EP1673355A1 - Derives de triazoles substitues en tant qu'antagonistes de l'oxytocine - Google Patents

Derives de triazoles substitues en tant qu'antagonistes de l'oxytocine

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Publication number
EP1673355A1
EP1673355A1 EP04769366A EP04769366A EP1673355A1 EP 1673355 A1 EP1673355 A1 EP 1673355A1 EP 04769366 A EP04769366 A EP 04769366A EP 04769366 A EP04769366 A EP 04769366A EP 1673355 A1 EP1673355 A1 EP 1673355A1
Authority
EP
European Patent Office
Prior art keywords
triazol
methoxypyridin
methyl
fluoro
methoxymethyl
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Withdrawn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
EP04769366A
Other languages
German (de)
English (en)
Inventor
Alan Pfizer Global Research & Development BROWN
David Pfizer Global Research & Development ELLIS
Christopher R. Pfizer Global R. & D. SMITH
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
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 GB0322159A external-priority patent/GB0322159D0/en
Priority claimed from GB0403150A external-priority patent/GB0403150D0/en
Priority claimed from GB0415110A external-priority patent/GB0415110D0/en
Application filed by Pfizer Ltd, Pfizer Inc filed Critical Pfizer Ltd
Publication of EP1673355A1 publication Critical patent/EP1673355A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • 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
    • A61P15/06—Antiabortive agents; Labour repressants
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/10—Drugs for disorders of the endocrine system of the posterior pituitary hormones, e.g. oxytocin, ADH
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to a class of substituted 1 ,2,4-triazoles with -activity as oxytocin antagonists, uses thereof, processes for the preparation thereof and "
  • compositions containing said inhibitors have utility in a " variety of therapeutic areas including sexuaj dysfunction, particularly premature ejaculation (P E )
  • R 1 is selected from-
  • R 2 is selected from:
  • a 5-7 memberecl N-linked heterocycle containing _1 -3 heteroatoms selected from N,O and S " said ring-being optionally substituted with one or more groups selected from -(C ⁇ -C 6 )a!kyl, (C ⁇ -C ⁇ )alkoxy and C(O)NR 7 R 8 ,
  • R "3 is selected from- H and (C G 6 )alkyl
  • R 4 is selected from-H, (C C 6 )alkyl and OR 9 ;
  • R 5 is selected " from halo ⁇ (C ⁇ -C 6 )alkyl, (CrC 6 )alkoxy, NR 7 R 8 , NR 7 C(O)R 10 and " 25 N[C(O)R 10 ]i;
  • R- ⁇ - selected from H, halo, (C C 6 )alkyl, (Cj-C 6 )alkoxy, cyano, NR 7 R 8 , NR 7 C ' (O)R 1 , N[C(O)R 10 ] 2 and C(O)NR 7 R 8 ;
  • R' and R ⁇ , ⁇ hich may -be the same or different, are selected from H and - (C C 6 )alkylf ' . . _- _ . . - R 9 is (CrC ⁇ )alkyl, which is optionally substituted with with one or more groups each ⁇ ndepende ' ntly selected from (C 1 -C 6 )alkoxy and an N-linked 5-7 membered - heterocycle containing 1-3 heteroatoms-selected from N, O and S; and - -_-_
  • R 10 is setected ' from (C C 6 )alkyl and (C ⁇ -C 6 )alkoxy;
  • allkyl and alkoxy groups may be . straight or branched and contain 1 to 6 carbon .a tom ⁇ ahd preferably 1 to 4 carbon atoms.
  • Examples 0 " ⁇ T alkyl include methyl, isopropyl, n-butyl 7 . isobutyl, sec-butyl, pentyl and hexyl.
  • Halo means fluoro, chloro, bromo of iodo and is preferably fluoro. 5
  • heterocycle may be saturated, partially , saturated or aromatic.
  • Examples- of - heterocyclic groups are thiolanyl, pyrrotidinyl, pyrrolinyl, - tr dazolidinyl, imidazolinyl, sulfolanyl, dioxolanyl, dihydropyranyl, tetrahydropyranyl, p peridmyl, pyrazolinyl, pypaz lidinyl dioxanyi ⁇ mo ⁇ holinyl, dithianyl, thiomorpholinyl, 30 piperazinyl, azepinyl, oxazepinyl, thiazepinyl, thiazolinyl and diazapanyl.
  • aromatic heterocyclic .groups are furyl, thienyl, pyrrolyl, oxazolyl, thiazolyi, imidazolyl, pyrazolyl,- isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, -pyrirnidinyl, pyrazinyl, pyridazinyl, triazinyl.
  • substituted means substituted by one or- more defined groups In the case- where groups may be selected from a number of alternative groups, the selected groups may be the same or different - _ -
  • the present invention comprises compounds of formula (I) wherein - " . -
  • Z is C-H or N
  • R 1 is selected from
  • a phenyl ring substituted with two or more substituents which may be the slS ⁇ pe or different, each independently selected from halo, (CrGf atkyl, (C ⁇ -C ⁇ )alkoxy, cyano, C(Q)NR 7 R 8 , NR 7 R ⁇ l -NR 7 C(O)R 10 and
  • a -five to seven membered- aromatic heterocyclic ring containing -1-3 hetero atoms selected from N , O and S and N-oxides thereof, said ring being optionally substituted with two or more substituents, which may be the same ⁇ different, selected from halo, (CrC 6 )alkyl, (C ⁇ -C 6 )alkoxy,_ " " cyano, C(O)NR 7 R 8 , NR 7 R 8 , NR 7 C(O)R 10 and N[C(O)R 10 ] 2 ,
  • N[C(O)R 1 ⁇ 0 ⁇ ⁇ ] 2 and (li) a 5-7 membered N-linked heterocycle containing 1-3 heteroatoms selected from N.O -and S, said ring optionally substituted wittTone or more - groups selected from (C ⁇ -C ⁇ )alkyl, (CrC 6 )alkoxy and C(O)NR 7 R 8 ;
  • R 3 is selected from H and (C C 6 )alkyl
  • R 4 is selected from H, (C C 6 )alkyl and OR 9 ,
  • R 5 is (C C 3 )alkyl, (d-G ⁇ alkoxy or NR 7 R 8 ; - . - ⁇ " -
  • R 6 is H, halo, (C C 6 )alkyl, (C ⁇ -C 6 )alkoxy J cyano or NR 7 R 8 ,
  • R 9 is (CrC ⁇ )alkyl optionally substituted with (C ⁇ -C 6 )alkoxy
  • R 10 is selected from (C C 6 )alkyl and (C C 6 )alkoxy,
  • the present invention comprises compounds of formula (1) wherein - - - " - - : .
  • R 1 is selected from (i) a phenyl ring substituted with two substituents, which may be the same or different, each independently selected from halo,_ (C ⁇ -C 3 )alkyl, (CrC 3 )alkoxy, and cyano; and
  • R 2 is selected from' - ⁇
  • R 3 is " selected from H ah ' d (Ci-C 6 )alkyl; - - -
  • R 4 is selected from H,-(C C 6 )alk l and OR 9 ; .-
  • R 5 is (CrC 3 )alkyl, (C C 3 )aJkoxy or NR 7 R 8
  • R° is H, (Cr € 6 )alkyl, (G ⁇ -C 6 )alko> y or NR 7 D R8.
  • R' " and R 8 , " which may be the same or different, are selected from. H . and- 25 " - (C ⁇ -C ⁇ )alkyl;
  • R 9 is (C -C 6 )alkyl optionally substituted with methoxy
  • the -present invention comprises compounds of formula (I) wherein W and ⁇ are each independently CH or N and X and V are each CH;
  • R 1 is a phenyl ring substituted with two substituents, which may be the same or - - different, each independently selected from fluoro, chloroy-methyl, methoxy, and. cyano;
  • TO ''" ⁇ R 2 - is " selected from -H, methoxy, ethoxy, -2-methoxyethoxy, .dimethylamino, - '"'"' 1,2, " 3-triazbl2-yl and pyrollidinyl, the latter- being -ropti.onally- " substituted by CONH 2 ; ⁇ --. ⁇ : - • - ' -
  • R 3 is selected from.Hand (-C ⁇ -C 6 )alkyl
  • R 5 is methoxy
  • Preferred embodiments of the compounds of formula (l)-according. to the above aspects are those that incorporate two or. mo ⁇ e of the following preferences-
  • 1 or 2 of the groups V, ⁇ /V, X and Y represent N when the remainder
  • ⁇ ' " represent C-R 6 .- - " - ⁇ ' • ' .. •' " ⁇ - ⁇ " - ⁇ ⁇ - ⁇ ⁇ ⁇ ” :• ' . ⁇ . ;. , x-_x . x . "L': n apVeferred . emodiment, Xis CH. ⁇ ⁇ - .-- .- - .-.-.
  • V; and Y are ea ⁇ h independently CH, " C-OCH 3 or N.
  • W and Y are each independently CH or N.
  • W and Y are each independently CH or N and X ancrV are each CH
  • Z is h . - 5 " In another preferred emodiment, Z is CH
  • R is selected from _ - _- _
  • R 1 is selected from
  • a phenyl ring -substituted ⁇ ⁇ th.-two-sub&t ⁇ tuents which may be he same or different, eaGh independently selected from halo, (C ⁇ -Ce)alkyl, C ⁇ -C 6 )alkoxy, cyano, C( )NR 7 R 8 , NR 7 R 8 , NR 7 C(O)R 10 and N[C(O)R 10 ] 2 ,
  • R 1 is selected from _ _ .
  • a phenyl nrrg substituted with two substituents which may be the same or different, " each independently selected from halo, (C C 3 )alkyl, (CrC 3 )alkoxy and cyano, and _ - -
  • R 1 is a phenyl ring substituted with two substituents,- which may " be the same or different, each independently selected from fluoro, chloro, methyl, methoxy and cyano " - ⁇ .
  • R 1 is py ⁇ dine-N-oxide substituted with two methyl groups _ _
  • R 2 rs selected from
  • R 2 is selectedjrom
  • R 2 is selected from , methoxy, ethoxy, 2-methoxyethoxy, dimethylamino, 1 ,2,3-triazol-2-yl and pyroHidinyl, .the latter being optionally -substituted by CONH 2 . .
  • R 2 is selected from H and methoxy* x - _ -
  • R 3 is H or (C ⁇ -C 3 )alkyl. - . , _
  • R 3 is H. - - - .
  • R 4 is H ⁇ C C ⁇ alkyl or OR 9 . . " " 0 - More preferably, R 4 is H, (C r C 3 )alkyl or (C C 3 )alkoxy._ Most preferably, R 4 is H,-methyLor methoxy: - ⁇ -In a preferred embodiment, R 4 is H. - - . -_ _
  • R 5 is (Ci-C 3 )alkyl, (C C 3 )alkoxy or NR 7 R ⁇ : 5 - More-preferabJy, " R 5 is (C C 3 )alkoxy or NR 7 R ⁇ - - - _-
  • R 5 is methoxy or NHCH 3 - . - -
  • R 5 is methoxy
  • R 6 is H, halo, (C ⁇ -C 6 )alkyl, (C C 6 )alkoxy, cyano or N_R 7 R 8 0 - More preferably, R 6 is H, (C C 6 )alkyl, (C ⁇ -C 6 )alkoxy or NR 7 R 8 .
  • . ⁇ 6 is H, (C ⁇ -C 3 )alkyl or (C ⁇ -C 3 )alkoxy,_
  • R- 6 s JH, methyl or methoxy.- - . - _ - - - " _
  • R 6 is H or methyL
  • R 6 is H 5
  • R 7 is H or (C C 3 )alkyl - . . . _-. . -
  • R 7 is ⁇ or methyl . . ⁇
  • R 8 is H or (C C 3 )alkyl 0 - Most preferably, R 8 is H or. methyl -- - . - .
  • R 9 is ⁇ C ⁇ -C 6 )alkyl optionally substituted -with (Cg_-C 6 )alkoxy. More preferably, R 9 is (C 1r C 6 )alkyl optionally substituted with methoxy. Most preferably, R ⁇ is methyl: - - - " - "" " _---
  • Preferred compounds of formula (I) are: . - - . - "
  • Pharmaceutically acceptable salts of the compounds of formula (I) comprise the acid ' addition salts thereof; ' - . . -. . " ⁇ ⁇ - • - • ...
  • Suitable acid addition salts are formed from “ acids which form " ⁇ on-toxic salts.
  • salts of. compounds of formula (I) may be prepared ⁇ - ⁇ r bybne or more 5 of three methods: , _ - - - ,. . _ , - _..
  • the jesulting salt may precipitate out and be collected by filtration or may be recovered.by evaporation of -the solvent.
  • The. degree of ionisation in the resulting salt may -vary from 15 " - completely -ionised to almost . non-ionised.., ⁇ - • .. - • •...- ⁇ • , , ⁇ . . . . _, .. / . ⁇ .
  • references to compounds of formula (I) include references to salts, solvates and complexes thereof and to solvates and complexes of salts thereot X : . - ; - - . - . . -_. ⁇ -
  • the compounds of . the - invention include compounds of formula (I) as hereinbefore defined ⁇ - including all polymorphs and crystal habits- .thereof,
  • prodrugs- and isomer.s thereof including, .optical, geometric and ta ⁇ tomeric
  • prodrugs- may .be founeUn Pro-drugs as Novel Delivery Systems, Vol. 14, ACS
  • Prodrugs- invention can,- for example, be produced by replacing appropriate functionalities present in the compounds of formula (I) with certain . moieties known to those skilled in the art as ' pro-moieties' :as described, 25 if ⁇ r example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985). ⁇ .--•:
  • prodrugs in accordance with, the invention include - ;..- • ; "
  • the compound _of formula (I) contains a phenyl moiety, a phenol - " derivative thereof.(-Ph - -PhOH), and - _- - .. _ “ (vi) - where the compound of formula (I) contains an- amide group, a carboxylic " " - - - acid derivative thereof (-CONH 2 -> C ⁇ OH) - . .
  • Included within the -scope of the present invention are all stereorsomers, 15 geometric " isomers and tautomeric forms of the compounds of- formula (I), "includinc/compounds exhibiting more than one type-of isomerism, and mixtures - " " of one- or more thereof Also- included are acid addition salts, wherein- the cou rteriori is optically active, for example, cf-lactate, or racemic, for example, dl- tartrate "" - " - ⁇ : - - " ' _ - -
  • Cisltrans Isomers may be separated by conventional-techniques well known to - those skilled in the art, for example, chromatography. and " -fractional crystallisation - - " - r _ -
  • the racemate (or a racemic precursor) may be reacted with _a suitable optically active compound, for example, an alcohol, or,, in t e ' case where the compound of formula f) contains an acidic or basic moiety, a base or acid such as 1-phenylethylam ⁇ ne or tarta ⁇ c acid
  • a suitable optically active compound for example, an alcohol, or,, in t e ' case where the compound of formula f) contains an acidic or basic moiety, a base or acid such as 1-phenylethylam ⁇ ne or tarta ⁇ c acid
  • the resulting diastereome ⁇ c " mixture may be separated by chromatography and/or fractional crystallization - and one or both of the diastereoisomers converted to the corresponding pure - " enantiomer(s) by means-well known to a skilled person - . - -
  • Stereoisomeric conglomerates may be separated by conventional techniques known to those skilled in the art - see, for example, Stereochemistry of Organic Compounds by f..L ⁇ Elrel and S H Wilen (Wiley, New- York, 1994). " — -5
  • the present invention includes " all pharmaceutically acceptable -isotopically- labelled compounds of formula " (I) wherein one or more..atoms-are replaced by ⁇ atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in mature - 0 - - ' ⁇ " - ⁇ - - - --. -_ - - .
  • isotopes suitable for inclusion in the compounds'-of -the invention include isotopes of hydrogen, such as 2 H and 3 H, carbon, suclras 11 C, 13 C and C, chlorine, such as 36 CI, fluorine,- such as 1 ⁇ F, iodine ⁇ ⁇ such as 123 ind 125 l, nitrogen, such as 13 N and 15 N, oxygen, " such as 15 O, 17 O and 1 ⁇ O, phosphorus, 5 - " such as ⁇ P, and sulphur, such as 35 S - % .
  • Substituti ⁇ n with heavier isotopes such as deuterium; i.e. 2 H may afford certain " ⁇ therapeutic ' advantages resulting from greater metabolic r stability, for example,, - increased " v ' n V/Vb • half-life or reduced dosage requirements, and-hence may-be. " ' " preferred " in some circumstances. - r_ - - - _. ⁇ - ⁇ -- . - -. - -
  • Substitutiorrwith ' positron-emitting isotopes such as - 11 .C, 18 F, 15 O and 13 N, can be - ' "" useful in Positron Emission Topography (PET) studies " for-examining. substrate - - rece ⁇ tor occupancy. --- ⁇ ⁇ — ' • - - ⁇ --- . -
  • Ts ⁇ topically-labeled ⁇ compounds of formula " (I) can generally be prepared. . by ' '' ⁇ ⁇ '' cbnverit ⁇ orfal technique known t ⁇ " those skilled - in the art " or by processes; 1 analogous to those described in the accompanying Examplesand Preparations using a appropriate ⁇ sotOpiCally-labeled reagent in place of the npn-labeled-
  • “Pharmaceutically acceptable solvates in accordance with the invention include- th ⁇ se " wherein " the solvent " of crystallisation maybe isotopically. substituted, e.g: ⁇ - ? - "•' b ⁇ b d ' ⁇ -acetoneV d 6 -DMSO. " ' - ' - ' ⁇ ⁇ _-.- ⁇ - ⁇ ⁇ : ⁇ : ⁇ ' ⁇ .. - • . x - ⁇ -- ⁇ - " resort; " -
  • rHs ⁇ operi to a r person skilled In the art to ⁇ utihely -select the form of intermediate ⁇ which provides the- best c ' ⁇ mbinato ⁇ f features for this purpose;
  • Such features include the melting " point, solubil ⁇ tyrprocessability and-yield of the intermediate
  • compositions suitable for the delivery- of compounds of the present invention-and methods for their preparation will be readily apparent “ to those skilled " in the art Such compositions and methods foe their preparation " 20 may be found, for example, in Remington's Pharmaceutical Sciences. t9th "Edition (Mack Publishing Company, 1995) X ._ -
  • the compounds of the invention may be administered orally- Oral administration may involve swallowing, so that the compound enters the gastrointestinal tractr or buccal or sublingual administration may be employed by which -the compound enters the blood stream directly from the mouth- - -
  • Formulations suitable for oral administration include solid formulations- such as- tablets, capsules containing particulates, liquids, or powders, lozenges (including liqu ⁇ d-f ⁇ lled), "" chews, multi- and nano-part ⁇ culates--gels, solid solut ⁇ on r Irposome,- films, ovules, sprays and liquid formulations - "
  • Liquid formulations include suspensions, - solutions, syrups - and- elixirs. Such formulations may be employed- as fillers in soft or hard capsules and typically
  • - comprise a carrier, for example, water., ethanol, polyethylene glycol, propylene . ": 5 " glycol, methylce!lulo " se,-or a suitable oil, and one or more- emulsifying agents-
  • Liquid formulations may -also be- prepared by the - - - recohstitutiori of a solid, for example, -from a sachet. .- - - perennial -- - _ _
  • the compounds " of the "invention may also be used- in fast-dissolving, fast- _ 10 disintegrating " dosage forms such as " those described in Expert Opinion in
  • disintegrants include sodium - starch- glycolater- sodium - carboxymethyl - cellulose, . calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, -poly vinylpyrrolidone, " methyl cellulose, microcrystalline cellulose, lower alkyi-substituted hydroxypropyl cellulose, starch, • 20 " pregelatinised starch " and sodium alginate. ⁇
  • disintegrant will -
  • ⁇ " comprise from 1 weight % " to 25 weight %, preferably from 5 weight " % to 20 ⁇ ⁇ " weight % of the dosage form. - - - - -- - .. .- '" - -
  • Binders are generally used to impart cohesive qualities to a tablet formulation.
  • Suitable- binders include microcrystalline cellulose, gelatin, sugars r polyethylene ⁇ glycorxnatural and synthetic gums, polyvinylpyrrolidone, pregelatinised starch, - hydroxypropyl " cellulose and hydroxypropyl methylcellulose. Tablets miay also
  • diluents such as lactose (monohydrate, .spray-dried - monohydrate, " -- — anhydrous and the like), mannitol, xylitol, dextrose, sucrose r . -sorbito " " 30 " mfc ' rocry stall) ne cellulose, starch and dibasic calcium phosphate dihydrate. ..-. -
  • ' ⁇ - "' '- "" -Tabtets may also Optionally comprise surface active agents, such as-sodium-_ " " lauryl sulfate and polysorbate 80, and glidants such. as silicon dioxide -and talc.
  • surface active agents may comprise from 0.2 weight % to . 5 weight % of the tablet, and glidants may comprise from 0 2 weight % to 1 weight % of the tablet
  • Tablets also generally contain lubricants such as magnesium stearate, calcium -stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate Lubricants generally comprise from 0 25 ⁇ weight % to 10 weight % preferably from 0,5 weight % to 3 weight % of the tablet - - _ _ "
  • lubricants such as magnesium stearate, calcium -stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate
  • Lubricants generally comprise from 0 25 ⁇ weight % to 10 weight % preferably from 0,5 weight % to 3 weight % of the tablet - - _ _ "
  • ingredients include anti-oxidants, colourants, flavouring agents, 'preservatives and laste-masking-agents
  • Exemplary tablets contain up to about 80% drug, from about 10 weight % to about 90 weight % binder. frcm about 0 weight % to about 85_ weight % diluent, -from about 2 weight % to about 10 weight % disintegrant, and from about 0 25 weight % to about 10_we ⁇ ght % lubricant
  • -Tablet blends may be compressed directly or by roller. to form tablets Tablet blends or portions of blendsjnay alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tabletting
  • the final formulation may comprise one or more layers and may be coated or uncoated, i jnay even be encapsulated - _
  • Consumable oral films for human or veterinary use are typically pliable water- soTuble or water-swellable thin-film dosage forms which may be rapidly dissolving or mucoadhesive and typically comprise a compound, of formula (I), a ⁇ f ⁇ lm- ⁇ " " forming polyrner, a " -b ⁇ nder a solvent, a humectant, a-plasticiser,- a stabiliser or- emulsifier, a viscosity-modifying agent and a solvent, Some, components of the formulation may perform more than one function
  • Trie-compound offormula (I) may be water-soluble or insoluble.
  • a water-soluble compound typically comprises from 1 weight % to 80 weight %, morextypically
  • proteins, or synthetic hydfocolloids is typically present in the range 0.01 to 99 weight %, more typically " in the range 30 to 80 weight % -
  • ingredients include " anti-oxidants, colorants, flavourings- and flavour enhancersT preservatives; salivary stimulating agents, cooling agents, co : solvents (including oils), - emo1lients r bulking agents, anti-ioammg -agents, surfactants and taste-ma " sking agents.
  • Films in aecordance with the invention are typically prepared by evaporative " drying of thin aqueous films coated onto a peelable backing support or paper. This may be done in a drying oven or tunnel, typically a combined coater dryer, -or by freeze-drying or vacuuming. " . _ _-_ _ _ .
  • 25 -Solid formulations, for oral administration may be.formulated to bejmmediate anoVor modified release.
  • Modified release formulations include delayed-, sustained-7 pulsed-, controlled-, targeted and programmed release.
  • Suitable modified release formulations for the purposes of the invention are 30 " " described iri US Patent No 6,106,864. Details of. other suitable release technologies such as high energy-dispersions and osmotic and coated particles " ⁇ - are to " be found “ in Pharrhaceutical Technology ⁇ n-l ⁇ ne r .25.(2), 1-14, by Verm a et. al (2001) The use of chewing gum to achieve controlled release is described in “ WO 00/35298 . " " " "
  • parenteral formulations are typically .aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH -of from 3-to 9), but, for somefapplications, they may be more suitably formulated as a " sterile non-aqueous solution or as a -dried-form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water
  • parenteral formulations under sterile conditions-, for example, -0 by lyophilisation may readily be accomplished using standard pharmaceutfeal techniques well known to those skilled in the art
  • solubility of compounds of formula (I) used in the preparation of parenteral “solutions may " be ⁇ creased by the use of appropriate formulation techniques,5 such as the mcorporat on-of solubility-enhancing agents -_ ⁇ _
  • Formulations for- parenteral administration may be formulated to "" be " ⁇ mmed ⁇ ate ⁇ and/or modified release Modified release formulations include delayed-, sustained-, " pulsed-,- controlled-, targeted and programmed release " Thus0 compounds of the invention may be formulated as a solid; semi-solid, or - thixotropic " liquid for administration as_ an. implanted depot providing modified ⁇ release- of the active " compound Examples of such formulations- include drug- - coated stents and poly(o7-lact ⁇ c-coglycol ⁇ c)ac ⁇ d (PGLA) microspheres - opical " Administration -
  • the compounds of the invention may also be administered topically to. the skin or m ⁇ cosa, that is, dermally or transdermally.
  • Typical formulations for his purpose include gels, hydrogels, lotions, solutions, creams, ointments, dgsting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used.
  • Typical ".carriers include alcohol, water, " mineral oil, liquid -petrolatum, white petrolatum, " glycerin, polyethylene glycol and propylene glycol. Penetration enhancers maybe ⁇ ncorporate ' d - see, forexample. Pharm Sci, 88 (10),-955-958, by Finnm and Morgan -(October 1999).. - ___
  • topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or need]e-free ⁇ e. ⁇ xPowderject ⁇ - M , BiojectTM, etc.) injection. _. __. -
  • Formulations " for topical administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, - sustained-; pulsed-, controlled-, targeted and programmed release ⁇
  • the compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a- dry powder (either alone, as a mixture,- for example,- in . a dry blend with lactose, or as a mixed component particle,- for
  • phospholipids such as phosphatidylcholine
  • phospholipids such as phosphatidylcholine
  • the " powder may- comprise a bioadhesive agent, for example, chitosan of cyclodext ⁇ n. - ⁇
  • the pressurised container, pump, spray, atomizer, or nebuliser contains- a solution or suspension cf the compound(s) of the invention comprising, for example " , ethanol, - aqueous " ethanol, or a suitable -alternative agent for dispersing, solubilisirig, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid. - -.. - ; - . -. - - -
  • the drug product Prior to use " in a dry powder or suspension formulation, the drug product, is , micronised to a size suitable for delivery by inhalation .(typically less, thian “ _5 microns). This may be " achieved by any appropriate comminuting method, such- as spiral jet milling, fluid bed jet-milling, supercritical, fluid processing- to form nanoparticles, high pressure homogenisation, or spray drying.
  • lactose may be anhydrous or in the form of the monohydrate, preferably the latter
  • suitable_excipients include dextran; glucose, ma . ftose r sorbitol, xylitol, fructose, sucrose and trehalose.
  • a " suitable solution formulation for use in. an atomiser - musing electrohydrodynamics to produce a fine mist may contain from I ⁇ g .to 2Omg of " " the compound of the ⁇ nvent ⁇ on_per actuation and the actuation volume-may vary . from 1 ⁇ l to 100 ⁇ l "
  • a typical formulation may comprise a compound ofjormula (I), propylene glycol, sterile water, ethanol and sodium chloride.
  • Alternative -soJvents- which may be used instead of propylene glycol include glycerol and polyethylene glycol ' - - ⁇ _ _ .- "
  • Suitable flavours such as menthol and levomenthoj, or sweeteners, -such as-. saccharin 1 orsaccha ⁇ ri sodium, may be added to those formulations ' , of the invention" intended forinhaled/intranasal administration - - : " Formulations for inhaled/intranasal ,administration may be formulated to be. immediate and/or modified release using, for example, PGLA. Modified release formulations include delayed-, sustained ⁇ , pulsed . -, controlled-, targeted ; and 5 programmed release. .. .... - - -- . - . -- _ . ⁇
  • the -dosage unit is determined
  • the " invention are typically arranged-, to administer, a metered dose or "puff 10 " containing from 2 to 30mg of the compound of formula (I).
  • the overall daily . ⁇ - • dose- will typically be in the range 50 to 100mg which may be administered, in a single dose or,- more usualb .,,as " divided.doses throughout the day. - . ...
  • The- compounds of the invention may be administered rectally or vaginally, for " example, in the form of. a.suppository,. pessary, or enema;. Cocoa. butter. is a traditional suppository base, but various alternatives may be " used as appropriate, - x
  • Formulations for rectal/vaginal —administration; may- be- formulated . ' to- be imi iediate and/or modified release modifier.Modified release, formulations; . iricrude •
  • the compounds of the invention may also be administered directly to .
  • the eye or ear typically in the - form of drops of a micronised suspension or solution in isotonic, pH-adjusted, sterile saline, Other formulations -suitable for ocular and
  • aural administration include ointments, , biodegradable (e,g : absorbabl . e gel
  • pbfyme ' r such as crossed-linked polyacrylic acid,, p ⁇ lyvinylalcohol,. hyaluronic acid, a " cel ⁇ ulosic -_-. polymer, for example, -hydroxypropylmethylcellulose, hydroxyethylcellulosex or. methyl cellulose, or a heteropolysaccharide polymer, for " - : - ' " •" ⁇ . " .. " -.. ... . - . .. -__
  • - ''"''' - exarripleTgelah gum may be incorporated together- with, a preservative; such- as ; 5 benzalkonium chloride.
  • a preservative such- as ; 5 benzalkonium chloride.
  • Such formulations - may .also be- delivered by " "" iontophoresis. - - - " ⁇ ⁇ . ⁇ . :.. ,--: ⁇
  • Formulations for ocular ' /aural administration may be formulated to be immediate and/or modified releases Modified, release " formulations include delayed-,
  • the compounds of the invention may be combined .with soluble macromo
  • Dr ⁇ gf-cyclodextrin complexesx ⁇ for example, are found, to be generally useful for most dosage forms " and administration .routes. Both inclusion, and non : constituio complexes may be used. As an alternative to direct comp ⁇ exation with the drug, .
  • cyclodextriri may be used as an auxiliary additive, i.e. as a carrier, diluent or
  • the kit ofthe invention comprises two_or more separate , pharmaceutical - 5" conopositions, at least one of which contains a compound of formula (I) in accordance with -the invention, and means -for, separately retaining said compositions such " as a container, divided bottle, or divided foil packet
  • the kit of the invention is particularly suitable for administering, different dosage forms,- for. example; oral and parenteral, for administering, the separate compositions at. different dosage intervals, or for titrating . the separate compositions against one another; To assist compliance; the kit typically -
  • the total daily dose of the compounds of " " " the " invention is typfcally " in the range 50mg to, 100mg depending, . of course, on. the mode of administration arid efficacy.
  • Fo example oral administration may ;. : -. require .a. total daily dose of from 50mg to 100mg-
  • the total daily dose may be ,.. ad.rn ⁇ istered.in single or divided " doses and may, at the physician's discretion,- . 25 " fall outside Of the typical range given herein. . " 1 • ' . ' - ' "
  • references herein to "freatmeritin include references ,,, “ , to curative, " palliative and prophylactic treatment.
  • " - - ' ⁇ ' " - ' '"'”"' ' ... conditions comprise heating 1 equivalent of aryl ester (II) and 1.2-3 equivalents - of hydrazine monohyrate in methanol at reflux for 18-48 hours.
  • Compounds of formula (IV) may be prepared from compounds of formula (lll).by- 5 process step (ii), whicl comprises reaction with N,N-dimethylacetamide dimethyl ⁇ '" ' ' acetal (available - from . Aldrich). - in a suitable -solvent: -such as N,N-dimeth " ylformarriide, N-methyl pyrroiidine or toluene followed by the " addition of a suitable acid catalyst such as trifluoroacetic-acid, para-toluenesulfonic acid, ⁇ - "" camphor sulfonic acid, or hydrochloric acid.
  • a suitable -solvent such as N,N-dimeth " ylformarriide, N-methyl pyrroiidine or toluene followed by the " addition of a suitable acid catalyst such as trifluoroacetic-acid, para-toluenesulfonic acid, ⁇ - "" camphor
  • 3-amihopyridine in the presence " of a suitable acid, such as trifluoroacetic acid,
  • Compounds " bf formula (I) may be prepared from compounds of formula (V) by 25 process step (iv), which comprises a Suzuki coupling reaction with a suitable b ⁇ ronic acid such as 2,3-dimethylphenyl boronic acid (commercially available), in - a suitable solvent, in the presence of a base and a palladium catalyst, such as - [2- (Dimethylamino- ⁇ N)methyl]phenyl- ⁇ C](tricyclohexylphosphine)- " - (trifluoroacetato- ⁇ O-(SP-4-3)-palladium, prepared as described in” ' 30- . Organometallics, 2003, 22 (5), 987-999. "
  • Compounds of formula (VIII) may be prepared from compounds of formula (VII) by process step (in), which comprises reaction - with a suitable aniline .or
  • 3-am ri ⁇ pyridine in the -presence of a suitable acid such as .as trifluoroacetic acid, para-toluenesulfonic acid, camphor- sulfonic acrd, or hydrochloric acid, in a " - suitable solvent such as xylene, which is heated at 150°C.
  • a suitable acid such as trifluoroacetic acid, para-toluenesulfonic acid, camphor- sulfonic acrd, or hydrochloric acid
  • a suitable solvent such as xylene
  • Typical conditions comprise heating 1 equivalent of 1 ,2,4-oxadiazole (VII), 3 equivalents of aniline/aminopyridfne and 0 04-0 1 equivalents of para-toluenesulfonic acid in xylene at 150°C for 18-22 hours
  • Compounds of formula (I) may be prepared from compounds of formula (VIII) by pjrocess step (iv), which comprises a Suzuki coupling reaction as -described in .scheme 1. - . _ " " ⁇ .
  • Compounds of formula (IX) can be prepared from aryl hydrazides of formula (III) by process step (v) L which comprises reaction with a suitable acid chloride, such as chloreacetyl chloride, in the presence of a base, such as t ⁇ ethyiamine, " N-methyl morpholine, sodium carbonate or potassium hydroxide Typical conditions comprise reacting 1 0 equivalents of aryl hydrazide (III), 1 0-1.3 equivalents of chloroacetyl chloride, 1 2-2 0 equivalents of N-methyl morpholine in dichloromethane at 25°C.
  • a suitable acid chloride such as chloreacetyl chloride
  • a base such as t ⁇ ethyiamine, " N-methyl morpholine, sodium carbonate or potassium hydroxide
  • Typical conditions comprise reacting 1 0 equivalents of aryl hydrazide (III), 1 0-1.3 equivalents of chloroacetyl chloride, 1 2-2 0 equivalent
  • - Compounds of -formula (X) can be prepared from compounds of formula (IX) by process step (vi), which comprises reaction with a suitable dehydrating agent such as phosphorous oxychlo ⁇ de, tnfluoromethanesulfonic anhydride, or phosphorous pentachloride between a temperature of 25°C and " 110°C Typical conditions comprise heating 1 0 equivalent of compound (IX) in phosphorous oxychlo ⁇ de at 1 10°C for 4 hours
  • Typical conditions comprise heating 1 0 equivalent of compound (IX) in phosphorous oxychlo ⁇ de at 1 10°C for 4 hours
  • Compounds of formula (XI) can be prepared from alkyl chlorides ofJormula (X) ⁇ by process step (vii), which comprises reaction with a suitable primary or secondary a " mine_(HNR z R 8 ) or a 5-7 membered N-linked heterocycle, optionally in the presence of a base such as potassium carbonate, sodium carbon
  • a suitable solvent such as acetonitrile or - N,N-dimethylformamJde, by heating at 25-50°C for 2-18 hours.
  • Typical conditions comprise reacting -1 equivalent of.-alkyl chloride (X), 1.5 equivalent " of amine (HNR 7 R 8 ) or 5-7 membered N-linked heterocycle and 2 equivalents of potassium carbonate in. acetonitrile for 18 hours at 25°C. _ - "
  • Compounds of- formula (XII) may be preparedfrom compounds of formula (XI) by proeess- step (iii) f - -which comprises reaction with a suitable._aniline or 3-a . miriopyridine, in the presence of a suitable acid, such as trifluoroacetic acid, - para-toluenesulfonic acid, camphor -sulfonic acid, .or hydrochloric .acid, in a 15 " -suitable solvent such as xylene ⁇ heated at 150°C. Typical conditions comprise , heating 1 equivalent o ⁇ t 2,4-oxadiazole (XI), 3- . equivalent of aniline/aminopyridfne- and 0 04-0..1 equivalents of para-toluenesulfonic add in xylene.at 15 )°C for 18-24 hours
  • Compounds of formula (I) - may be . prepared from compounds of formula (Xll).by process step (iv), which comprisies reaction with a suitable boronic acid such as .2,3-dimethylphenyl boronic acid (commercially available), in a suitable solvent, in -.- the, -presence of a -suitable base and palladium catalyst as described in. - scheme T. 25 _. ;
  • a suitable boronic acid such as .2,3-dimethylphenyl boronic acid (commercially available)
  • compounds of general formula (XV) can be prepared from compounds of general formula (XIV) by process “step “ (viii), " using methods analogous to steps (v) and (vi), as described in scheme 2 or steps (v), (vi) arid “ (yii) " as described in scheme 3
  • Compounds- of general formula (XV) may be prepared from compounds (cf general formula (IV) by process step (iv) as described in scheme 1.
  • Compounds of formula (I) and (VIIJ) may be prepared from compounds of 5 formula " (XIV) and-(lll) respectively by process step (ix),- which comprises. sequential " reaction with a dimethylacetamide dimethylacetal in-a suitable solvent " " 'such a " s tetrahydofurancr acetic " acid heated at 55-60°C followed by reaction with a suitable aniline or aminopyridme in the presence of a suitable acid-such as " acetic acid heated at 90-100°C -Typical conditions comprise heating 1 0 10 " equivalent of acyl - hydrazide, - 1.5- equivalents of dimethylacetamide - dimethylacetal (Aldrich) in THF at 55°C for 2 hours followed by.the addition of. "" '" ⁇ 1.5 " equivalents of 2-methoxy-5 ' -aminopyridine (Aldrich) and heating in acetic-acid - at 90°C for 5 hours..
  • the compounds of the invention are useful because they have pharmacological activity in mammals; including humans. More particularly, they are useful in the 5 "" treatment or prevention of " a disorder- in which modulation of the levels .of oxytocin ' could provide " a beneficial-- effect.
  • Disease -states that may be mentioned include ' sexual dysfunction, particularly - premature - ejaculation, preterrh labour, " complications in labour, appetite and feeding disorders, benign prostatic hyperplasia, premature birth, dysmenorrhoea, congestive heart failure, " 1O arterial hypertension, - liver- -cirrhosis, " nephrofic hypertension, occular hypertension, obsessive compulsive disorder and neuropsychiatric disorders ⁇ - -
  • SD sexual dysfunction
  • SD disorders have been divided into female sexual dysfunction (FSD) disorders and male sexual dysfunction (MSD) disorders (Melman et al, J. Urology, 1999. 161. " 5-11).
  • 25 -FSD can be defined as the difficulty or inability " of a woman to find satisfaction in sexual expression.
  • FSD is a collective ' term for several diverse female sexual disorders (Leiblum, S R-, (1998) Definition and classification of female sexual disorders. Int J Impotence Res , T0-, S104-S106; Berman, J R., -Herman, l T &- Go Tstein I. (1999) Female " sexual dysfunction: Incidence,- pathophysiol ⁇ gy,
  • FSD FSD - The categories of FSD are best defined by contrasting them to the phases of normal female sexual response' desire, arousal and orgasm Leiblum, S.R.
  • ⁇ riferested ⁇ partner or when exposed to_ other erotic stimuli.
  • Arousal is the .
  • Vascular response to sexual stimulation an important component of which is " genital engorgement and includes -increased vaginal lubrication,- elongation of the vagina and increased genital sensation/sensitivity.
  • Orgasm is the release of sexual tension that has culminated during arousal. -
  • FSD occurs when a woman- has an. -inadequate or- unsatisfactory response " in any "" of these phases, - usually desire, arousal or orgasm.
  • FSD categories include hypoaGtive -sexual desire disorder, sexual arousal disorder, orgasmic " disorders and sexual pain disorders.
  • the compounds of the invention will improve the genital response to sexual stimulation- (as in female "sexual arousal disorder)-; in -doing so .it may_a!so improve the associated pain, , distress and discomfort associated . with- ⁇ ntercourse and- so treat other- female sexual disorders.
  • a compound of the invention in the preparation of a medicament for the - -treatment or " prophylaxis of hypoactive sexual desire disorder-;, sexual arousal " disorder " , orgasmic disorder and sexual -pain disorder, more- referably fof the treatment or prophylaxis of sexual arousal disorder, orgasmic disorder,- arid sexual pain disorder ⁇ -and ⁇ most preferably in the -treatment orxprophylaxis of sexual arousal disorder
  • Hypoactive sexual desire disorder ⁇ _s present if a woman -has no or-ljttle-desire to - be sexual, arid has no or few sexual thoughts or fantasies.
  • This type of FSD can be caused by low testosterone levels, due either to natural menopause or to "surgical menopause. - Other causes include illness, medications, atigue, depression and anxiety.
  • Female sexual arousal disorder is characterised by inadequate genital response to sexual stimulation.
  • the genitalia do not undergo the engorgement that characterises " normal sexual arousal.
  • the - vaginaL walls are poorly ⁇ lubricated, so that intercourse is painful, Orgasms may be impeded.
  • Arousal, disorder canrbe caused by reduced oestrogen at menopause or after childbirth ⁇ " " and -during lactation, as well as " by illnesses, with vascular components such as diabetes and atherosclerosis. .Other causes result from treatment with diuretics, antihistamines, antidepressants eg SSRIs or antihypertensive agents.
  • Sexual pain -disorders (includes dyspareunia and vaginismus) is characterised by pain resulting from penetration and may be caused by medications which reduce lubrication, endometriosis, pelvic inflammatory disease, inflammatory bowel disease or urinary tract problems.
  • FSO consists of several subtypes that express symptoms in separate phases of the sexual " response cycle, there- is not a single therapy.
  • Treatment of FSD. is--gradually evolving- as more clinical and basic science , studies " -are dedicated - to the investigation of this- medjcal . problem.
  • Femaje sexual complaints are not all psychological in pathophysiology, especially for those individuals who " may have a component of vasculogenic dysfunction (eg
  • Empirical drug therapy includes oestrogen administration- " (topically or . as . hormone -replacement therapy), aridrogens. or mood-altering drugs such as buspifone or trazodone. These treatment options are often unsatisfactory due to low efficacy .or unacceptable side effects,
  • the arousal response consists -of- vasocongestien . in the. pelvisx vaginal - lubrication and expansion and swelling of the external genitalia.
  • the disturbance - causes marked distress and/or- interpersonal difficulty;
  • FSAD is a highly prevalent sexual 7 disorder affecting pre-,, peri-, and post men ⁇ pausal ( ⁇ HRT) women. - It is associated with concomitant disorders such as depression, cardiovascular diseases, diabetes- andJJG disorders * .
  • MSD Male sexual - dysfunction
  • MED male erectile dysfunction
  • PE a relatively common sexual dysfunction in men. - It has been defined in several different- ays but the most widely accepted is the Diagnostic and Statistical Manual ofMental Disorders IV one-which states:
  • J PE is a lifelong -persistent or recurrent ejaculation with minimal sexual " stimulation before,- upon or shortly after penetration and. before the patientwishes it. -The clinician must take into account "- factors that " affect duration of the excitement phase, such as age; novelty o the sexual partner- or- stimulation, arid .frequency . of sexual activity. The " disturbance causes marked distress of interpersonal difficulty.”
  • ⁇ - Ejaculation comprises two sepajgite components - emission and- ejaculation.
  • Emission is the deposition of seminal fluid and- sperm from the distal epididymis, . vas deferens " , seminal vesicles and prostrate into the prostatic urethra. --Subsequent- to this ⁇ deposition- is the forcible expulsion of the s . eminal .contents from- he urethra! meatus. ⁇ jaculation is distinct from orgasm, which is purely a
  • a pulse of oxytocin in peripheral serum accompanies ejaculation in mammals.
  • In- nan oxytOGiir but not vasopressin plasma concentrations are significantly raised
  • Oxytocin does .not induce ejaculation itself; this process is 100% under nervous control via ⁇ 1-adrenoceptor/sympathetic nerves originating from the lumbar region of the spinal cord.
  • oxytocin may have a role in the peripheral ejaculatory response. It co ⁇ ld serve -15 mod ⁇ late he contraction of ducts and glandular lobules throughout the male
  • one aspect of the invention provides for the use of a compound of formula (1), without the proviso, in the preparation of a medicament for the prevention or treatment of sexual dysfunction, preferably male sexual "dysfunction, most preferably premature ejaculation.
  • another aspect of the invention provides, for the use of a compound ot formula (J),- without the proviso, in .the-.pceparation of . a- medicament ior the -prevention or-treatment of preterm labour and complications in labour.
  • Oxytocin - has a role in feeding , it reduces ⁇ the desire to eat (Arletti ef -a/,, Peptides ⁇ 989, 10,-89). By inhibiting oxytocin it is possible to increase.the desire to eat. Accordingly oxytocin inhibitors-are -useful in treating appetite and feeding disorders. -
  • Oxytocin is implicated as one- of the causes of benign, prostatic .hyperplasia 25- " -- (BPH)r Analysis of prostate tissue have show that -patients wjth BPH have. ncreased levels- of -oxytocin (Nicholson & Jen kin, -Adv.- Exp. Med. & Biol, 1995, 395, 529). Oxytocin antagonists can help treat this condition.
  • Another aspect of the invention provides for.the.use of -a compound
  • Oxytocin has a role -in the causes of dysmenorrhdea .due to its activity, as a uterine vasoconstrictor (Akerlurid, Ann. NY " Acad. Sci., 1994, 734,- ⁇ 7). Oxytocin - antagonists can have a therapeutic effect on this condition.
  • a further aspect of the invention provides for the use of a compound of formula (I), without ;the " proviso, in the preparation of a medicament- for the prevention of treatment of dysfriehorrhoea.
  • the compounds -of the " present invention may be coadministered with one .or,: more ' agents selected from:
  • adrenefgic receptor antagonists include: phentolamirie, -prazosin, phentolamine mesylate, " trazodone, alfuzosiri, indoramin; naftopidil, tamsulosiri, pheri ⁇ xybenzamirie, " ra ⁇ wolfa alkaloids, Recordaff 15/2739,
  • suitable ⁇ 2 - adrenergic receptor antagonists include dibenamine, " tolazoline, trimazosin, “ efaroxan,7 yohimbine, “ idazoxan ⁇ lonidiri and ' dibenarnirie; suitable non-selective ⁇ -
  • adrenergic receptor antagonists include dapiprazole; further ⁇ - adrenergic receptor antagonists are .described in PCT application WO99/30697
  • statins e.g. statins
  • 5HT2Ar 5HT2O, 5HT3, 5HT6. and/or 5HT7 receptors including those
  • NEP nhibitors preferably wherein-said NEP.is EC 3.4.24.11 . and more preferably wherein said NEP inhibitor is a selective inhibitor for
  • a selective NEP inhibitor is a selective 15 - . " inhibitor -for EC 3.4.24.11 , -which .has an JC 50 of-less than 100nM (e.g. ompatrilat, sampat ⁇ lat) suitable NEP inhibitor compounds -are described
  • Aporhbrphine - teachings on the use of apomorphine as a pharmaceutical r may be found in US-A-5945117; 25 ⁇ 9) ⁇ Dopamine agonists (in particular selective D2 2 selective D3, selective D4
  • D2-l ⁇ ke agents such as Pramipexole (Pharmacia Upjohn compound number PNU95666), ropinirole, apomorphine, surmaniroje,
  • PDE5 inhibitors for use with the invention include' 4-br ' ⁇ mo-5-(pyridylmethylamin ⁇ )-6-[3-(4-chlorophenyl)-propoxyl-
  • More preferred PDE5 inhibitors for use with the invention are. selected from the group:
  • a particularly " preferred PDE5 , inhibitor is 5-[2-ethpxy-5-(4-methyj,-1- "-piperazinylsulph " onyJ)phenyl]-1-methyl-3-n-propyl-1 ,6-dihydro-7H-pyrazoloJ4,3- d]pyrimidin-7-one (sildenafil) (also known as 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3- propyl-1H-pyrazolo[4 " ,3 d]pyrimidin-5-yl)-4-ethoxyphenyl]sulphonyl]-4- methylpiperazine)- and ⁇ " pharrnaceutical . ly acceptable salts thereof.
  • SUdenafil- . citrate is a preferred ' salt ⁇ -
  • Preferred agents for ' coadministration with the compounds of the present invention are -PDE5 " inhibitors " ,-- selective serotonin reuptake inhibitors (SSRIs), vasopressin V 1A antagonists, ⁇ -adrenergic receptor antagonists, NEP inhibitors, dopamine agonists and melariocortin receptor agonists as described above.
  • Particularly preferred agents for coadministration are PDE5 inhibitors, SSRIs, and ⁇ i A antagonists as described herein.
  • FBS Foetal Bovine Serum
  • Cells - used are CHO-OTR/NFAT- ⁇ -Lactamase.
  • the NFAI- ⁇ -lactamase expression construct was transfected into the CHO-OTR cell line " and clonal " populations were isolated, via fluorescence activated cell sorting (FACS). An appropriate clone.was selected to develop the assay.
  • a separate 384-well cell plate was used to generate an oxytocin dose response curve. (10 ⁇ l antagonist diluent was added to every well. O ⁇ l of - oxytocin was then added The cells are then treated as per
  • the compounds of the present invention all exhibit oxytocin antagonist activity, expressed as a Ki value, of less than 500nM, Preferred examples have Ki values of less than 200nM and particularly preferred examples have Ki values of less than 50nM.
  • the compound of example 8 has a Ki value of 3nM.
  • the title product was prepared by the method of preparation 8 using 20 6-chloronic ⁇ tinic acid hydrazide. 19.0g, 90% yield of the " desired product was produced, " - -.
  • the tftle product was prepared by the method of preparation 8 using the hydrazide of preparation 6 and chloroacetyl chloride: 4.30g, 59%. yield of the desired product was produced,
  • the title compound was prepared by the method of preparation 13 using the product of preparation 9 provide 7 93g, 40% yield of title compound as a rust brown solid
  • the title compound was prepared by the method of preparation 13 using the product of preparation 10 1 38g, 38% yield of the desired product was produced as a light brown solid
  • the title compound was prepared by- the method of preparation 13 using the product of preparation 11 30g, 35% of the desired product was produced as a brown solid
  • the title product was prepared by the method of - preparation iy using -2,3-dimethylphenyl boronic acid and the chloro compound of preparation 15.
  • Preoaration 42 was purified by column chromatography on silica gel, eluting with pentaneethyl acetate, 100:0 to 90.10.
  • Preparation 48 was purified by column chromatography on silica gel, eluting with d ⁇ chloromethane methanol.0 88 ammonia, 99 1 0 1 to 97'3:0.1 , followed by trituration with diethyl ether
  • Preparation 49 was purified by column c romatography on silica gel, eluting with ethyl acetate pentane, 10 90 to 100 0, followed by trituration with diethyl ether.
  • Preparation 50 was purified by re-crystallisation from ethyl acetate.
  • Preparation 51 was purified by column chromatography on silica gel, eluting with dichforomethane:methanol:0.88 ammonia, 100:0:0 to 99:1 :0.1.
  • para-Toluenesulfonic acid (20mg, cat ) was added to a . mixture of the products of preparations 55 (400mg, 1 56mmol) and 56 (470mg, .3.12mmol in methanol (8mL) and the mixture was heated under reflux for 10 hours. The mixture was then treated with sodium hydrogen carbonate solution and the aqueous mixture was extracted with, ethyl acetate (x3) The combined organic solutions were washed with brine, dried .over sodium sulfate and concentrated in vacuo to afford the title product as a-yellow oil in 25% yield, 122mg.
  • Oxaly] chloride (1.14mL,..13.09mmol), was added dropwise to an ice-cold suspension of 6-chloro-pyridazine-3-carboxylic acid [(1.9g, 11.9mmol), J. Her. Chem. 29(6), 1583-92; .1992] in a mixture of dichloromethane (50mL) " and N,N-dimethylform " amide (1 drop) and the mixture was stirred for 1 hour at room temperature The reaction mixture was then evaporated under reduced pressure and the residue was diluted with dichloromethane (30mL) and cooled to 0°C. Methanol (485 ⁇ L, 11.9mmol) was added and the mixture was stirred at 0°C for 1 hour.
  • the title compound was " prepared from “the product of .preparation 61 and' phosphorous oxychloride, using the 1 method of preparation 13.
  • the crude " product was purified by column chromatography- on silica gel, elutirig with dichl ⁇ romethane:methanolforce 99:1 to 98:2, to afford the desired compound as a - beige solid in 15%.yield. x ⁇ - .. x ... . • • - . ; " : . .. .
  • the title compound was prepared from the product of preparation 6 and N,N-d ⁇ methylacetam ⁇ de dimethyl acetal, using the method of preparation 4, as a 20 white solid in 47% yield ⁇ ,
  • Methoxyacetyl chloride (733 ⁇ L, 8.02mmol) was added to an ice-cold suspension 20 of the product of preparation 87 (1.16g, 5 73mmol) in dichloromethane (20mL) and triethylamine (1.2mL, 8 61 mmol) and the mixture was stirred for 18 hours at room temperature ⁇ The reaction mixture was then washed with water and brine, - dried over sodium sulphate and concentrated in vacuo to give a pale yellow gum.
  • the gum was purified by column chromatography on silica gel, eluting with 25 - dich!oromethane: . methanol_, .100 0 0 to 95:5, to afford the title compound as a
  • the title compound was. prepared from the product of preparation 89 :and 5 arriinb-2-ihethoxypyridine, using the method of preparation 18, -as a pale yellow. " foarri i 29% yield; •- - - - --- . .
  • the bromo compound of preparation 5 (100mg, 0 29mmol), the palladium complex of preparation 3 (10mg, cat ), caesium carbonate (440mg, 1.35mmo! and the appropriate boronic acid (0.73mmol) were suspended in 1,4-dioxan (5r ⁇ L) and " the reaction mixture heated to 120°C for 90 minutes. Additional 1 ,4-dioxari (4fhL) was added and the reaction mixture heated to f ⁇ °C for a further 4 hours.
  • reaction mixture was filtered under vacuum, washing through with dichloromethane
  • the filtrate was concentrated in vacuo and the-residue purified - by column chromatography on silica gel eluting with dichloromethane:methanol:0 68 ammonia 95:5:0:5 to yield the desired product.
  • the title product was prepared by the method of preparation 18 using the product of preparation 19 and 5-am ⁇ no-2-methoxypy ⁇ d ⁇ ne 140rrig, 15% yield of the desired product was produced
  • the title product was prepared by the method -of preparation 18 using the . . product of preparation 20 and 5-amino : 2-methoxypyridine. 325mg, . 36% of the desired product . was produced. - -
  • the bro o compoun of preparaton mg, . mmo , 2,3 : diri ⁇ ethylphenyl- boronic acid (61 mg, 0.41 mmol) and the palladium complex of preparation 3 (10mg) were dissolved in 1 ,2-dimethoxyethane (4mL) and the solution was treated with sodium carbonate (5 ⁇ mg, 0 55mmol).
  • the reaction mixture was heated -to reflux for. 1 hour and then concentrated in vacuo.
  • the resjdue was taken-up in ethyl acetate (25mL) and washed with water (25mL), 2M sodium hydroxide solution (25mL) and brine (25mL).
  • reaction mixture was concentrated in vacuo and- the residue purified by colur n chromatography on -. silica gel. eluting with dichl6rofhethane:metha ol:0. ⁇ ammonia :.100:0.0 to 99,5:0.5:0,05. to 99:1:0; to
  • the title product was prepared by the method of. example 14 using the chloro compound of preparation 30 (200mg, 0.66mmol) and the product of-preparation x 29 (240mg, 0.99mmol). 68m " g,- 27% yield of the title product was prepared as a white solid. . - - - - HNMR(CDCI 3 , 400MHz) ⁇ : 2.40(s, 3H), 2.43(s, 3H), 4.01(s, 3H), 6.90(d, 1H), 7.50-7.55(m, 2H), 7.57(s, 1H), 7.60(s, 1.H), 8.0 ⁇ (d, 1 H), 8.41(d, 1HJ, 9.55(d, 1H).
  • the title compound was prepared using the method of example 11 , using the oxadiazole compound of preparation 32 and 5-ammo-2-methoxy pyridine, as a pale green solid (325mg, 30%>)
  • The> chloro compound of preparation 52 (230mg, 0.67mmol), the palladium complex of preparation 3 (10mg, cat ), caesium carbonate (64 ⁇ mg, 2.01 mmol) and 4-ffuoro-2-methylphenylboron ⁇ c acid (143mg, 0 94mmol) were suspended in 1 ,4-d ⁇ oxan (4mL) and the reaction mixture heated to 1 10°C for 2 hours.

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Abstract

L'invention concerne une classe de triazoles-1,2,4 substitués de formule (I) présentant une activité en tant qu'antagonistes de l'oxytocine, leurs utilisations, des procédés pour leur préparation et des compositions contenant lesdits inhibiteurs. Ces inhibiteurs sont utiles dans une grande variété de champs thérapeutiques, y compris les dysfonctionnements sexuels, et notamment l'éjaculation précoce.
EP04769366A 2003-09-22 2004-09-10 Derives de triazoles substitues en tant qu'antagonistes de l'oxytocine Withdrawn EP1673355A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB0322159A GB0322159D0 (en) 2003-09-22 2003-09-22 New substituted triazoles for use as novel pharmaceuticals
GB0403150A GB0403150D0 (en) 2004-02-12 2004-02-12 Novel pharmaceuticals
GB0415110A GB0415110D0 (en) 2004-07-05 2004-07-05 Substituted triazole derivatives as oxytocin antagonists
PCT/IB2004/002977 WO2005028452A1 (fr) 2003-09-22 2004-09-10 Derives de triazoles substitues en tant qu'antagonistes de l'oxytocine

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EP1673355A1 true EP1673355A1 (fr) 2006-06-28

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AR (1) AR045791A1 (fr)
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NL (1) NL1027084C2 (fr)
PA (1) PA8613001A1 (fr)
PE (1) PE20050950A1 (fr)
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US7745630B2 (en) 2003-12-22 2010-06-29 Justin Stephen Bryans Triazolyl piperidine arginine vasopressin receptor modulators
ME01498B (me) * 2004-11-18 2014-04-20 Synta Pharmaceuticals Corp Jedinjenja triazola koja modulišu aktivnost hsp90
AP2007004047A0 (en) * 2005-01-20 2007-06-30 Pfizer Ltd Substituted triazole derivatives as oxtocin antagonists
CA2602383A1 (fr) * 2005-03-21 2006-09-28 Pfizer Limited Derives de triazole substitues utilises en tant qu'antagonistes d'oxytocine
DE602006003416D1 (de) * 2005-03-21 2008-12-11 Pfizer Ltd Substituierte triazolderivate als oxytocinantagonisten
BRPI0613570B8 (pt) 2005-07-09 2021-05-25 Astrazeneca Ab composto, composição farmacêutica e uso de um composto ou um sal farmaceuticamente aceitável do mesmo
CA2618103A1 (fr) * 2005-08-10 2007-02-15 Pfizer Limited Derives de triazole substitues en tant qu'antagonistes d'oxytocine
FR2903985B1 (fr) 2006-07-24 2008-09-05 Sanofi Aventis Sa Derives de n-(amino-heteroaryl)-1h-indole-2-carboxamides, leur preparation et leur application en therapeutique
FR2904316B1 (fr) 2006-07-31 2008-09-05 Sanofi Aventis Sa Derives de n-(amino-heteroaryl)-1h-indole-2-carboxamides, leur preparation et leur application en therapeutique.
DE102006059710A1 (de) * 2006-12-18 2008-06-19 Freie Universität Berlin Substituierte 4-Hydroxypyridine
FR2910473B1 (fr) 2006-12-26 2009-02-13 Sanofi Aventis Sa Derives de n-(amino-heteroaryl)-1h-pyrrolopyridine-2- carboxamides, leur preparation et leur application en therapeutique.
SG2014014013A (en) 2008-09-22 2014-07-30 Cayman Chemical Co Inc Multiheteroaryl compounds as inhibitors of h-pgds and their use for treating prostaglandin d2 mediated diseases
PL3037101T3 (pl) 2014-12-22 2019-06-28 Ferring B.V. Terapia antagonistą receptora oksytocyny w fazie lutealnej w celu implantacji i uzyskania ciąży u kobiet poddawanych technikom wspomaganego rozrodu
JP2020502211A (ja) 2016-12-21 2020-01-23 江蘇恒瑞医薬股▲ふん▼有限公司 縮合環基を有するアザシクロブチルトリアゾール誘導体、その製造方法および医薬におけるその使用
CN113149961B (zh) 2016-12-28 2022-11-22 江苏恒瑞医药股份有限公司 氮杂双环基取代的三唑类衍生物、其制备方法及其在医药上的应用
TW202016091A (zh) * 2018-06-20 2020-05-01 大陸商江蘇恆瑞醫藥股份有限公司 一種ｏｔｒ抑制劑的可藥用鹽、晶型及製備方法
CN113004250B (zh) * 2019-12-19 2022-07-26 上海森辉医药有限公司 一种制备取代的三唑衍生物的方法

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JP2000063363A (ja) * 1998-08-12 2000-02-29 Yamanouchi Pharmaceut Co Ltd 新規なトリアゾール誘導体
AU2000223275A1 (en) * 2000-02-08 2001-08-20 Yamanouchi Pharmaceutical Co..Ltd. Novel triazole derivatives
KR100776119B1 (ko) * 2000-05-19 2007-11-16 아스텔라스세이야쿠 가부시키가이샤 트리아졸 유도체
EP1273580B1 (fr) * 2001-07-05 2005-06-15 Pfizer Products Inc. Sulfonyl heteroaryl triazoles comme agent anti-inflammatoire et analgetique
US7468385B2 (en) * 2001-12-20 2008-12-23 Laboratoires Serono Sa Triazoles as oxytocin antagonists

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UY28524A1 (es) 2005-04-29
BRPI0414663A (pt) 2006-11-21
PE20050950A1 (es) 2005-11-11
CA2539297A1 (fr) 2005-03-31
JP2007505888A (ja) 2007-03-15
AR045791A1 (es) 2005-11-16
PA8613001A1 (es) 2005-08-04
WO2005028452A9 (fr) 2005-07-21
NL1027084A1 (nl) 2005-03-24
NL1027084C2 (nl) 2006-01-24
WO2005028452A1 (fr) 2005-03-31
TW200526606A (en) 2005-08-16
MXPA06003158A (es) 2006-06-05

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