EP1313701A1 - Derives de la phenoxybenzylamine inhibiteurs selectifs du recaptage de la serotonine - Google Patents

Derives de la phenoxybenzylamine inhibiteurs selectifs du recaptage de la serotonine

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Publication number
EP1313701A1
EP1313701A1 EP01956734A EP01956734A EP1313701A1 EP 1313701 A1 EP1313701 A1 EP 1313701A1 EP 01956734 A EP01956734 A EP 01956734A EP 01956734 A EP01956734 A EP 01956734A EP 1313701 A1 EP1313701 A1 EP 1313701A1
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EP
European Patent Office
Prior art keywords
methyl
compound
formula
compounds
pharmaceutically acceptable
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP01956734A
Other languages
German (de)
English (en)
Inventor
Mavis Diane Adam
Mark David Andrews
Mark Leonard Elliott
Geoffrey Edward Gymer
David Hepworth
Harry Ralph Howard Jr.
Donald Stuart Middleton
Alan Stobie
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pfizer Ltd
Pfizer Inc
Original Assignee
Pfizer Ltd
Pfizer Inc
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Publication date
Priority claimed from GB0021593A external-priority patent/GB0021593D0/en
Priority claimed from GB0107116A external-priority patent/GB0107116D0/en
Application filed by Pfizer Ltd, Pfizer Inc filed Critical Pfizer Ltd
Publication of EP1313701A1 publication Critical patent/EP1313701A1/fr
Withdrawn legal-status Critical Current

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    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
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    • 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
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    • 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
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    • 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
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • 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
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
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    • 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
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    • 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
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    • 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
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    • 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
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    • 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
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    • 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

Definitions

  • This invention relates to novel diphenyl ether compounds which inhibit monoamine reuptake.
  • compounds of the present invention exhibit activity as selective serotonin re-uptake inhibitors (SSRIs) and have utility therefore in a variety of therapeutic areas.
  • SSRIs serotonin re-uptake inhibitors
  • the compounds of the present invention are useful in the treatment or prevention of a variety of disorders, including those in which the regulation of monoamine transporter function is implicated, such as depression, attention deficit hyperactivity disorder, obsessive-compulsive disorder, post-traumatic stress disorder, substance abuse disorders and sexual dysfunction including premature ejaculation, and to pharmaceutical formulations containing such compounds.
  • the invention provides a compound of general formula (I), pharmaceutically acceptable salts, solvates or polymorphs thereof;
  • R 1 and R 2 which may be the same or different, are H, C r C 6 alkyl or
  • R 6 , R 7 , R 8 and R 10 which may be the same or different, are hydrogen or C 1-6 alkyl optionally substituted independently by one or more R 12 ;
  • R 9 is C 1-6 alkyl optionally substituted independently by one or more R 12 ;
  • R 1 is hydrogen, d.
  • R 12 is F (preferably up to 3), OH, CO 2 H, C 3 . 6 cycloalkyl, NH 2 , CONH 2 , C 1-6 alkoxy, C,.
  • any alkyl group may be straight or branched and is of 1 to 6 carbon atoms, preferably 1 to 4 and particularly 1 to 3 carbon atoms.
  • any carbocyclyl group contains 3 to 8 ring-atoms, and may be saturated, unsaturated or aromatic.
  • Preferred saturated carbocyclyl groups are cyclopropyl, cyclopentyl or cyclohexyl.
  • Preferred unsaturated carbocyclyl groups contain up to 3 double bonds.
  • a preferred aromatic carbocyclyl group is phenyl.
  • the term carbocylic should be similarly construed.
  • carbocyclyl includes any fused combination of carbocyclyl groups, for example naphthyl, phenanthryl, indanyl and indenyl.
  • any heterocyclyl group contains 5 to 7 ring-atoms up to 4 of which may be hetero-atoms such as nitrogen, oxygen and sulfur, and may be saturated, unsaturated or aromatic.
  • heterocyclyl groups are furyl, thienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, dioxolanyl, oxazolyl, thiazolyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyranyl, pyridyl, piperidinyl, dioxanyl, morpholino, dithianyl, thiomorpholino, pyridazinyl, pyrimidinyl, pyraziny
  • heterocyclyl includes fused heterocyclyl groups, for example benzimidazolyl, benzoxazolyl, imidazopyridinyl, benzoxazinyl, benzothiazinyl, oxazolopyridinyl, benzofuranyl, quinolinyl, quinazolinyl, quinoxalinyl, dihydroquinazolinyl, benzothiazolyl, phthalimido, benzofuranyl, benzodiazepinyl, indolyl and isoindolyl.
  • heterocyclic should be similarly construed.
  • Halo means fluoro, chloro, bromo or iodo.
  • R 1 and R 2 which may be the same or different, are hydrogen or C r C 6 alkyl. More preferably hydrogen or methyl.
  • R 3 is preferably methyl or ethyl.
  • the ring is preferably a heterocyclic ring. More preferably, the linkage contains one or two sulfur atoms.
  • R 4 and R 5 are not both hydrogen.
  • R 4 and R 5 which may be the same or different, are
  • X is hydrogen, hydroxy, CONR 6 R 7 , SO 2 NR 6 R 7 , NR 8 SO 2 R 9 , SR 10 , SOR 9 or SO 2 R 10 wherein R 6 , R 7 , R 8 , R 9 and R 10 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, triazolyl, imidazolyl, oxazolyl, pyrazolyl, pyridinyl or pyrimidinyl).
  • R 4 and R 5 which may be the same or different, are: -(CH 2 ) P -X, where p is 0 or 1 ;
  • X is hydrogen, hydroxy, CONR 6 R 7 , SO 2 NR 6 R 7 or NR 8 SO 2 R 9 ;
  • R 6 and R 7 which may be the same or different, are hydrogen or C C 3 alkyl optionally substituted by hydroxy, -CONH 2 or C,-C 3 alkoxy (preferably methoxy);
  • R 8 is hydrogen, hydroxyethyl or methyl; or R 9 is methyl, ethyl, isopropyl, trifluoromethyl or methoxyethyl; or triazolyl, imidazolyl or pyrazolyl.
  • R 4 is hydrogen
  • R 6 and R 7 which may be the same or different, are hydrogen, C,-C 3 alkyl optionally substituted by hydroxy, -CONH 2 or C r C 3 alkoxy (preferably methoxy). More preferably R 6 and R 7 , which may be the same or different, are hydrogen or methyl, more preferably still hydrogen.
  • R 12 is preferably oxadiazolyl, triazolyl, imidazolyl, oxazolyl, pyrazolyl, pyridinyl or pyrimidinyl. More preferably triazolyl, imidazolyl or pyrazolyl.
  • R 6 and R 7 together with the nitrogen to which they are attached, form a heterocyclic ring, preferred rings are pyrrolidine or piperidine rings each of which may be substituted by OH or CONH 2 or a morpholine ring which may be substituted by CONH 2 .
  • R 11 is hydrogen or C 1-6 alkyl.
  • R 8 is hydrogen, hydroxyethyl or methyl. More preferably hydrogen.
  • R 9 is methyl, ethyl, isopropyl, trifluoromethyl or methoxyethyl. More preferably methyl or ethyl (preferably methyl).
  • R 10 is methyl or ethyl.
  • p is 1 or 0, more preferably 0.
  • R 1 and R 2 which may be the same or different, are hydrogen or methyl; when present, R 3 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 or heterocyclic ring which may be saturated, unsaturated or aromatic, 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; and
  • R 4 and R 5 which may be the same or different, are (CH 2 ) P -X, where p is 0 or 1 ;
  • X is hydrogen, hydroxy, CONR 6 R 7 , SO 2 NR 6 R 7 , NR 8 SO 2 R 9 , SR 10 , SOR 9 or SO 2 R 10 and wherein R 6 and R 7 , which may be the same or different, are hydrogen, C r C 3 alkyl optionally substituted by hydroxy, -CONH 2 or C r C 3 alkoxy (preferably methoxy); or R 6 and R 7 , together with the nitrogen to which they are attached, may form a morpholine, pyrrolidine or piperidine ring each of which may be substituted by OH or CONH 2 ;
  • R 8 is hydrogen, hydroxyethyl or methyl (preferably hydrogen);
  • R 9 is methyl, ethyl, isopropyl, trifluoromethyl or methoxyethyl; and
  • R 10 is methyl
  • R 1 and R 2 which may be the same or different, are hydrogen or methyl; when present, R 3 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 ring containing 1 or 2 sulfur atoms; and R 4 and R 5 , which may be the same or different, are
  • X is hydrogen, hydroxy, CONR 6 R 7 , SO 2 NR 6 R 7 or NR 8 SO 2 R 9 ; wherein R 6 and R 7 , which may be the same or different, are hydrogen, C r C 3 alkyl optionally substituted by hydroxy, -CONH 2 or C r C 3 alkoxy (preferably methoxy); R 8 is hydrogen, hydroxyethyl or methyl; R 9 is methyl, ethyl, isopropyl, trifluoromethyl or methoxyethyl; or triazolyl, imidazolyl or pyrazolyl.
  • R 1 and R 2 which may be the same or different, are hydrogen or methyl; when present R 3 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-membered heterocyclic ring containing 1 or 2 sulfur atoms;
  • R 4 is hydrogen, and -(CH 2 ) P -X, where p is 0 or 1;
  • X is hydrogen, hydroxy, CONR 6 R 7 , SO 2 NR 6 R 7 or NR 8 SO 2 R 9 ; wherein R 6 and R 7 , which may be the same or different, are hydrogen, C 1 -C 3 alkyl optionally substituted by hydroxy, -CONH 2 or C r C 3 alkoxy (preferably methoxy);
  • R 8 is hydrogen, hydroxyethyl or methyl;
  • R 9 is methyl, ethyl, isopropyl, trifluoromethyl or methoxyethy
  • R 4 and R 5 are not both hydrogen.
  • Preferred compounds are:
  • R 4 or R 5 may be representative of a 5- or 6-membered heterocyclic ring containing 1 , 2 or 3 heteroatoms selected from N, S and O; and in addition, R 6 and R 7 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 solvates thereof with the proviso that both R 4 and R 5 are not H.
  • substituted means substituted by one or more defined groups.
  • groups may be selected from a number of alternatives groups, the selected groups may be the same or different.
  • the term independently means that where more than one substituent is selected from a number of possible substituents, those substituents may be the same or different.
  • the invention provides a compound of general formula I and pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 3 , Z and Y are as defined in the first aspect; and R 4 and R 5 , which may be the same or different, are -(CH 2 ) P -A', wherein p is 0, 1 or 2 and A' is a polar group.
  • polar groups may be defined as those having a negative ⁇ -value (see C Hansch and A Leo, 'Substituent Constants for Correlation Analysis in Chemistry and Biology', Wiley, New York, 1979). In this system,
  • H has a ⁇ -value of 0.00
  • -OCH 3 has a ⁇ -value of -0.02
  • -SO 2 NH 2 has a ⁇ -value of -
  • More preferred polar groups have a more negative ⁇ -value: thus, preferred groups have ⁇ -values of a greater negative value than -0.1 , more preferably a greater negative value than -0.5, and most preferably a greater negative value than -1.0. Even when p is other than zero in the above definition, the definition of A' is based on the above reference as if p was zero.
  • the compounds of the invention have the advantage that they are selective inhibitors of the re-uptake of serotonin (SRIs) (and so are likely to have reduced side effects), they have a rapid onset of action (making them suitable for administration shortly before an effect is required), they have desirable potency and associated properties.
  • SRIs serotonin
  • Compounds that selectively inhibit the re-uptake of serotonin, but not noradrenaline or dopamine, are preferred.
  • the pharmaceutically or veterinarily acceptable salts of the compounds of formula I which contain a basic centre are, for example, non-toxic acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acid, with carboxylic acids or with organo-sulfonic acids.
  • Examples include the HCl, HBr, HI, 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 pamoate salts.
  • Compounds of the invention can also provide pharmaceutically or veterinarily acceptable metal salts, in particular non-toxic alkali and alkaline earth metal salts, with bases.
  • Examples include the sodium, potassium, aluminium, calcium, magnesium, zinc, diolamine, olamine, ethylenediamine, tromethamine, chloine, megulamine and diethanolamine salts.
  • 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, Marcel Dekker Inc, New York 1996, Volume 13, page 453-497.
  • the compounds, their pharmaceutically acceptable salts, their solvates and polymorphs, defined in any aspect of the invention are referred to as "compounds of the invention".
  • the pharmaceutically acceptable solvates of the compounds of the invention include the hydrates thereof.
  • the compounds of the invention may possess one or more chiral centres and so exist in a number of stereoisomeric forms. All stereoisomers and mixtures thereof are included in the scope of the present invention. Racemic compounds may either be separated using preparative HPLC and a column with a chiral stationary phase or resolved to yield individual enantiomers utilising methods known to those skilled in the art. In addition, chiral intermediate compounds may be resolved and used to prepare chiral compounds of the invention.
  • the invention includes individual isomers as well as mixtures thereof.
  • the invention includes individual tautomers as well as mixtures thereof.
  • the invention includes individual isomers as well as mixtures thereof.
  • the invention includes individual diastereoisomers as well as mixtures thereof.
  • Separation of diastereoisomers or E and Z isomers may be achieved by conventional techniques, e.g. by fractional crystallisation, chromatography or H.P.L.C.
  • An individual enantiomer of a compound of the invention may be prepared from a corresponding optically pure intermediate or by resolution, such as by H.P.L.C. of the corresponding racemate using a suitable chiral support or by fractional crystallisation of the diastereoisomeric salts formed by reaction of the corresponding racemate with a suitable optically active acid or base, as appropriate.
  • the compounds of the invention may exist in one or more tautomeric forms. All tautomers and mixtures thereof are included in the scope of the present invention. For example, a claim to 2-hydroxypyridinyl would also cover its tautomeric form, ⁇ -pyridonyl. It will be appreciated by those skilled in the art that certain protected derivatives of compounds of the invention, which may be made prior to a final deprotection stage, may not possess pharmacological activity as such, but may, in certain instances, be administered orally or parenterally and thereafter metabolised in the body to form compounds of the invention which are pharmacologically active. Such derivatives may therefore be described as "prodrugs". Further, certain compounds of the invention may act as prodrugs of other compounds of the invention.
  • prodrugs of compounds of the invention are included within the scope of the invention.
  • suitable pro-drugs for the compounds of the present 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" by H. Bundgaard, Elsevier, 1985, Chapter 1 (the disclosures in which documents are incorporated herein by reference).
  • Preferred prodrugs for compounds of the invention include: esters, carbonate esters, hemi- esters, phosphate esters, nitro esters, sulfate esters, sulfoxides, amides, carbamates, azo- compounds, phosphamides, glycosides, ethers, acetals and ketals.
  • the invention also includes all suitable isotopic variations of the compounds of the invention.
  • An isotopic variation is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine such as 2 H, 3 H, 3 C, 4 C, 15 N, 17 0, 18 0, 31 P, 32 P, 35 S, 18 F and 36 CI, respectively.
  • Certain isotopic variations of the invention for example, those in which a radioactive isotope such as 3 H or 14 C is incorporated, are useful in drug and/or substrate tissue distribution studies.
  • Tritiated, i.e. 3 H, and carbon-14, i.e. 14 C isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium, i.e. 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances.
  • isotopic variations of the compounds of the invention can generally be prepared by conventional procedures such as by the methods or preparations described in the Examples and Preparations hereafter using appropriate isotopic variations of suitable reagents.
  • Compounds of general formula (I) may be prepared from compounds of formula (II) by reaction with an amine of general formula HNR 1 R 2 , or with a suitable salt form thereof, together with a hydride reducing agent in a suitable solvent (see Scheme 1).
  • suitable solvents include protic solvents such as ethanol, and sodium borohydride is an appropriate reducing agent as exemplified by Example 36 herein.
  • tetrahydrofuran/ dichloromethane is a suitable solvent system and sodium triacetoxyborohydride is a suitable reducing agent.
  • HNR 1 R 2 such as the hydroehloride
  • an auxiliary base to aid solubility of the HNR 1 R 2 salt, such as triethylamine may optionally be added along with acetic acid, as exemplified by Example 25 herein.
  • Compounds of formula (II) may be prepared in turn from the coupling of compounds of general formula (IV) with aldehyde compounds of general formula (III), wherein L is a suitable leaving group such as halogen (F, Cl, Br or I) or a sulfonate ester such as trifluoromethanesulfonate or methanesulfonate, preferably L is F or Cl.
  • L is a suitable leaving group such as halogen (F, Cl, Br or I) or a sulfonate ester such as trifluoromethanesulfonate or methanesulfonate, preferably L is F or Cl.
  • Such coupling reaction may be accomplished by techniques known in the art, such as via reaction with potassium carbonate in a suitable solvent such as dimethylformamide under appropriate reaction conditions such as elevated temperature and in an inert atmosphere.
  • the invention provides a process for preparing compounds of general formula (I) from compounds of the general formula (ll).
  • R 4 and/or R 5 may be introduced after ether coupling (see Scheme 2).
  • Compounds of general formula (I) may be prepared from compounds of general formula (la), i.e. compounds of general formula (I) where R 4 and R 5 are hydrogen.
  • Compounds of general formula (la) may be prepared from (Ila) in an analogous fashion to the preparation of (I) from (II) (see Scheme 1), while compounds of general formula (Ila) may be prepared from (IV) and (Ilia) in an analogous fashion to the preparation of (II) (see Scheme 1).
  • SCHEME 2
  • the invention provides a process for preparing compounds of general formula (I) from compounds of the general formula (la).
  • R 4 /R 5 are halogen
  • Suitable halogenating agents include trifluoromethanesulfonic acid and ⁇ /-iodosuccinimide and suitable inert solvents include dichloromethane.
  • R 4 /R 5 are -NO 2
  • a suitable nitrating agent such as an alkali metal nitrate
  • suitable solvents include trifluoroacetic acid.
  • R 4 /R 5 is -SO 2 NR 6 R 7 by reaction of an intermediate sulfonyl chloride with the requisite amine of formula HNR 6 R 7 in a suitable solvent.
  • suitable solvents include a mixture of water and dichloromethane and the reactions are generally performed at or below room temperature.
  • the intermediate sulfonyl chlorides may be prepared from compounds of formula (la) by reaction with chlorosulfonic acid under low temperature conditions in the presence of a solvent which does not adversely affect the reaction, either with or without subsequent treatment with a chlorinating agent such as phosphorus oxychloride, phosphorus pentachloride, oxalyl chloride or thionyl chloride in a solvent which does not adversely affect the reaction.
  • Suitable solvents for the reaction with chlorosulfonic acid include trifluoroacetic acid and a typical reaction temperature is 0 °C.
  • Suitable solvents for the reaction with chlorinating agents include acetonitrile and suitable conditions include at reflux, as illustrated in Example 12 herein.
  • compounds of formula (Iq), where R s is -SO 2 NR 6 R 7 may be prepared via the intermediate sulfonyl chlorides (XVIII) from compounds of formula (la) by reaction of (la) with chlorosulfonic acid, either with or without subsequent treatment with a chlorinating agent such as phosphorus oxychloride, phosphorus pentachloride, oxalyl chloride or thionyl chloride, followed by reaction with HNR 6 R 7 (see scheme 2a).
  • Reaction conditions typically comprise low temperature.
  • the reaction can take place either neat, i.e. in the absence of solvent, or in the presence of an inert solvent which does not adversely affect the reaction.
  • the intermediate sulfonyl chloride (XVII) may be isolated, purified and then reacted with HNR 6 R 7 , alternatively it may be generated in situ, without isolation, and then reacted with HNR 6 R 7 .
  • the invention provides a process for preparing compounds of general formula (I) from compounds of the general formula (II).
  • a process for preparing compounds of formula (Iq) by reacting compounds of formula (la) in a suitable solvent, with chlorosulfonic acid, either with or without subsequent treatment with a chlorinating agent such as phosphorus oxychloride, phosphorus pentachloride, oxalyl chloride or thionyl chloride, to give compounds of formula (XVIII) followed by reaction with HNR 6 R 7 to give compounds of formula (Iq).
  • a chlorinating agent such as phosphorus oxychloride, phosphorus pentachloride, oxalyl chloride or thionyl chloride
  • R 4 /R 5 When R 4 /R 5 is halogen such as chloro, bromo or iodo, it may be converted to cyano via reaction with a cyanide salt in the presence of a Pd(0) or (ll)catalyst in a high boiling solvent at elevated temperatures.
  • Suitable Pd catalysts include palladium tetrakis(triphenylphosphine), suitable cyanide salts include Zn(CN) 2 and suitable high boiling solvents which do not adversely affect the reaction include dimethylformamide as exemplified by Example 78 herein;
  • R 4 /R 5 is halogen such as chloro, bromo or iodo
  • it may be converted to the corresponding ester -CO 2 R by treatment with carbon monoxide at high pressure with a Pd(0) or (II) catalyst, in an alcohol solvent (ROH wherein R is C ⁇ - C 4 alkyl), in the presence of a base at elevated temperatures.
  • a Pd(0) or (II) catalyst in an alcohol solvent (ROH wherein R is C ⁇ - C 4 alkyl)
  • R is C ⁇ - C 4 alkyl
  • the reaction may be carried out at pressures in the region of about 100 p.s.i, whilst suitable Pd catalysts include dichlorobis(triphenylphosphine) palladium (II), suitable bases include triethylamine and suitable alcohol solvents include methanol as exemplified by Preparation 50 herein;
  • R 4 /R 5 When R 4 /R 5 is nitro, it may be reduced to the corresponding -NH 2 group via treatment with a reducing agent in a protic solvent at, or above, room temperature.
  • Suitable reducing agents include iron powder / calcium chloride
  • suitable protic solvents include aqueous ethanol and a typical reaction temperature is from about 70°C to about 100°C, preferably about 90°C, as exemplified by Example 103 herein;
  • R 4 /R 5 When R 4 /R 5 is -NH 2 , it may be converted to the corresponding -NHSO 2 R 9 group by reaction with a sulfonylating agent in the presence of a base in an inert solvent which does not adversely affect the reaction at, or below, room temperature.
  • Suitable sulfonylating agents include methanesulfonyl chloride, suitable bases include triethylamine and suitable inert solvents include dichloromethane as exemplified by Example 128 herein; v) When R /R 5 is a -NHSO 2 R 9 group, it may be converted to the corresponding - NR 8 SO 2 R 9 group via treatment with an alkylating agent and a base in a suitable inert solvent.
  • suitable alkylating agents include methyl iodide
  • suitable bases include potassium carbonate and suitable inert solvents include acetonitrile, as exemplified by Preparation 88 herein;
  • R 4 /R 5 is a nitrile -CN, it may be converted to the corresponding -C(O)NH 2 group by hydrolysis under basic, oxidative or acid conditions.
  • Basic hydrolysis is preferably conducted with a hydroxide salt such as potassium hydroxide in a protic solvent such as .-butanol at elevated temperatures, as exemplified in Example 79 herein.
  • R 4 /R 5 is an ester -CO 2 R, it may be reduced to the corresponding alcohol group -CH 2 OH via treatment with a hydride reducing agent, such as lithium aluminium hydride, as exemplified by Preparation 69 herein;
  • R 4 /R 5 is an ester -CO 2 R, it may be converted to the corresponding acid - CO 2 H by treatment with a suitable hydroxide salt in the presence of water and a suitable co-solvent.
  • suitable hydroxide salts include lithium hydroxide and suitable co-solvents include tetrahydrofuran, as exemplified by Preparation 55 herein;
  • R 4 /R 5 When R 4 /R 5 is an acid -CO 2 H, it may be converted to the corresponding amide - CONR 6 R 7 by treatment with a coupling agent, a base and an amine HNR 6 R 7 in a suitable inert solvent which does not adversely affect the reaction.
  • Suitable coupling agents include 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydroehloride in the presence of 1-hydroxybenzotriazole, suitable bases include triethylamine and suitable solvents include dichloromethane, as exemplified by Preparation 59 herein;
  • R /R 5 When R /R 5 is halogen such as chloro, bromo or iodo, it may be converted to an ⁇ , ⁇ -unsaturated amide, by treatment with acrylamide, a Pd(0) or (II) catalyst and a suitable base, in an inert solvent which does not adversely affect the reaction, at elevated temperatures.
  • Suitable Pd catalysts include palladium (II) acetate in the presence of tri(o-tolyl)phosphine, suitable bases include triethylamine and suitable inert solvents include acetonitrile as exemplified by Example 50 herein;
  • R 4 /R 5 When R 4 /R 5 is an ⁇ , ⁇ -unsaturated amide, it may be converted to - CH 2 CH 2 CO 2 NH 2 , by treatment with a suitable reducing agent at an appropriate temperature, in a suitable solvent which does not adversely affect the reaction.
  • suitable reducing agents include samarium diiodide at room temperature and suitable solvents include tetrahydrofuran containing a small amount of water, as exemplified by Example 51 herein;
  • R 4 /R 5 When R 4 /R 5 is -CH 2 OH, it may be converted to -CH 2 NR 8 SO 2 R 9 by means of a Mitsunobu reaction at an appropriate temperature, in a suitable solvent which does not adversely affect the reaction.
  • Suitable reagents include diethyl azodicarboxylate, triphenylphosphine and .ert-butyl methylsulfonylcarbamate, 0°C is a suitable reaction temperature and tetrahydrofuran is a suitable solvent as exemplified by Preparation 72 herein;
  • compounds of general formula (I) having a particular NR 1 R 2 group may be converted into other compounds of general formula (I) having a different NR 1 R 2 group.
  • compounds of general formula (I) having a particular NR 1 R 2 group may be converted into other compounds of general formula (I) having a different NR 1 R 2 group.
  • compounds of general formula (I) may be prepared from compounds of formula V (see Scheme 3) wherein L is as defined for Scheme 1 and T is a group which can be converted into CH 2 NR 1 R 2 .
  • suitable T substitutents include: -CO 2 R 10 , -CN and -C(0)NR 1 R 2 .
  • Compounds of general formula (V) may be prepared in turn by the coupling of compounds of general formula (VI) and compounds of the general formula (IV). Reagents and conditions for such coupling reactions are as previously defined for the coupling of compounds of general formulae (IV) and (111) in Scheme 1.
  • Compounds of formula (VI) may be prepared by aromatic electrophilic substitution of compounds of formula (VII) to give compounds of formula (VI) directly.
  • compounds of formula (VI) may be prepared in two or more steps; aromatic electrophilic substitution of compounds of formula (VII) to give intermediate compounds which then undergo further reaction to give compounds of formula (VI).
  • the intermediate compounds may be isolated or generated in situ without isolation.
  • a preferred route is shown in Scheme 5.
  • the invention provides compounds of formulae (II), (Ila) and (V) as defined above.
  • diaryl ethers may be prepared using a number of synthetic methodologies. For a review of methodologies see J S Sawyer, Tetrahedron, 56 (2000) 5045-5065, incorporated herein by reference.
  • the compounds of the invention are useful because they have pharmacological activity in mammals, including humans. More particularly, they are useful in the treatment or prevention of a disorder in which the regulation of monoamine transporter function is implicated.
  • Disease states that may be mentioned include hypertension, depression (e.g. depression in cancer patients, depression in Parkinson's patients, postmyocardial infarction depression, subsyndromal symptomatic depression, depression in infertile women, paediatric depression, major depression, single episode depression, recurrent depression, child abuse induced depression, post partum depression and grumpy old man syndrome), generalized anxiety disorder, phobias (e.g. agoraphobia, social phobia and simple phobias), posttraumatic stress syndrome, avoidant personality disorder, premature ejaculation, eating disorders (e.g. anorexia nervosa and bulimia nervosa), obesity, chemical dependencies (e.g. addictions to alcohol, cocaine, heroin, phenobarbital, nicotine and benzodiazepines), cluster headache, migraine,
  • Alzheimer's disease obsessive-compulsive disorder, panic disorder, memory disorders (e.g. dementia, amnestic disorders, and age-related cognitive decline (ARCD)), Parkinson's diseases (e.g. dementia in Parkinson's disease, neuroleptic-induced parkinsonism and tardive dyskinesias), endocrine disorders (e.g.
  • hyperprolactinaemia vasospasm (particularly in the cerebral vasculature), cerebellar ataxia, gastrointestinal tract disorders (involving changes in motility and secretion), negative symptoms of schizophrenia, premenstrual syndrome, fibromyalgia syndrome, stress incontinence, Tourette's syndrome, trichotillomania, kleptomania, male impotence, attention deficit hyperactivity disorder (ADHD), chronic paroxysmal hemicrania, headache (associated with vascular disorders), emotional lability, pathological crying, sleeping disorder (cataplexy) and shock.
  • ADHD attention deficit hyperactivity disorder
  • headache associated with vascular disorders
  • emotional lability pathological crying
  • sleeping disorder cataplexy
  • shock shock.
  • disorders of particular interest include depression, attention deficit hyperactivity disorder, obsessive-compulsive disorder, post-traumatic stress disorder, substance abuse disorders and sexual dysfunction including (in particular) premature ejaculation.
  • Premature ejaculation may be defined as persistent or recurrent ejaculation before, upon or shortly after penile penetration of a sexual partner. It may also be defined as ejaculation occurring before the individual wishes [see 'The Merck Manual', 16 th edition, p 1576, published by Merck Research Laboratories, 1992].
  • the invention provides:
  • a compound of the invention in the manufacture of a medicament for the treatment or prevention of a disorder in which the regulation of monoamine transporter function is implicated, for example depression, attention deficit hyperactivity disorder, obsessive-compulsive disorder, post-traumatic stress disorder, substance abuse disorders or sexual dysfunction including premature ejaculation;
  • a method of treatment or prevention of depression, attention deficit hyperactivity disorder, obsessive-compulsive disorder, post-traumatic stress disorder, substance abuse disorders or sexual dysfunction including premature ejaculation which comprises administering a therapeutically effective amount of a compound of the invention to a patient in need of such treatment or prevention;
  • a compound of the invention for the treatment or prevention of a disorder in which the regulation of monoamine transporter function is implicated for example depression, attention deficit hyperactivity disorder, obsessive-compulsive disorder, post-traumatic stress disorder, substance abuse disorders or sexual dysfunction including premature ejaculation.
  • a compound of the invention for treating premature ejaculation for example depression, attention deficit hyperactivity disorder, obsessive-compulsive disorder, post-traumatic stress disorder, substance abuse disorders or sexual dysfunction including premature ejaculation.
  • the compounds of the invention may be administered alone or as part of a combination therapy. If a combination of active agents are administered, then they may be administered simultaneously, separately or sequentially.
  • the compounds of the invention may be combined with the following preferably for the treatment of PE:
  • Alpha-blockers e.g. phentolamine, doxazasim, tamsulosin, terazasin, prazasin and Example 19 of WO9830560.
  • a possible rationale for alpha-blockers treating premature ejaculation is as follows. Muscular activity of the ejaculatory smooth muscles (vas deferens, seminal vesicles and urethra) are controlled by the sympathetic nervous system through the release of noradrenalin. Noradrenalin acts on the alpha 1 adrenoreceptors, stimulating muscle contractions, leading to seminal emission and subsequently ejaculation. Blocking these receptors will therefore inhibit ejaculation.
  • Dopamine D2 agonists e.g. Premiprixal, Pharmacia Upjohn compound number PNU95666.
  • Melanocortin receptor agonists e.g. Melanotan II.
  • PGE1 receptor agonists e.g. alprostadil
  • NRIs Noradrenaline Re-uptake Inhibitors
  • SRIs Serotonin Re-uptake Inhibitors
  • DRIs Dopamine Re-uptake Inhibitors
  • 5-HT3 antagonists e.g. ondansetron and granisetron.
  • 5-HT3 antagonists e.g. ondansetron and granisetron.
  • 5-HT3 receptors present in the lumen of the posterior portion of the urethra, are stimulated by 5- HT in the semen during seminal emission, leading to a sensitisation of the spinal relex pathway which leads to ejaculation. Therefore, an antagonist would prevent this sensitisation and thus delay ejaculation.
  • PDE inhibitors such as PDE2 (e.g. erythro-9-(2-hydroxyl-3-nonyl)-adenine) and
  • Example 100 of EP 0771799-incorporated herein by reference and in particular a PDE5 inhibitor (e.g. sildenafil, 1- ⁇ [3-(3,4-dihydro-5-methyl-4-oxo-7- propylimidazo[5, 1 -f]-as-trazin-2-yl)-4-ethoxyphenyl]sulfonyl ⁇ -4-ethylpiperazine i.e. vardenafil / Bayer BA 38-9456 or IC351 (see structure below, lcos Lilly)).
  • a PDE5 inhibitor e.g. sildenafil, 1- ⁇ [3-(3,4-dihydro-5-methyl-4-oxo-7- propylimidazo[5, 1 -f]-as-trazin-2-yl)-4-ethoxyphenyl]sulfonyl ⁇ -4-ethylpiperazine i.e. vardenafil / Bayer BA 38-9456 or
  • the compounds of the invention can be administered alone but in human therapy will generally be administered in admixture with a suitable pharmaceutical excipient, diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
  • the compounds of the invention can be administered orally, buccally or sublingually in the form of tablets, capsules (including soft gel capsules), ovules, elixirs, solutions or suspensions, which may contain flavouring or colouring agents, for immediate-, delayed-, modified-, sustained-, dual-, controlled-release or pulsatile delivery applications.
  • the compounds of the invention may also be administered via intracavernosal injection.
  • the compounds of the invention may also be administered via fast dispersing or fast dissolving dosage forms.
  • Such tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate, glycine, and starch (preferably corn, potato or tapioca starch), disintegrants such as sodium starch glycollate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose
  • HPC high-density polyethylene glycol
  • lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included.
  • Solid compositions of a similar type may also be employed as fillers in gelatin capsules.
  • Preferred excipients in this regard include lactose, starch, a cellulose, milk sugar or high molecular weight polyethylene glycols.
  • the compounds of the invention, and their pharmaceutically acceptable salts may be combined with various sweetening or flavouring agents, colouring matter or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.
  • Modified release and pulsatile release dosage forms may contain excipients such as those detailed for immediate release dosage forms together with additional excipients that act as release rate modifiers, these being coated on and/or included in the body of the device.
  • Release rate modifiers include, but are not exclusively limited to, hydroxypropylmethyl cellulose, methyl cellulose, sodium carboxymethylcellulose, ethyl cellulose, cellulose acetate, polyethylene oxide, Xanthan gum, Carbomer, ammonio methacryiate copolymer, hydrogenated castor oil, carnauba wax, paraffin wax, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, methacrylic acid copolymer and mixtures thereof.
  • Modified release and pulsatile release dosage forms may contain one or a combination of release rate modifying excipients.
  • Release rate modifying excipients may be present both within the dosage form i.e. within the matrix, and/or on the dosage form, i.e. upon the surface or coating.
  • Fast dispersing or dissolving dosage formulations may contain the following ingredients: aspartame, acesulfame potassium, citric acid, croscarmellose sodium, crospovidone, diascorbic acid, ethyl acrylate, ethyl cellulose, gelatin, hydroxypropylmethyl cellulose, magnesium stearate, mannitol, methyl methacryiate, mint flavouring, polyethylene glycol, fumed silica, silicon dioxide, sodium starch glycolate, sodium stearyl fumarate, sorbitol, xylitol.
  • dispersing or dissolving as used herein to describe FDDFs are dependent upon the solubility of the drug substance used i.e. where the drug substance is insoluble a fast dispersing dosage form can be prepared and where the drug substance is soluble a fast dissolving dosage form can be prepared.
  • 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 they may be administered by infusion techniques.
  • parenteral administration they are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood.
  • the aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary.
  • the preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
  • dosage levels and other dosage levels herein are for the average human subject having a weight range of about 65 to 70 kg.
  • the skilled person will readily be able to determine the dosage levels required for a subject whose weight falls outside this range, such as children and the elderly.
  • the daily dosage level of the compounds of the invention or salts or solvates thereof will usually be from 10 to 500 mg (in single or divided doses).
  • tablets or capsules of the compounds of the invention may contain from 5 mg to 250 mg of active compound for administration singly or two or more at a time, as appropriate.
  • the physician in any event will determine the actual dosage which will be most suitable for any individual patient and it will vary with the age, weight and response of the particular patient.
  • the above dosages are exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited and such are within the scope of this invention.
  • compounds of the invention may be taken as a single dose on an "as required" basis (i.e. as needed or desired).
  • a tablet formulation could typically contain between about 0.01 mg and 500mg of a compound of the invention whilst tablet fill weights may range from 50mg to 1000mg.
  • An example formulation for a 10mg tablet is illustrated:
  • the compounds of the invention can also be administered intranasally or by inhalation and are conveniently delivered in the form of a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray or nebulizer with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetra- fluoro-ethane, a hydrofluoroalkane such as 1 ,1 ,1 ,2-tetrafluoroethane (HFA 134A [trade mark]) or 1 ,1,1 ,2,3,3,3-heptafluoropropane (HFA 227EA [trade mark]), carbon dioxide or other suitable gas.
  • a suitable propellant e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetra- fluoro-ethane, a hydrofluoroalkane such as 1 ,
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the pressurised container, pump, spray or nebulizer may contain a solution or suspension of the active compound, e.g. using a mixture of ethanol and the propellant as the solvent, which may additionally contain a lubricant, e.g. sorbitan trioleate.
  • a lubricant e.g. sorbitan trioleate.
  • Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated to contain a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.
  • Aerosol or dry powder formulations are preferably arranged so that each metered dose or "puff' contains from 1 to 50 mg of a compound of the invention for delivery to the patient.
  • the overall daily dose with an aerosol will be in the range of from 1 to 50 mg which may be administered in a single dose or, more usually, in divided doses throughout the day.
  • the compounds of the invention may also be formulated for delivery via an atomiser.
  • Formulations for atomiser devices may contain the following ingredients as solubilisers, emulsifiers or suspending agents: water, ethanol, glycerol, propylene glycol, low molecular weight polyethylene glycols, sodium chloride, fluorocarbons, polyethylene glycol ethers, sorbitan trioleate, oleic acid.
  • the compounds of the invention can be administered in the form of a suppository 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 invention may also be dermally or transdermally administered, for example, by the use of a skin patch. They may also be administered by the ocular, pulmonary or rectal routes.
  • the compounds can be formulated as micronized suspensions in isotonic, pH adjusted, sterile saline, or, preferably, as solutions in isotonic, pH adjusted, sterile saline, optionally in combination with a preservative such as a benzylalkonium chloride.
  • a preservative such as a benzylalkonium chloride.
  • they may be formulated in an ointment such as petrolatum.
  • the compounds of the invention can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water.
  • 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: mineral 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 molecules. Formation of a drug-cyclodextrin complex may modify the solubility, dissolution rate, bioavailability and/or stability property of a drug molecule. Drug- cyclodextrin complexes are generally useful for most dosage forms and administration routes.
  • the cyclodextrin may be used as an auxiliary additive, e.g. as a carrier, diluent or solubiliser.
  • Alpha-, beta- and gamma-cyclodextrins are most commonly used and suitable examples are described in WO-A-91/11172, WO-A-94/02518 and WO-A-98/55148.
  • the daily dosage levels of compounds 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.
  • tablets will contain 1mg to 0.4g of compound for administration singly or two or more at a time, as appropriate.
  • the physician will in any event determine the actual dosage which will be most suitable for any particular patient and it will vary with the age, weight and response of the particular patient.
  • the above dosages are, of course only exemplary of the average case and there may be instances where higher or lower doses are merited, and such are within the scope of the invention.
  • Oral administration is preferred. Preferably, administration takes place shortly before an effect is required.
  • a compound of the invention is administered as a suitably acceptable formulation in accordance with normal veterinary practice and the veterinary surgeon will determine the dosing regimen and route of administration which will be most appropriate for a particular animal.
  • the invention provides a pharmaceutical formulation containing a compound of the invention and a pharmaceutically acceptable adjuvant, diluent or carrier.
  • TLC thin layer chromatography
  • hydroehloride salts were characterised as their hydroehloride salts.
  • a typical procedure for formation of hydroehloride salts is given in Example 12. The procedure can be carried out with other solvents e.g. diethyl ether or DCM.
  • the amide of Preparation 8 (760 mg, 2.07 mmol) was slurried in THF (10 mL) and the resulting suspension was treated with borane.tetrahydrofuran complex (1M solution in THF, 6.22 mL, 6.22 mmol) at room temperature. The resulting solution was heated at reflux for 5 hours under an atmosphere of dry nitrogen. The reaction was cooled to room temperature and treated cautiously with 6M HCl solution (6 mL). The resulting mixture was heated at reflux for 30 min. After cooling to room temperature the mixture was diluted with water (10 mL) and basified by cautious addition of potassium carbonate solid.
  • Formaldehyde (37% aq. solution, 282 ⁇ L, 3.76 mmol) was added to a suspension of the secondary amine from Example 1 (409 mg, 1.16 mmol) in DCM (20 mL) at room temperature under nitrogen. The resulting mixture was stirred for 15 minutes before the addition of sodium triacetoxyborohydride (984 mg, 4.64 mmol). The resulting reaction mixture was stirred for 5 hours before being basified with saturated NaHCO 3 solution (10 mL) and extracted with DCM (3x20 mL). The organic layers were washed with brine (10 mL), dried (MgSO 4 ) and evaporated to a yellow oil.
  • Example 12 In a repeat reaction, using 1 equivalent of formaldehyde to the amine of Example 1 , Example 12 was obtained in 78% yield after column chromatography [SiO 2 ; 95:5:0.5 to 90:10:1 (EtOAc/ MeOH/ 880 NH 3 )]. This was taken up in EtOAc and converted to the HCl salt by the addition of 1 M ethereal HCl. The resulting precipitate was filtered and dried in vacuo to give Example 12 HCl salt; m.p. 188°C.
  • Example 12 can also be formed from the amine of Example 1 by the method of Example 110.
  • Example 12 was also prepared as follows.
  • Example 29 Chlorosulfonic acid (106 ⁇ L, 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 temperature. Water (2 mL) was added, the mixture was adjusted to pH 6 with sat aq NaHCO 3 and extracted with DCM (2x5 mL). The organic extracts were dried (MgSO 4 ) and filtered and 8M methylamine in EtOH (0.3 mL) was added. After standing for 1 h the solvent was removed in vacuo and the residue was purified by column chromatography [SiO 2 ; 95:5:0.5 (DCM/ MeOH/ 880 NH 3 )].
  • Trifluoroacetic anhydride (0.96 mL, 6.8 mmol) was added to a solution of the amine of Example 48 (900 mg, 3.4 mmol) and triethylamine (1.9 mL, 13.6 mmol) in CH 2 CI 2 (15 mL) at 0°C and the mixture was stirred for 5 min. The solvent was removed in vacuo and the residue was partitioned between CH 2 CI 2 and water. The organic layer was washed with brine, dried (MgSO 4 ) and evaporated to give a yellow oil, which was used without further purification.
  • the protected amine of Preparation 59 (317 mg, 0.76 mmol) was dissolved in a saturated solution of HCl in DCM (25 mL) at 0°C and left for 1 h before being neutralised by the addition of 10% aq K 2 CO 3 (25 mL). Water (50 mL) was added and the layers were separated. The aqueous layer was extracted with DCM (25 mL) and the combined organic layers were dried (MgSO 4 ) and evaporated. The resulting oil was dissolved in EtOAc (10 mL) and treated with 1M ethereal HCl (1 mL).
  • Example 77 was prepared from the Boc protected sulfonamide of Preparation 74 by the method of Example 60 ;HCI salt: ⁇ H (CD 3 OD, 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 (1 H, d), 7.24 (1 H, d), 7.48 (1H, d); MS m/z (TS*) 395 (MH*).
  • Example 94 was also prepared as follows.
  • nitrile of Preparation 95 (720 mg, 1.99 mmol) was dissolved in a 1 M solution of BH 3 .THF in THF (10 mL, 10 mmol) and the mixture was heated at reflux for 3 h. After cooling to room temperature the reaction was quenched by the cautious addition of MeOH (10 mL). The solvent was evaporated, the residue was treated with 6M HCl (10 mL) and heated at reflux for 1 h. After cooling, the mixture was basified with 2M NaOH and the pH was adjusted to 7 with sat aq NH 4 CI.
  • Dicyclohexylcarbodiimide (460 mg, 2.23 mmol) was added to a solution of pentafluorophenol (413 mg, 2.24 mmol) in ether (10 mL) followed by formic acid (95 ⁇ L, 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 primary amine of Example 105 (411 mg, 1.1 mmol) in DCM (10 mL) was added. The mixture was stirred for 16 h then concentrated to an oily residue.
  • Methanesulfonyl chloride (371 ⁇ L, 4.79 mmol) was added to a solution of the aniline of Example 103 (725 mg, 2.4 mmol) and Et 3 N (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 temperature before the solvent was removed in vacuo. 2M NaOH (10 mL) was added to the residue and the mixture was stirred overnight. The resulting clear solution was neutralised by the addition of sat aq NH 4 CI and extracted with DCM (2x30 mL). The combined organic layers were dried (MgSO 4 ) and evaporated to give an oil.
  • the reaction was stirred at 0°C for 1 h then urea was added, to remove excess nitrite, until a negative test with starch/KI paper was obtained.
  • the mixture was allowed to warm to room temperature then added with stirring to a mixture of cone.
  • H 2 SO 4 55 mL
  • water 750 mL
  • the reaction was re-heated to 90°C and stirred at this temperature for 30 min.
  • the hot reaction mixture was filtered through Arbocel® then stirred at room temperature overnight.
  • the fluoroamide of Preparation 1 (732 mg, 3.15 mmol) was treated with 4-(methyltf ⁇ io)- m-cresol (commercially available) (535 mg, 3.47 mmol) and potassium carbonate (457 mg, 3.31 mmol) in DMF (10 mL). The mixture was heated at 100 °C for 5 hours. The solvent was removed by evaporation under reduced pressure and the residue was treated with 2M HCl (10 mL). The resulting suspension was extracted several times with dichloromethane. The combined dichloromethane layers contained a suspension and were evaporated to a solid residue.
  • the product from Preparation 30 was also prepared as follows.
  • the title compound was prepared from the alcohol of Preparation 71 by the method of Preparation 72 using trifluoromethanesulfonamide instead of tert-butyl methylsulfonylcarbamate.
  • the desired product was contaminated with tert-butyl 5-( ⁇ 3- ⁇ [(tert-butoxycarbonyl)(methyl)amino]methyl ⁇ -4-[3-methyl-4-
  • 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 Et 3 N (9.5 mL, 68.2 mmol) in DCM (60 mL). The mixture was stirred at room temperature for 3 h then poured into water and extracted with DCM (3 times). The combined organic extracts were dried (MgSO 4 ) and evaporated to give a dark, viscous oil.
  • Methanesulfonyl chloride (4.16 mL, 53.7 mmol) was added dropwise to a solution of the aniline of Preparation 83 (9.5 g, 24.5 mmol) and Et 3 N (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 temperature before the solvent was removed in vacuo. 2M NaOH (50 L) was added to the residue and the mixture was stirred for 30 min. The mixture was extracted with EtOAc and the organic layer was washed with brine, dried (MgSO 4 ) and evaporated to give an oil.
  • Fe powder (930 mg, 16.7 mmol) was added to the nitro compound of Preparation 41 (740 mg, 2.38 mmol) in AcOH (5 mL) and water (1 mL) and the mixture was stirred at room temperature for 16 h. The solvent was removed in vacuo, the residue was taken up in EtOAc (50 mL) and 10% aq K 2 CO 3 (50 mL) and filtered through Arbocel®. The organic layer was separated and the aqueous layer was extracted with EtOAc (50 mL).
  • the allyl ether from stage (ii) (800 mg, 4.16 mmol) was dissolved in THF (10 mL) and treated with palladium tetrakis(triphenylphosphine) (481 mg, 0.42 mmol) followed by sodium borohydride (944 mg, 25 mmol). The mixture was then heated to 45 °C and stirred at this temperature for 15 h. After cooling to room temperature the THF was evaporated and the residue partitioned between 2M NaOH solution (25 mL) and diethyl ether (25 mL). The aqueous layer was separated and the organic layer re-extracted with 2M NaOH solution (25 mL).
  • HEK-293 Human embryonic kidney cells (HEK-293) stably transfected with either the human serotonin transporter (hSERT), noradrenaline transporter (hNET) or dopamine transporter (hDAT) were cultured under standard cell culture techniques (cells were grown at 37°C and 5% CO 2 in DMEM-culture media (supplemented with 10% dialysed foetal calf serum (FCS), 2mM l-glutamine and
  • Assay plates were dried in a microwave oven, scintillation fluid added, and radioactivity measured. Potency of test compounds was quantified as IC 50 values (concentration of test compound required to inhibit the specific uptake of radiolabelled substrate into the cells by 50%).
  • SRI serotonin re-uptake inhibition
  • SRI serotonin re-uptake inhibition
  • SRI serotonin re-uptake inhibition
  • SRI serotonin re-uptake inhibition
  • the title compound of Example 16 had a serotonin re-uptake inhibition (SRI) IC 50 of 4.7 nM; the title compound of Example 29 had a serotonin re-uptake inhibition (SRI) IC 50 of 2.0 nM; and the title compound of Example 62 had a serotonin re-uptake inhibition (SRI) IC 50 of 3.7 nM.

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Abstract

L'invention porte sur un composé de formule générale (I) dans laquelle: R1 et R2 sont H, C¿1?-C6alkyle ou (CH2)d(C3-C6cycloalkyle) et où d = 0, 1, 2 ou 3; ou bien R?1 et R2¿ avec l'azote auquel ils sont fixés forment un cycle azétidine; Z ou Y est -SR3 et l'autre de Z ou de Y est halogène ou -R3; et où R3 est C¿1?-C4 alkyle facultativement substitué par fluor; sauf si R?3¿ n'est pas CF¿3?; ou Z et Y sont liés, si bien qu'avec avec les atomes d'interconnexion, Z et Y forment un cycle carbocyclique ou hétérocyclique. En plus des atomes de carbone, la liaison comporte un ou deux hétéroatomes sélectionnés indépendamment parmi oxygène, soufre et azote; R?4 et R5¿, qui peuvent être identiques ou différents, sont: A-X, et où A = -CH=CH- ou -(CH¿2?)p- où p est 0, 1 ou 2; X est hydrogène, F, CI, Br, I, CONR?6R7, SO¿2NR6R7, SO2NHC(=O)R6, OH, C1-4alkoxy, NR8SO2R9, NO2, NR6R11, CN, CO¿2R?10, CHO, SR?10, S(O)R9¿ ou SO¿2R?10; ou un cycle hétérocyclique à 5- ou 6- éléments contenant 1, 2 ou 3 hétéroatomes sélectionnés parmi N, S et O, facultativement substitué indépendamment par un ou plusieurs R13; et où R13 est hydroxy, C¿1?-C4alkoxy, F, C1-C6alkyle, haloalkyle, haloalkoxy, -NH2, NH(C1-C6alkyle) ou -N(C1-C6alkyle)2. Les composés de formule générale (I) inhibent le recaptage des monoamine et ont en particulier une activité d'inhibiteurs sélectifs du recaptage de la sérotonine..
EP01956734A 2000-08-31 2001-08-22 Derives de la phenoxybenzylamine inhibiteurs selectifs du recaptage de la serotonine Withdrawn EP1313701A1 (fr)

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GB0021593 2000-08-31
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
GB0107116 2001-03-21
PCT/IB2001/001521 WO2002018333A1 (fr) 2000-08-31 2001-08-22 Derives de la phenoxybenzylamine inhibiteurs selectifs du recaptage de la serotonine

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BRPI0507670A (pt) 2004-02-13 2007-07-17 Warner Lambert Co moduladores do receptor de androgênio
EP1737813A1 (fr) 2004-04-13 2007-01-03 Warner-Lambert Company LLC Modulateurs d'androgenes
CA2562672C (fr) 2004-04-22 2009-09-29 Warner-Lambert Company Llc Derives du type 4-cyano-phenoxy utilises comme modulateurs d'androgenes
JP4874965B2 (ja) 2004-07-08 2012-02-15 ワーナー−ランバート カンパニー リミテッド ライアビリティー カンパニー アンドロゲン調節剤
EP1781280A2 (fr) * 2004-08-18 2007-05-09 Warner-Lambert Company LLC Modulateurs des androgenes
BRPI0514675A (pt) * 2004-09-10 2008-06-17 Pfizer Prod Inc ligantes de éter difenìlico terapêuticos
TW200724139A (en) 2005-05-05 2007-07-01 Warner Lambert Co Androgen modulators
WO2007010350A1 (fr) * 2005-07-19 2007-01-25 Pfizer Products Inc. Synthèse d’éthers diphényliques à usage thérapeutique
US7939528B2 (en) 2005-10-13 2011-05-10 Glaxosmithkline Llc Heterocycle compounds
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CA2656075A1 (fr) * 2006-06-29 2008-01-03 Janssen Pharmaceutica N.V. Composes butyle et butynyle benzyle amine
AU2007265242A1 (en) 2006-06-29 2008-01-03 Janssen Pharmaceutica N.V. Substituted benzyl amine compounds
WO2008002818A1 (fr) * 2006-06-29 2008-01-03 Janssen Pharmaceutica N.V. Aminométhylbenzamides substitués
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US8642583B2 (en) 2008-10-30 2014-02-04 Janssen Pharmaceutica Nv Serotonin receptor modulators
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