent in a suitable solvent. 27 A process according to ciaim 2é which further comprises coupling unaer suitable5 reaction conditions a compound of formula fil,(II) with a compound of formula HNR'R 2 or with a suitable form of formula, together with a reducing agent in a suitable solvent. 27 A process according to which a compound of formula wherein L is a suitable leaving group such as haiogen or a suifonate ester suchas trifluoromethanesulfonate or methanesulfonate, with a compound of formulaIVSulfuran trifluoromethanesulfonate or methanesulphonate ester with a compound of formula IV to give the compound of formula 11. 28 An intermediate compound of formula II as defined in ciaim 26, with the proviso15 that (11) may not be 2 - ( (31, 41 - Methylenedioxy) phenoxy) benzaldehyde or 2 ( (31,41 - Methylenedioxy) phenoxy) 5-fluorobenzaldehyde. 29 A compound of general formula (1), or pharmaceutically acceptable salts,solvatés or polymorphe thereof, wherein R1, R2, Y and Z are as defined in ciaim1; and R4 and Rs, which may be the same or different, are -(CH2)P-A’, wherein p is0, 1 or 2 and A’ is a polar group. 30 A compound according to ciaim 21, wherein the polar group has a δ-value morenégative than -0.1.compound of formula II as defined in formula 26, with the proviso that (11) may not be 2 - ((31, 41 - Methylenedioxy) phenoxy) benzaldehyde or 2 ((31, 41 - Methylenedioxy) phenoxy) 5-fluorobenzaldehyde. A compound of general formula (1), or pharmaceutically acceptable salts, solvated or polymorphic thereof, wherein R1, R2, Y and Z are as defined in ciaim1; and R4 and R6, which may be the same or different, are - (CH2) P-A ', wherein p iso, 1 or 2 and A is a polar group. A compound according to the invention, the polar group has a morenative δ-value than -0.1.
OA1200300056A 2000-08-31 2001-08-22 Phenoxybenzylamine derivatives as selective seotonin re-uptake inhibitors. OA12372A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB0021593A GB0021593D0 (en) 2000-08-31 2000-08-31 Diphenyl ether compounds useful in therapy
GB0107116A GB0107116D0 (en) 2001-03-21 2001-03-21 Novel compounds

Publications (1)

Publication Number Publication Date
OA12372A true OA12372A (en) 2006-04-17

Family

ID=26244953

Family Applications (1)

Application Number Title Priority Date Filing Date
OA1200300056A OA12372A (en) 2000-08-31 2001-08-22 Phenoxybenzylamine derivatives as selective seotonin re-uptake inhibitors.

Country Status (32)

Country Link
EP (1) EP1313701A1 (en)
JP (1) JP2004507523A (en)
KR (1) KR20030029889A (en)
CN (1) CN1449380A (en)
AP (1) AP2001002265A0 (en)
AR (1) AR031867A1 (en)
AU (1) AU2001278650A1 (en)
BG (1) BG107544A (en)
BR (1) BR0113610A (en)
CA (1) CA2420969A1 (en)
CZ (1) CZ2003467A3 (en)
DO (1) DOP2001000242A (en)
DZ (1) DZ3414A1 (en)
EA (1) EA200300206A1 (en)
EE (1) EE200300084A (en)
HN (1) HN2001000191A (en)
HR (1) HRP20030141A2 (en)
HU (1) HUP0303385A2 (en)
IL (1) IL154343A0 (en)
IS (1) IS6704A (en)
MA (1) MA26945A1 (en)
MX (1) MXPA03001848A (en)
NO (1) NO20030842L (en)
NZ (1) NZ523951A (en)
OA (1) OA12372A (en)
PA (1) PA8526701A1 (en)
PE (1) PE20020346A1 (en)
PL (1) PL360743A1 (en)
SK (1) SK2012003A3 (en)
TN (1) TNSN01131A1 (en)
UY (1) UY26924A1 (en)
WO (1) WO2002018333A1 (en)

Families Citing this family (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6403597B1 (en) * 1997-10-28 2002-06-11 Vivus, Inc. Administration of phosphodiesterase inhibitors for the treatment of premature ejaculation
US6436938B1 (en) * 2001-01-22 2002-08-20 Pfizer Inc. Combination treatment for depression
US20020107244A1 (en) * 2001-02-02 2002-08-08 Howard Harry R. Combination treatment for depression
US20020183306A1 (en) * 2001-05-30 2002-12-05 Pfizer Inc. Combination treatment for sleep disorders including sleep apnea
GB0318706D0 (en) * 2003-08-08 2003-09-10 Pfizer Ltd Selective serotonin reuptake inhibitors in the treatment of disease
CA2554696C (en) 2004-02-13 2009-06-30 Warner-Lambert Company Llc Androgen receptor modulators
EP1737813A1 (en) 2004-04-13 2007-01-03 Warner-Lambert Company LLC Androgen modulators
WO2005102990A1 (en) 2004-04-22 2005-11-03 Warner-Lambert Company Llc Androgen modulators
CA2570047C (en) 2004-07-08 2010-09-28 Warner-Lambert Company Llc 4-cycloalkoxy benzonitriles as androgen modulators
US20090105349A1 (en) * 2004-08-18 2009-04-23 Warner-Lambert Company Llc Androgen modulators
CA2580024A1 (en) * 2004-09-10 2006-03-16 Pfizer Products Inc. Therapeutic diphenyl ether ligands
TW200724139A (en) 2005-05-05 2007-07-01 Warner Lambert Co Androgen modulators
WO2007010350A1 (en) * 2005-07-19 2007-01-25 Pfizer Products Inc. Synthesis of therapeutic diphenyl ethers
WO2007047397A2 (en) 2005-10-13 2007-04-26 Smithkline Beecham Corporation Phenol ethers as modulators of the opioid receptors
EP1976495A2 (en) * 2006-01-06 2008-10-08 Aarhus Universitet Compounds acting on the serotonin transporter
US7767666B2 (en) 2006-06-29 2010-08-03 Janssen Pharmaceutica Nv Butyl and butynyl benzyl amine compounds
JP2009544579A (en) 2006-06-29 2009-12-17 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ Substituted benzylamine compounds
EP2046747A1 (en) * 2006-06-29 2009-04-15 Janssen Pharmaceutica N.V. Substituted aminomethyl benzamide compounds
WO2010059390A1 (en) 2008-10-30 2010-05-27 Janssen Pharmaceutica Nv Modulators of serotonin receptor
US8642583B2 (en) 2008-10-30 2014-02-04 Janssen Pharmaceutica Nv Serotonin receptor modulators
KR101043200B1 (en) * 2010-11-08 2011-06-21 성시민 Air filling device of breathing air tank
DE112011104795T5 (en) 2011-01-27 2013-10-31 Hewlett-Packard Development Company, L.P. Computer apparatus for connection to a portable device
KR20210135521A (en) 2019-03-06 2021-11-15 다이이찌 산쿄 가부시키가이샤 pyrrolopyrazole derivatives

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ZA923283B (en) * 1991-05-29 1993-01-27 Akzo Nv Phenoxyphenyl derivatives
NZ271833A (en) * 1993-08-19 1997-08-22 Warner Lambert Co Substituted 2(5h)-furanone (or thiophenone or pyrrolone) derivatives
CZ293595A3 (en) * 1995-11-09 1999-12-15 Farmak A. S. Derivatives of n,n-dimethyl-2-(arylthio)benzylamine, their salts, processes of their preparation and their use in medicaments
EP1071648A2 (en) * 1998-03-13 2001-01-31 Merck Frosst Canada &amp; Co. Carboxylic acids and acylsulfonamides, compositions containing such compounds and methods of treatment
EE200100441A (en) * 1999-02-23 2002-12-16 Pfizer Products Inc. Monoamine reuptake inhibitors for the treatment of central nervous system disorders
GB0007884D0 (en) * 2000-03-31 2000-05-17 Pfizer Ltd Diphenyl ether compounds useful in therapy

Also Published As

Publication number Publication date
DOP2001000242A (en) 2002-05-15
NZ523951A (en) 2004-09-24
AU2001278650A1 (en) 2002-03-13
PL360743A1 (en) 2004-09-20
DZ3414A1 (en) 2002-03-07
CA2420969A1 (en) 2002-03-07
TNSN01131A1 (en) 2005-11-10
EP1313701A1 (en) 2003-05-28
AR031867A1 (en) 2003-10-08
HUP0303385A2 (en) 2004-03-01
PE20020346A1 (en) 2002-05-08
WO2002018333A1 (en) 2002-03-07
EE200300084A (en) 2005-02-15
MXPA03001848A (en) 2003-06-04
EA200300206A1 (en) 2003-06-26
IL154343A0 (en) 2003-09-17
IS6704A (en) 2003-01-30
AP2001002265A0 (en) 2001-09-30
MA26945A1 (en) 2004-12-20
NO20030842D0 (en) 2003-02-24
KR20030029889A (en) 2003-04-16
CN1449380A (en) 2003-10-15
PA8526701A1 (en) 2003-07-28
HRP20030141A2 (en) 2003-04-30
HN2001000191A (en) 2002-03-11
BR0113610A (en) 2003-06-24
NO20030842L (en) 2003-04-28
SK2012003A3 (en) 2004-06-08
JP2004507523A (en) 2004-03-11
UY26924A1 (en) 2002-03-22
BG107544A (en) 2003-10-31
CZ2003467A3 (en) 2004-04-14

Similar Documents

Publication Publication Date Title
NZ523951A (en) Phenoxybenzylamine derivatives as selective serotonin re-uptake inhibitors
AU784934B2 (en) Diphenyl ether compounds useful in therapy
AU2002244898B2 (en) Phenyl heterocyclyl ether derivatives as serotonin re-uptake inhibitors
US20020052395A1 (en) Diphenyl ether compounds useful in therapy
AU2002244898A1 (en) Phenyl heterocyclyl ether derivatives as serotonin re-uptake inhibitors
CA2356065C (en) Phenoxyphenylheterocycle derivatives as ssris
US6610747B2 (en) Phenoxybenzylamine derivatives as SSRIs
WO2004016593A1 (en) Diaryl compounds as monoamine reuptake inhibitors