WO1998001450A1 - Spiro-piperidine derivatives and their use as therapeutic agents - Google Patents

Spiro-piperidine derivatives and their use as therapeutic agents Download PDF

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Publication number
WO1998001450A1
WO1998001450A1 PCT/GB1997/001710 GB9701710W WO9801450A1 WO 1998001450 A1 WO1998001450 A1 WO 1998001450A1 GB 9701710 W GB9701710 W GB 9701710W WO 9801450 A1 WO9801450 A1 WO 9801450A1
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WIPO (PCT)
Prior art keywords
compound
formula
oxa
methoxy
phenyl
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PCT/GB1997/001710
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French (fr)
Inventor
Neil Roy Curtis
Ian Thomas Huscroft
Janusz Jozef Kulagowski
Christopher John Swain
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Merck Sharp & Dohme Limited
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Publication date
Application filed by Merck Sharp & Dohme Limited filed Critical Merck Sharp & Dohme Limited
Priority to US09/202,551 priority Critical patent/US6071928A/en
Priority to EP97928357A priority patent/EP0912579A1/en
Priority to AU32681/97A priority patent/AU722660B2/en
Priority to JP10504893A priority patent/JP2000513728A/en
Publication of WO1998001450A1 publication Critical patent/WO1998001450A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems

Definitions

  • This invention relates to a class of azacyclic compounds which are useful as tachykinin antagonists. More particularly, the compounds of the invention are spiro-substituted azacyclic derivatives.
  • WO 94/20500 discloses spiroazacychc derivatives as substance P antagonists.
  • WO 94/20500 relates to spirocychc piperidine derivatives containing a l,8-d ⁇ azasp ⁇ ro[5.5]undecane core.
  • the present invention provides compounds of the formula (I).
  • R represents Ci Galkyl, C2 calkenyl, Cz ⁇ alkynyl, C ;cycloalkyl, C3 ⁇ cycloalkylC ⁇ - ⁇ alkyl, which groups are optionally substituted by a group selected from hvdroxy, Ci lalkoxy or NR a R b , where R a and R b each independently represent hydrogen or C ⁇ -4alkyl; or R represents a Ci 4alkyl group substituted by the group ⁇ r, and optionally further substituted by one or both of the groups R 4 and R ⁇
  • R 1 represents hydrogen, hydroxy, Ci Galkyl, C2 Galkenyl, C calkynyl C ⁇ 7cycloalkyl, CJ ⁇ cycloalkylC ⁇ -4alkyl, Ci calkoxy, fluoroCi calkyl, fluoroCi Galkoxy, hydroxyCi 4alkyl, Ci GalkoxyC ⁇ .4alkyl, C ⁇ -6alkoxyC ⁇ 4alkoxy, fluoroCi calkoxyC i -lalkyl, C2 ⁇ alkenyloxy, C) rcycloalkoxy, C s -cycloalkylCi galkoxy.
  • R 1 and R 1 ' each independently represent hydrogen, C i -lalkyl or fluoroCi lalkyl
  • R 3 represents hydrogen, halogen, Ci calkyl, C 2 -calkenyl, C2-r > alkynyl, fluoroCi.calkyl, Ci-calkoxy, fluoroCi-calkoxy, C37cycloalkyl, C3.7cycloalkylC ⁇ 4alkyl, hvdroxy, phenoxy, benzyloxy, trimethylsilyl, nitro, cyano, SR a , SOR a , S0 2 R a , NR a R b , COR a , CO 2 R a , CONR a R b , SO 2 NR a R b , OCi 4alkylNR a R b , NR a COR d , or Ci 4alkyl substituted by a C ⁇ .4alkoxy, hydroxy, cyano or CO2R a group, where R a and R b are as previously defined and R d is Ci calkyl
  • R a and R b are each independently hydrogen or Ci 4alkyl, or together R 4 and R 5 represent an oxo group or when R 4 and R 5 are attached to the same carbon atom, they may be joined together to form a C3 scycloalkyl ring
  • Ar represents phenyl optionally substituted by one or two substituents selected from halogen, Ci calkyl, Ci calkoxy, CF3, OCF3, NO2, CN, SR a , SOR a , SO 2 R a , COR a , CO 2 R a , (CH 2 ) r CONR a R b , (CH 2 )rNR a R or (CH 2 )rNR a COR b .
  • R 7 is hydrogen or Ci lalkyl, Cj -cycloalkyl, Ci CvcloalkvlC ⁇ lalkvl. or C. 4alkyl substituted by Ci 4alkoxy or hydroxyl
  • R 8 is hydrogen or C ⁇ .4alkyl, Ci -cycloalkyl, Cj 7cycloalkylC ⁇ 4alkyl, or C2 jalkyl substituted by Ci 4alkoxy, hvdroxyl or a 4, 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, O and S, or R 7 , R 8 and the nitrogen atom to which they are attached form a he eroaliphatic ring 01 4 to 7 ring atoms, optionally substituted by one or two groups selected from hydroxy or Ci 4alkoxy optionally substituted by a Ci 4aIkoxy or hydroxyl group, and optionally containing a double bond, which ring may optionally contain an oxygen or sulphur ring
  • R 9 and R 10 each independently represent hydrogen, halogen, Ci Galkyl, CH 2 OR e , oxo, CO 2 R a or CONR R where R a and R b are as previously defined and R e represents hydrogen, Ci calkyl or phenyl;
  • X represents -CH2, or -CH 2 CH2-
  • a preferred sub-class of compounds of formula (I) is that wherein R 1 represents halogen, Ci calkyl, C 2 calkenyl, C2 calkynyl, C3 7cycloalkyl,
  • R 4 and R each independently represent Cualkyl, C ⁇ .4alkoxyC ⁇ -4alkyl, bydroxyC ⁇ -4alkyl or C ⁇ -4alkylNR a R b where R a and R b are each independently hydrogen or Ci-calkyl, or together R 4 and R 5 represent an oxo group or when R 4 and R 5 are attached to the same carbon atom, they may be joined together to form a Gn-scycloalkyl ring.
  • a preferred class of compound of formula (I) is that wherein R 1 is hydrogen, Ci-calkoxy, fluoroCi-calkoxy, C3-7cycloalkoxy, halogen or NR a R b ; in particular a hydrogen atom or a methyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, cyclopropoxy or cyclobutoxy group; and especially a hydrogen atom or a methoxy or cyclopropoxy group.
  • a particularly preferred class of compound of formula (I) is that, wherein R 1 is a methyl, trifluoromethyl. methoxy, ethoxy, isopropoxy or trifluoromethoxy group, especially a methoxy group. R 1 is preferably in the 2'- ⁇ ortho) position on the phenyl ring drawn in formula (I).
  • R 2 is a hydrogen, fluorine or chlorine atom, especially a hydrogen atom.
  • R 3 is halogen, Ci-calkyl, fluoroCi-calkyl, Ci- ⁇ alkoxy, fluoroCi-calkoxy, cyano or a
  • R : ' is halogen or fluoroC ⁇ . ⁇ ;alkoxy, especially fluorine, trifluoromethoxy or 2.2.2- t ⁇ fluoroethoxy, or a 5-membered aromatic heterocychc group as previously defined
  • a further preferred class of compound of formula (I) is that wherein R ! is the group
  • R 11 is hydrogen, halogen, Ci-calkyl, Ci calkoxy, CF3, OCF3, NO2, CN, SR a , SOR", SO 2 R a , COR a , CO 2 R a , (CH 2 ) r CONR a R b , (CH 2 ) r NR a R b or (CH >) r NR a COR , where R a and R b are hydrogen or C ⁇ -4alkyl, and r is zero, 1 or 2
  • R 11 is preferably hydrogen, halogen, Ci 4alkyl, especially methyl, or CF3.
  • a particularly preferred group represented by R n is CFj.
  • the group R 3 is preferably m the 5'-pos ⁇ t ⁇ on on the phenyl ring drawn in formula (I) (i.e R 3 is para to the group R 1 )
  • Another preferred class of compound of formula (I) is that wherein R represents a Ci 4alkyl group (especially a Ci 2alkyl group) substituted by the group Ar, and optionally substituted by one or both of the groups R 4 and R " '
  • R 4 is Ci 4alkyl, especially methyl, or R 4 and R together represent an oxo group Ar preferably represents a phenyl ring, optionally substituted by one or two halogen atoms, especially chlorine or fluorine, or Ci lkoxv, especially methoxy
  • R 9 and R 10 are preferably attached at the 8- and 9- positions
  • R 9 and R 10 are hydrogen and, more preferably, R 9 and R 10 are both hydrogen atoms.
  • -CH2- One favoured group of compounds of the present invention are of the formula (la) and pharmaceutically acceptable salts thereof
  • R, R 1 , R 2 and R 3 are as defined in relation to formula (I) and the broken line is an optional double bond
  • R 1 , R 2 , R 3 and R 4 are as defined in relation to formula (I), the broken line is an optional double bond, and R 12 and R are each independently hydrogen, halogen or Ci Galkoxy
  • R 1 , R 2 and R 3 are defined in relation to formula (1), the broken line is an optional double bond, and R 12 and R 13 are each independently hydrogen, halogen or Ci-oalkoxy.
  • Ar represents an optionally substituted 5- or 6-membered heterocychc ring containing 1 to 3 nitrogen atoms
  • suitable rings include: pyrrole, pyrazole, lmidazole, 1 ,2,3-triazole, 1 ,2,4-t ⁇ azole, pyridine, pyridaz e. py ⁇ midine, pyrazine and 1,3,5-triaz ⁇ ne.
  • Z may be a linear, branched or cyclic group.
  • Favourably Z contains 1 to 4 carbon atoms and most favourably 1 or 2 carbon atoms.
  • a particularly favourable group Z is CH 2 .
  • R 7 may aptly be a C;.4alkyl group or a C 2 . ⁇ alkyl group substituted by a hydroxyl or Cicalkoxy group
  • R 8 may aptly be a Gi- ialkyl group or a C ⁇ alkyl group substituted by a hydroxyl or Cicalkoxy group
  • R 7 and R 8 may be linked so that, together with the nitrogen atom to which they are attached, they form an azetidinyl, pyrrolidinyl, piperidyl, morpholino.
  • group NR 7 R 8 represents a heteroaliphatic ring of 4 to 7 ring atoms and said ring contains a double bond
  • a particularly preferred group is 3- pyrrolme.
  • NR 7 R 8 represents a non-aromatic azabicyclic ring -ystem
  • a system may contain between 6 and 12, and preferably between 7 and 10, ring atoms.
  • Suitable rings include , r )-azab ⁇ cyclo[2.1.1]hexyl, ⁇ -azabu:ycloi2.2.1 ]heptyl, (>-azabtcyclo[3.2.1 ]ocl.yl, 2-azab ⁇ :yclo(2.2.2joctyi 6-azab ⁇ cyclo(3.2.21nonyl, 6-azab ⁇ :yclo
  • R 8 represents a G 2 -4alkyl group substituted by a 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, ⁇ and S
  • suitable rings include pyrrohdmo, pipendino, piperazino, morphohno, or thiomorphohno
  • nitrogen containing heteroaliphatic rings especially pyrrohdmo and morphohno rings.
  • Z is preferably CH 2 or CH2CH2, and especially CH2.
  • the group NR 7 R 8 preferably represents ammo, methylamino, dimethvlamino diethylamino, azetidinyl, pyrrohdmo and morphohno
  • R 1 and R 2 are attached to adjacent carbon atoms and are joined together such that there is formed a 5- or 6-membered saturated or unsaturated ring containing one or two oxygen atoms, there is formed a fused ring moiety uch as 2,3-d ⁇ hydrobenzofuran, benzofuran, 3,4-d ⁇ hydro-2H- l -benzopyran, 2H- 1 - benzopyran, 1 ,3-benzod ⁇ oxole or 1 ,4-benzod ⁇ oxan.
  • Particularly preferred is 2,3- dihydrobenzofuran where the oxygen atom corresponds to the position of R 1 .
  • R 1 and R 2 are attached to adjacent carbon atoms and are joined together such that there is formed a 5-membered saturated or unsaturated ring containing one nitrogen atom and optionally one oxygen atom, there is formed a fused ring moietv such as indole, indoline, benzoxazole, benzoxazohne, benzisoxazole or benzisoxazohne
  • Certain particularly apt compounds of the present invention include those wherein R 3 is a group selected from pyrrole, furan, thiophene, py ⁇ dine, pyrazole, lmidazole, oxazole, isoxazole, thiazole, isothiazole, pyrazine, py ⁇ midine, py ⁇ dazine, t ⁇ azole, oxadiazole, thiadiazole, t ⁇ azine, and tetrazole, each heteroaryl group being optionally substituted as previously defined.
  • Particularly preferred compounds of the present invention are those wherein R 3 is a group selected from furan, py ⁇ dine, py ⁇ midine, lmidazole, t ⁇ azole and tetrazole, each heteroaryl group being optionally substituted as previously defined.
  • alkyl or "alkoxy as a group or part of a group means t hat, the group is straight or branched
  • Preble alkvl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-bulyl and t-but yl
  • Examples of Preble alkoxy groups include methoxy, ethoxy, n-propoxy. l-propoxy, n- butoxy, s-butoxy and t-butoxy.
  • fluoroCi-calkyl and “fluoroCi-calkoxy” means a C ⁇ - ⁇ ;alky) or d.,;alkoxy group in which one or more (in particular, 1 to 3) hydrogen atoms have been replaced by fluorine atoms.
  • fluoroCi-ialkyl means a C ⁇ -4alkyl group in which one or more (in particular 1 to 3) hydrogen atoms have been replaced by fluorine atoms.
  • fluoroCi- aalkyl and fluoroC ⁇ -3alkoxy groups for example, CF. , CF CHsF, GH2CHF2, CI I.CFJ. OGF3, OGH2GH2F, OGH2GHF2 or OCH 2 CF 3 , and most especially CFa, OCFa and OClisCFs.
  • hydroxyC ⁇ .4alkyl means a C ⁇ .4alkyl group in which one or more (in particular 1 or 2, especially 1 ) hydrogen atoms have been replaced by hydroxy groups, for example CH2OH or CH2CH2OH.
  • cycloalkyl groups referred to herein may represent, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • a suitable cycloalkyialkyl group may be, for example, cyclopropylmethyl.
  • cycloalkoxy groups referred to herein may represent, for example, cyclopropoxy or cyclobutoxy.
  • a suitably cycloalkylalkoxy group may be, for example, cyclopropylmethoxy.
  • alkenyl and alkynyl as a group or part of a group means that, the group is straight or branched. Examples of suitable alkenyl groups include vinyl and ally!. A suitable alkynyl group is propargyl.
  • halogen means fluorine, chlorine, bromine and iodine. The most apt halogens are fluorine and chlorine of which fluorine is preferred, unless otherwise stated.
  • Specific compounds within the scope of this invention include: 7-benzyl-3-(2-methoxyphenyl)- l-oxa-7-azasp ⁇ ro[4,5]dec-3-ene; 7-benzyl-3-(2-methoxy-5-(r)-t ⁇ fluoromethyl- lH-tetrazol- l-yl)phenyl)- l -oxa-7- azasp ⁇ ro
  • the compounds of formula (1) may be prepared in the form of a pharmaceutically acceptable salt, especially an acid addition salt.
  • a pharmaceutically acceptable salt especially an acid addition salt.
  • the salts of the compounds of formula (I) will be non- toxic pharmaceutically acceptable salts.
  • Other salts may, however, be useful in the preparation of the compounds according to the invention or of their non-toxic pharmaceutically acceptable salts.
  • Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, fuma ⁇ c acid, p-toluenesulphonic acid, maleic acid, succmic acid, acetic acid, citric acid, tartanc acid, carbonic acid, phosphoric acid or sulphuric acid.
  • Salts of amine groups may also comprise quaternary ammonium salts in which the amino nitrogen atom carries a suitable organic group such as an alkyl, alkenyl, alkynyl or aralkyl moiety.
  • suitable pharmaceutically acceptable salts thereof may include metal salts such as alkali metal salts, e.g. sodium or potassium salts; and alkaline earth metal salts, e.g. calcium or magnesium salts.
  • the salts may be formed by conventional means, such as by reacting the free base form of the product with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is removed in vacua or by freeze drying or by exchanging the anions of an existing salt for another anion on a suitable ion exchange resin.
  • the present invention includes within its scope prodrugs of the compounds of formula (1) above.
  • prodrugs will be functional derivatives of the compounds of formula (I) which are readily convertible in vivo into the required compound of formula (1).
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, m "Design of Prodrugs", ed. H. Bundgaard. Elsevier, 1985.
  • a prodrug may be a pharmacologically inactive derivative of a biologically active substance (the "parent drug” or “parent molecule”) that requires t ransformation within the body in order to release the active drug, and that has improved delivery properties over the parent drug molecule.
  • the transformation in ⁇ ro may be tor example, as the result of some metabolic process, such as chemical or enzymatic hydrolysis of a carboxyhc, phosphoric or sulphate ester, or reduction or oxidation of a susceptible functionality.
  • the present invention includes within its scope solvates of the compounds of formula (I) and salts thereof, for example, hydrates.
  • the compounds according to the invention may have at least two asymmetric centres, and may accordingly exist both as enantiomers and as diastereoisomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.
  • the compounds of the formula (I), (la), (lb), (Ic) and (Id) will have the preferred stereochemistry of the 5-pos ⁇ t ⁇ on that is possessed by the late eluting enantiomer of Example 2.
  • the compounds of the formula (I), (l a), (lb), (Ic) and (Id), in which Y is -GH 2 - or -CH2CH2- will have the relative stereochemistry of the 3- and 5-pos ⁇ t ⁇ ons that is possessed by the compound of Example 22 (i.e. 3-( ⁇ ).5-( ?) or 3-(S),5-(S)):
  • compositions according to the invention are in unit dosage forms such as tablets, pills, capsules, powders, granules, solutions or suspensions, or suppositories, for oral, parenteral or rectal administration, or administration by inhalation or insufflation.
  • the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention or a non-toxic pharmaceutically acceptable sail thereof .
  • a pharmaceutical carrier e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water
  • a pharmaceutical carrier e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium
  • This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention.
  • the tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate
  • the liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles
  • Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvmyl-pyrrohdone or gelatin.
  • compositions for administration by injection include those comprising a compound of formula (I), as the active ingredient, in association with a surface- active agent (or wetting agent or surfactant) or in the form of an emulsion (as a water-in-oil or oil-in-water emulsion)
  • Suitable surface-active agents include, in particular, non-ionic agents, such as polyoxyethylenesorbitans (e.g. TweenTM 20, 40, 60, 80 or 85) and other sorbitans (e.g. SpanTM 20, 40, 60, 80 or 85)
  • Compositions with a surface-active agent will conveniently comprise between 0 05 and 5% surface-active agenl , and preferably between 0 1 and 2.5% I t, will be appreciated that other ingredients may be added, for example mannitol or other pharmaceutically acceptable vehicles, if necessary
  • Suitable emulsions may be prepared using commercially available lat emulsions, such as I ntrahpidTM, LiposynTM, lnfonutrolTM, LipofundinTM and LipiphysanTM
  • the active ingredient may be either dissolved in a pre-mixed emulsion composition or alternatively it may be dissolved in an oil (e.g soybean oil, safflower oil, cottonseed oil, ses
  • emulsions will typically contain up to 20% oil, for example, between 5 and 20%.
  • the fat emulsion will preferably comprise fat droplets between 0.1 and l.O ⁇ m, particularly 0.1 and 0.5 ⁇ m, and have a pH in the range of 5.5 to 8.0
  • Particularly preferred emulsion compositions are those prepared by mixing a compound of formula (I) with IntrahpidTM or the components thereof (soybean oil, egg phosphohpids, glycerol and water).
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders
  • the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as set out above.
  • the compositions are administered by the oral or nasal respiratory route for local or systemic effect
  • Compositions in preferablv sterile pharmaceuticallv accept able solvents may be nebulised by use of inert gases. Nebulised solutions may be breathed directly from the nebulising device or the nebulising device may be attached to a face mask, tent or intermittent positive pressure breathing machine.
  • Solution, suspension or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.
  • the present invention futher provides a process for the preparation of a pharmaceutical composition comprising a compound of formula (I), which process comprises bringing a compound of formula (I) into association with a pharmaceutically accept able carrier or excipient
  • the compounds of formula (1) are of value in the treatment of a wide va ⁇ etv of clinical conditions which are characterised bv the presence of an excess of t achvkinin, in particular substance P, activity
  • an excess of fachykinin, and in particular substance P, activity is implicated in a variety of (hsorders of the central nervous system.
  • Such disorders include mood disorders, such as depression or more particularly depressive disorders, for example, single episodic or recurrent major depressive disorders and dysthymic disorders, or bipolar disorders, for example, bipolar I disorder, bipolar I I disorder and cyclothymic fhsorder; anxiety disorders, such as panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, specific phobias, for example, specific animal phobias, social phobias, obsessive-compulsive disorder, stress disorders including post-traumatic stress disorder and acute stress disorder, and generalised anxiety disorders; schizophrenia and other psychotic disorders, for example, schizophreniform disorders, schizoaffective disorders, delusional disorders, brief psychotic disorders, shared psychotic disorders and psychotic disorders with delusions or hallucinations; dele ⁇ um.
  • mood disorders such as depression or more particularly depressive disorders, for example, single episodic or recurrent major depressive disorders and dysthymic disorders, or bipolar disorders, for example, bipolar I disorder, bipolar I
  • dementia and amnestic and other cognitive or neurodegenerative disorders, such as Alzheimer's disease, senile dementia.
  • dementia of the Alzheimer's type, vascular dementia, and other dementias for example, due to HIV disease, head trauma, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, or due to multiple aetiologies; Parkinson's disease and other extra-pyramidal movement disorders such as medication-induced movement disorders, for example, neuroleptic-induced parkinsonism.
  • neuroleptic malignant syndrome neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia, neuroleptic-induced tardive dvskinesia and medication-induced postural tremour
  • substance-related disorders arising from the use of alcohol, amphetamines (or amphetamine-hke substances) caffeine, cannabis, cocaine, hallucinogens, inhalants and aerosol propellants, nicotine, opioids, phenylglycidine derivatives, sedatives, hypnotics, and anxiolytics, which substance-related disorders include dependence and abuse, intoxication, withdrawal, intoxication dele ⁇ um, withdrawal dele ⁇ um, persisting dementia, psychotic chsorders, mood (hsorders.
  • demyehnating diseases such as MS and ALS and other neuropathological disorders such as peripheral neuropathy, for example diabetic and chemotherapy-induced neuropathy, and postherpetic neuralgia, t ⁇ geminal neuralgia, segmental or intercostal neuralgia and other neuralgias, and cerebral vascular disorders due to acute or chronic cerebrovascular damage such as cerebral infarction, subarachnoid haemorrhage or cerebral oedema.
  • Tachykinin. and in particular substance P. activity is also involved m nociception and pain.
  • the compounds of the present invention will therefore be of use in the prevention or treatment of diseases and conditions in which pam predominates, including soft tissue and peripheral damage, such as acute trauma, osteoarth ⁇ tis, rheumatoid arthritis, musculo-skeletal pain, particularly after trauma, spinal pain, dental pain, myofascial pain syndromes, headache, episiotomy pam, and burns; deep and visceral pain, such as heart pain, muscle pain, eye pam, orofacial pain, for example, odontalgia, abdominal pain, gynaecological pain, for example, dysmenorrhoea, and labour pain; pain associated with nerve and root damage, such as pain associated with peripheral nerve disorders, for example, nerve entrapment and brachial plexus avulsions, amputation, peripheral neuropathies, ti douloureux, atypical facial pain, nerve root damage
  • Tachykinin, and in particular substance P, antagonists may also be of use in the treatment of respiratory diseases, particularly those associated with excess mucus secretion, such as chronic obstructive airways disease, bronchopneumonia, chronic bronchitis, cystic fibrosis and asthma, adult respiratory distress syndrome, and bronchospasm; inflammatory diseases such as inflammatory bowel disease, psoriasis, fibrositis, osteoarth ⁇ tis, rheumatoid arthritis, pruritus and sunburn; allergies such as eczema and rhinitis; hypersensitivity disorders such as poison ivy; ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, and the like; ophthalmic conditions associated with cell proliferation such as proliferative vitreoretinopathy; cutaneous diseases such as contact dermatitis, atopic dermatitis, urticaria, and other eczemato l dermatitis.
  • Tachykinin. and in particular substance P, antagonists may also be of use in the treatment, of gastrointestinal (GI) disorders, including inflammatory disorders and diseases of the Gl tract such as gastritis, gastroduodenal ulcers, gastric carcinomas, gastric lymphomas, disorders associated with the neuronal control of viscera, ulcerative colitis, Crohn' disease, irritable bowel syndrome and emesis, including acute, delayed or anticipatory emesis such as emesis induced by chemotherapy, radiation, toxins, viral or bacterial infections, pregnancy, vestibular disorders, for example, motion sickness, vertigo, dizziness and Meniere's disease, surgery, migraine, variations in intercranial pressure gastro-oesophageal reflux disease, acid indigestion, over indulgence in food or drink, acid stomach, waterbrash or regurgitation, heartburn, for example, episodic, nocturnal or meal-induced heartburn, and dyspepsia.
  • GI gastrointestinal
  • GI gastrointestinal
  • GI gastrointestinal
  • Tachykinin, and in particular substance P, antagonists may also be of use in the treatment of a variety of other conditions including stress related disorders; reflex sympathetic dystrophy such as shoulder/hand synchOnie, adverse immunological reactions such as rejection of transplanted tissues and disorders related to immune enhancement or suppression such as systemic lupus erythematosus; plasma extravasation resulting from cytokine chemotherapy, (hsorders of bladder function uch as cystitis, bladder detrusor hyper-re flexia and incontinence; fibrosing and collagen diseases such as scleroderma and eosinophihc fasciohasis; (hsorders of blood flow caused by vasodilation and vasospastic (hseases such as angina, vascular headache, migraine and Revnaud's disease; and pain or nociception attributable to or associated with any of the foregoing conditions, especially the transmission of pam in migraine.
  • reflex sympathetic dystrophy such as shoulder/hand synchOn
  • the compounds of formula (I) are also of value in the treatment of a combination of the above conditions, in particular in the treatment of combined post-operative pain and post-operative nausea and vomiting.
  • the compounds of formula (1) are particularly useful in the treatment of emesis, including acute, delayed or anticipatory emesis, such as emesis induced by chemotherapy, radiation, toxins, pregnancy, vestibular disorders, motion, surgery, migraine, and variations in intercranial pressure.
  • the compounds of formula (I) are of use in the treatment of emesis induced by antineopla tic (cytotoxic) agents including those routinely used in cancer chemotherapy, and emesis induced by other pharmacological agents fur example rohpram.
  • chemotherapeutic agents include alkylating agents, for example, nitrogen mustards, ethyleneimine compounds, alkyl sulphonates and other compounds with an alkylating action such as nitrosoureas, cisplatm and dacarbazine; antimetabohtes, for example, folic acid, pu ⁇ ne or py ⁇ midine antagonists; mitotic inhibitors, for example, vmca alkaloids and derivatives of podophyllotoxin; and cytotoxic antibiotics.
  • alkylating agents for example, nitrogen mustards, ethyleneimine compounds, alkyl sulphonates and other compounds with an alkylating action such as nitrosoureas, cisplatm and dacarbazine
  • antimetabohtes for example, folic acid, pu ⁇ ne or py ⁇ midine antagonists
  • mitotic inhibitors for example, vmca alkaloids and derivatives of podophyllotoxin
  • cytotoxic antibiotics
  • chemotherapeutic agents are described, for instance, by D. J. Stewart in Nausea and. Vomiting: Recent. Research and Clinical Advances, Eds. ⁇ . Kucharczyk el al, CRC Press Inc., Boca Raton, Florida. USA ( 1991) pages 177-203, especially page 188.
  • chemotherapeutic agents include cisplatm, dacarbazine (DTIC), dactinomycin, mechlorethamine (nitrogen mustard), streptozocin, cyclophosphamide, carmustine (BGNU), lomustme (CCNU), doxorubicin (adriamycin), daunorubicin, procarbazine, mitomycin, cytarabine, etoposide, methotrexate, 5-fluorourac ⁇ l, vinblastine, vinc ⁇ stine, bleomycm and chlorambucil [R. J . Gralla et al in Cancer Treatment
  • the compounds of formula (I) are also of use in the treatment of emesis induced by radiation including radiation therapy such as m the treatment of cancer, or radiation sickness; and in the treatment of post-operative nausea and vomiting.
  • a further aspect of the present invention comprises the compounds of formula (I) in combination with a 5-HT. ⁇ antagonist, such as ondansetron, granisetron or tropisetron, or other anti-emetic medicaments, for example, a dopamine antagonist such as metoclopramide or domperidone, or GABAB receptor agonists such as baclofen.
  • a 5-HT. ⁇ antagonist such as ondansetron, granisetron or tropisetron, or other anti-emetic medicaments, for example, a dopamine antagonist such as metoclopramide or domperidone, or GABAB receptor agonists such as baclofen.
  • a compound of formula (1) either alone or in combination with one or more other anti-emetic therapeutic agents, may be administered in combination with an anti-inflammatory corticosteroid.
  • an anti-inflammatory corticosteroid such as dexamethasone.
  • betamethasone triamcinolone, t ⁇ amcinol ⁇ ne acetonide, flunisohde, budesonide, or others such as those disclosed m US patent nos 2,789, 1 18, 2,990.401, 3,048,581 , 3, 126.375, 3,929,768, 3,996.359, 3,928,326 and 3, 749, 712.
  • Dexamethasone (DecadronTM) is particularly preferred.
  • a compound of formula (I) may be administered in combination with a chemotherapeutic agent such as an alkylating agent, antimetabohte, mitotic inhibitor or cytotoxic antibiotic, as described above.
  • a chemotherapeutic agent such as an alkylating agent, antimetabohte, mitotic inhibitor or cytotoxic antibiotic, as described above.
  • the currently available dosage forms of the known therapeutic agents for use in such combinations will be suitable.
  • the compounds of formula (1) are also particularly useful in the treatment of pain or nociception and or inflammation and disorders associated therewith such as, for example, neuropathy, such as diabetic and chemotherapy-induced neuropathy, postherpetic and other neuralgias, asthma, osteroarth ⁇ tis, rheumatoid arthritis and headache including migraine, acute or chronic tension headache, cluster headache, temporomandibular pain and maxillary sinus pain.
  • neuropathy such as diabetic and chemotherapy-induced neuropathy
  • postherpetic and other neuralgias such as diabetic and chemotherapy-induced neuropathy
  • postherpetic and other neuralgias such as asthma, osteroarth ⁇ tis, rheumatoid arthritis and headache including migraine, acute or chronic tension headache, cluster headache, temporomandibular pain and maxillary sinus pain.
  • the compounds of formula (I) are also particularly useful in the treatment of depression including depressive disorders, for example, single episodic or recurrent mapr depressive disorders, and dysthymic disorders, depressive neurosis, and neurotic depression; melancholic depression including anorexia, weight loss, insomnia and early morning waking, and psychomotor retardation; atypical depression (or reactive depression) including increased appetite, hypersomnia, psychomotor agitation or irritability, anxiety and phobias; seasonal affective disorder; or bipolar (hsorders or manic depression, for example, bipolar I disorder, bipolar 11 disorder and cyclothymic disorder.
  • depressive disorders for example, single episodic or recurrent mapr depressive disorders, and dysthymic disorders, depressive neurosis, and neurotic depression
  • melancholic depression including anorexia, weight loss, insomnia and early morning waking, and psychomotor retardation
  • atypical depression or reactive depression
  • bipolar hsorders or manic depression, for example, bipolar I disorder, bi
  • the present invention further provides a compound of formula (1) for use in therapy.
  • the present invention provides a compound of formula (I) for use in the manufacture of a medicament for the treatment of physiological disorders associated with an excess of tachykinins, especially substance P.
  • the present invention also provides a method for the the treatment or prevention oi physiological disorders associated with an excess of tachykinins, especially sub-t ance P, which method comprises administrat ion to a patient in need thereof of a tachykinin reducing amount of a compound of formula (I) or a composition comprising a compound of formula (1).
  • a combination of a compound according to the present invention and one or more other pharmacologically active agents suitable for the treatment of the specific condition may be administered to a patient simultaneously, sequentially or in combination.
  • a compound of formula (I) may be used in conjunction with a bronchodilator, such as a p2-adrenerg ⁇ c receptor agonist or tachykinin antagonist which acts at NK-2 receptors.
  • the compound of formula (i) and the bronchodilator may be administered to a patient simultaneously, sequentially or in combination.
  • a compound of the present invention may be employed with a leukotriene antagonists, such as a leukotriene D antagonist such as a compound selected from those disclosed in European patent specification nos. 0 480 717 and 0 604 1 14 and in US patent nos. 4,859,692 and 5,270,324. This combination is particularly useful in the treatment of respiratory diseases such as asthma, chronic bronchitis and cough.
  • the present invention accordingly provides a method for the treatment of a respiratory disease, such as asthma, which method comprises administration to a patient in need thereof of an effective amount of a compound of formula (I) and an effective amount of a bronchodilator.
  • a respiratory disease such as asthma
  • the present invention also provides a composition comprising a compound of formula (I), a bronchodilator, and a pharmaceutically acceptable carrier.
  • a compound of the present invention may be used in conjunction with other anti- migraine agents, such as ergotamines or 5-HT ⁇ agonists, especially sumat ⁇ ptan, narat ⁇ ptan, zolmat ⁇ ptan or ⁇ zat ⁇ ptan.
  • a compound of the present invention may be used in conjunction with an antagonist of N-methvl D-aspartate (NMI) ⁇ ), such as dizocilpine.
  • NMI N-methvl D-aspartate
  • a compound of the present invention may be used in conjunction with an antnnflammatory agent such as a bradykinin receptor antagonist.
  • a compound of the present invention may be used in conjunction with other analgesics, such as acetaminophen (paracetamol), aspirin and other NSAIDs and, in particular, opioid analgesics, especially morphine.
  • analgesics such as acetaminophen (paracetamol), aspirin and other NSAIDs and, in particular, opioid analgesics, especially morphine.
  • opioid analgesics especially morphine.
  • Specific anti- inflammatory agents include diclofenac, lbuprofen, lndomethacin, ketoprofen, naproxen, piroxicam and suhndac.
  • Suitable opioid analgesics of use in conjunction with a compound of the present invention include morphine, codeine, dihydrocodeine, diacetylmorphine, hydrocodone, hydromorphone, levorphan ⁇ l, oxymorphone, alfentanil, buprenorphine, butorphanol, fentanyl, sufentanyl, mepe ⁇ dine, methadone, nalbuphine, propoxyphene and pentazocine; or a pharmaceutically acceptable salt thereof.
  • Preferred salts of these opioid analgesics include morphine sulphate, morphine hydrochlo ⁇ de, morphine tartrate, codeine phosphate, codeine sulphate, dihydrocodeine bitartrate, diacetylmorphine hydrochlo ⁇ de, hydrocodone bitartrate, hydromorphone hydrochlonde, levorphanol tartrate, oxymorphone hydrochlo ⁇ de, alfentanil hydrochlonde, buprenorphine hydrochlonde, butorphanol tartrate, fentanyl citrate, mependine hydrochlonde. methadone hydrochlonde.
  • a pharmaceutical composition comprising a compound of the present invention and an analgesic, together with at least one pharmaceutically acceptable carrier or excipient.
  • a product comprising a compound of the present invention and an analgesic as a combined preparation for simultaneous, separate or sequential use in the treat ment or prevention of pain or nociception
  • a compound of t he present invention may be used in conjunction with ot her ant i- depressant or anti-anxiety agents.
  • Suitable classes of anti-depressant agent include norepineph ⁇ ne reuptake inhibitors, selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamine oxidase (RIMAs) serotonin and noradrenahne reuptake inhibitors (SNRIs), corticotropin releasing factor (GRF) antagonists ⁇ -adrenoreceptor antagonists and atypical anti- depressants
  • Suitable norepinephnne reuptake inhibitors include tertiary amine tricychcs and secondary amine tricychcs Suitable examples of tertiary amine tricychcs include amitriptyhne, clomipramine, doxepin, lmipramine and tnmipramine and pharmaceutically acceptable salts thereof Suitable examples of secondary amine tricychcs include amoxapine desipramine maprotihne nortnptyhne and protnptyhne, and pharmaceutically acceptable salts thereof
  • Suitable selective serotonin reuptake inhibitors include fluoxetine fluvoxamine paroxetine and sertrahne and pharmaceutically acceptable salts thereof
  • Suitable monoamine oxidase inhibitors include isocarboxazid phenelzine tranylcypromine and selegihne, and pharmaceutically acceptable salts thereof
  • Suitable reversible inhibitors of monoamine oxidase include moclobemide and pharmaceutically acceptable salts thereof
  • Suitable serotonin and noradrenahne reuptake inhibitors of use in the present invention include venlafaxine and pharmaceutically acceptable salts thereof
  • Suitable CRF antagonists include those compounds described in International Patent Specification Nos WO 94/1 643, WO 94/13644 WO 94/13661 WO 94/13676 and WO 94/13677
  • Suitable atypical anti-depressants include bupropion lithium nefazodone, trazodone and viloxazine, and pharmaceutically acceptable salts thereof
  • Suitable classes of anti-anxiety agent include benzocbazepmes and 5-HTn agonists or antagonists especially 5-HTIA partial agonists and corticotropin releasing factor (CRF) antagonists
  • Suitable benzodiazepines include alprazolam, chlordiazejioxide ⁇ lonazepam ⁇ hlorazepate diazepam halazepam lorazepam oxazepam and prazepam and jiharmaceutically accej)table salts thereof
  • Suitable 5- HT I ⁇ receptor agonists or antagonists include, in particular, the 5-HTI ⁇ receptor partial agonists buspirone, flesinoxan, gepirone and ipsapirone, and pharmaceutically acceptable salts thereof.
  • a pharmaceutical composition comprising a compound of the present invention and an anti-depressant or anti-anxiety agent, together with at least one pharmaceutically acceptable carrier or excipient.
  • a product comprising a compound of the present invention and an anti- depressant or anti -anxiety agent as a combined preparation for simultaneous, separate or sequential use for the treatment or prevention of depression and/or anxiety.
  • a compound of the present invention may be used in conjunction with other anorectic agents.
  • the present invention accordingly provides the use of a compound of formula (1) and an anorectic agent for the manufacture of a medicament for the treatment or prevention of eating disorders.
  • the present invention also provides a method for the treatment or prevention of eating (hsorders, which method comprises administration to a patient m need of ' sucn treatment an amount of a compound of formula (I ) and an amount of an anorectic agent, such that together they give effective relief.
  • a pharmaceutical composition comprising a compound of formula (1) and an anorectic agent, together with at least one pharmaceutically acceptable carrier or excipient.
  • the compound of formula (1) and anorectic agent may be present as a combined prej)arat ⁇ on for simultaneous, separate or sequential use for the treatment or prevention of eating (hsorders.
  • Such combined preparations may be, for example, in the form of a twin pack.
  • a product comprising a compound of formula (i) and an anorectic agent as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of eating disorders.
  • the present invention also provides a method for the treatment or prevention of obesity, which method comprises administration to a patient in need of such treatment an amount of a compound of formula (I) and an amount of an anorectic agent, such that together they give effective relief.
  • a compound of formula (I) and an anorectic agent for the manufacture of a medicament for the treatment, or prevention of bulimia nervosa.
  • the present invention also provides a method for the treatment or prevention of bulimia nervosa, which method comprises administration to a j)at ⁇ ent in need of such treatment an amount of a compound of formula (I) and an amount of an anorectic agent, such that together they give effective relief.
  • a compound of formula (I) and an anorectic agent for the manufacture of a medicament for the treatment or prevention of compulsive eating disorders.
  • the present invention also provides a method for the treatment or prevention of compulsive eating disorders, which method comprises administration to a patient in need of such treatment an amount of a compound of formula (I) and an amount of an anorectic agent, such that together they give effective relief.
  • a compound of formula (I) and an anorectic agent for the manufacture of a medicament for reducing the total body fat mass m an obese mammal, especially a human.
  • the present invention also provides a method for reducing the total body fat mass in an obese mammal, especially a human, which method comprises administration to a patient in need of such treatment an amount of a compound of formula (I) and an amount of an anorectic agent, such that together they give effective relief.
  • Suitable anoretic agents of use in combination with a compound of t he present invention include, but are not limited to, aminorex, amphechioral amphetamine, benzphetamine, chlorphentermine, clobenzorex, cloforex clominorex, clortermme, cyclexednne, dexfenfluramine, dextroamphetamine.
  • diethylpropion diphemethoxidine, N-ethylamphe famine, fenbutrazate fenfluramine, femsorex, fenproporex, fludorex, fluminorex, furfurylmethylamphetamme, levamfetamine, levophacetoperane. mazindol, mefenorex, metamfepramone, methamphetamine, norp.seudoephedrme. pentorex, phendi etrazine, jihenmetrazine, phentermine, jihenylpropanolamine picilorex and sibutramine; and pharmaceutically acceptable salts thereof.
  • Particularly jireferred anorectic agents include amphetamine and derivatives thereof such as amphetamine, benzphetamine, chlorphentermine, clobenzorex, cloforex, clotermine, dexfenfluramine, dextroamphetamine diethvlpropion, ⁇ '-ethylamphetamine, fenfluramine, fenproporex, furfurylmethylamphetamme, levamfetamine, mefenorex, metamfepramone, methamphetamine, norp.seudoephedrme, pentorex, phendimetrazine, phenmetrazine, jihentermme, phenylpropanolamine, picilorex and sibutramine, and pharmaceutically acceptable salts thereof.
  • amphetamine and derivatives thereof such as amphetamine, benzphetamine, chlorphentermine, clobenzorex, cloforex, clotermin
  • a jiarticularly suitable class of anorectic agent are the halogenated amphetamine derivatives, including chlorphentermine. cloforex. clortermme, dexfenfluramine. fenfluramine, picilorex and sibutramine, and pharmaceutically acceptble salts thereof;
  • halogenated amphetamine derivatives of use in combination with a compound of the present invention include, fenfluramine and dexfenfluramine, and pharmaceutically acceptable salts thereof.
  • I t will be ajipreciated that for the treatment or prevention of obesity the compounds of the pre.sent invention may also be used in combination w ith a selective serotonin reuptake inhibitor (SSRI).
  • SSRI selective serotonin reuptake inhibitor
  • the present invention accordingly provides the use of a compound of formula (I) and an SSRI for the manufacture of a medicament for the t reatment or prevention of obesitv
  • the present invention also provides a method for the t eatment or prevent ion of obesit v, which method comprises administ rat ion t o a jiat ient in need of such treatment an amount of a compound of formula (1) and an amount of an SSRI , such that together t hey give effective relief
  • a pharmaceutical composition for the treatment or prevention of obesity comprising a compound of formula (I) and an SSRI, together with at least one pharmaceutically acceptable carrier or excipient
  • the compound of formula (I) and SSRI may be present as a combined preparation for simultaneous, separate or sequential use for the treatment or prevention of obesity.
  • Such combined preparations may be, for example, in the form of a twin pack
  • a product comprising a compound of formula (I) and an SSRI as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of obesity
  • a compound of formula (I) and an SSRI for the manufacture of a medicament for reducing the total body fat mass in an obese mammal, especially a human
  • the present invention also provides a method for reducing the total body fat mass in an obese mammal, especially a human, which method comprises administration to the mammal an amount of a compound of formula (I ) and an amount of an SSRI, such that together they give effective relief
  • a pharmaceutical composition for reducing the total body fat mass in an obese mammal, especially a human comprising a compound of formula (I) and an
  • Suitable selective serotonin reuptake inhibitors of use in combination with a compound of the present invention include: fluoxetine, fluvoxamine, paroxetine and sertrahne and pharmaceutically acceptable salts thereof As used herein "obesity" refers to a condition wherebv a mammal has a
  • Body Mass I ndex (BM1 ) which is calculated as weight per height quar (kg/m 2 ), of al least 25 9 Conventionally, those persons with normal weight , have a BMI of 19 9 to less than 25 9
  • the obesitv herein may be due to any cause, whether genetic or environmental Examples of disorders that may result in obesity or be t he cause of obesity include overeating and bulimia, polycystic ovarian disease, cranioj aryngioma, the Prader-Wilh Syndrome, Frohhch's svndrome Type I I diabetes, GH -deficient subjects, normal variant short stature, Turner s syndrome, and other pathological conditions showing reduced metabolic activitv or a decrease in resting energy expenditure as a percentage of total fat-free mass, e.g, children with acute lymphoblastic leukemia
  • Treatment refers to reducing the BMI of the mammal to less than about 25 9 and maintaining that weight for at least 6 months The treatment suitably results in a reduction in food or calorie intake by the mammal
  • Prevention refers to preventing obesitv from occurring if the treatment is administered prior to the onset of the obese condition Moreover, if treatment is commenced in already obese subjects, such treatment is expected to prevent or to prevent the progression of, the medical sequelae of obesity, such as, e g , arteriosclerosis Type II diabetes, polycycstic ovarian disease, cardiovascular diseases, osteoarthritis, dermatological disorders, hypertension, insulin resistance, hypercholesterolemia, hypertnglyceridemia, and cholelithiasis Thus in one aspect this invention relates to the inhibition and/or complete suppression of l ogenesis in obese mammals, i e .
  • the invention ameliorates the conditions that are a consequence of the disease such as preventing or arresting the progression of polycystic ovarian disease so that the patient is no longer infertile, and increasing the insulin sensitivity and/or decreasing or eliminating the need or usage of insulin in a diabetic patient e.g , one with adult -onset diabetes or Type II diabetes
  • a further aspect of the present invention comprises the use of a compound of formula (1) for achieving a chronobiologic (circadian rhythm phase-shifting) effect and alleviating circadian rhythm disorders in a mammal
  • the present invention is f urther directed to the use of a compound of formula ( I) for blocking t he phase-shifting effect s of light in a mammal
  • the present invention further relates to the use of a compound of formula (i) for enhancing or improving sleep quality, in particular by increasing sleep efficiency and augmenting sleep maintenance, as well as for preventing and treating sleep disorders and sleep disturbances, in a mammal.
  • the present invention provides a method for the phase advance or phase delay in the circadian rhythm of a subject which comprises administering to the subject an appropriate amount of a compound ol ' formula (I) or a pharmaceutically acceptable salt thereof.
  • the administration to a subject of an appropriate amount of a compound of formula (I) is useful, for example, in the prevention or treatment of the following conditions to achieve chronobiologic effects and/or to alleviate circadian rhvthm phase disturbances: disorders of the sleep-wake schedule; jet lag; shift work; people who have a maladaption to work and off-work schedules; medical residents, nurses, firemen, policemen or those whose duties require alertness and wakefulness at evening or nighttime hours, or those deprived of sleep for various periods because of their duties or responsiblities; animal workers; the infantry, or other members of the armed forces whose duties require extreme levels of alertness and wakefulness, and those who may be sleep deprived in the performance of these duties; submariners, or people confined for research.
  • the present invention is useful, for example, in the prevention or treatment, of conditions associated with circadian rhyfhmicity as well as mental and physical disorders associated with travel across time zones and with rotating shift-work schedules.
  • the present invention provides a method for the prevention or treatment of a circadian rhythm disorder in a mammal, including time-zone change (jet-lag) syndrome, shift-work sleep disorder, delayed sleep-phase syndrome, advanced sleep-phase syndrome, and non-24-hour sleep- wake disorder, which comprises administering to the mammal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • a circadian rhythm disorder including time-zone change (jet-lag) syndrome, shift-work sleep disorder, delayed sleep-phase syndrome, advanced sleep-phase syndrome, and non-24-hour sleep- wake disorder
  • the present invention provides a method for shortening the time of remtrainment of circadian rhythms in a subject following a shift, in the sleep-wake cycle which comprises administering to the subject an appropriate amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the pre.sent invention provides a method for alleviating the effects of jet lag in a traveller, especially a mammal, which comprises administering to the traveller an alertness increasing amount of a compound of formula (I) or a pharmaceutically acceptable alt thereof.
  • the purpose of this embodiment is to assist the body to adjust physiologically to the changes in sleep and feeding patterns when crossing several time zones.
  • the present invention provides a method for resetting the internal circadian clock in a subject, for example shift workers changing from a day to a night shift or vice versa, which comprises administering to the subject an appropriate amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the pre.sent invention is further directed to the use of a compound of formula (1) or a pharmaceutically acceptable salt thereof, for enhancing or improving sleep quality as well as preventing and treating sleep disorders and sleep disturbances in a mammal.
  • the pre.sent invention provides a method for enhancing or improving sleep quality by increasing sleep efficiency and augmenting sleep maintenance.
  • the present invention provides a method for preventing and treating sleep disorders and sleep disturbances m a mammal which comprising the administration of a compound of formula ( I) or a pharmaceut ically acceptable salt thereof.
  • the present invention is useful for the treatment of sleeji disorders, including Disorders of Initiating and Maintaining Sleep (insomnias) ("DIMS”) which can arise from psychophysiological causes, as a consequence of psychiatric disorders (particularly related to anxiety), from drugs and alcohol use and abuse (particularly during withdrawal stages), childhood onset DIMS, nocturnal myoclonus and restless legs and non specific REM disturbances as seen in ageing.
  • DIMS Disorders of Initiating and Maintaining Sleep
  • the following outcomes in a subject which are provided by the present invention may be correlated to enhancement in sleep quality: an increase in the value which is calculated from the time that a subject sleeps divided by the time that a subject is attempting to sleep; a decrease in sleep latency (the time it takes to fall asleep); a decrease in the number of awakenings during sleep; a decrease in the time spent awake following the initial onset of sleep; an increase in the total amount of sleep; an increase the amount and percentage of REM sleep: an increase in the duration and occurrence of REM sleep; a reduction in the fragmentation of REM sleep; an increase in the amount and percentage of slow- wave (i.e.
  • stage 3 or 4 sleep sleep; an increase in the amount and percentage of stage 2 sleep; a decrease in the number of awakenings, especially in the early morning; an increase in daytime alertness; and increased sleep maintenance.
  • Secondary outcomes which may be provided by the pre.sent invention include enhanced cognitive function and increased memory retention.
  • the present invention is further useful for the prevention and treatment of sleep disorders and sleej) disturbances including sleep problems associated with insomnia, hypersomnia, sleep apnea, narcolepsy, nocturnal myoclonus, REM sleep interruptions, jet-lag, shift workers' sleep disturbances, dysomnias, night terror, insomnias associated with depression or with emotional/mood disorders, dysfunctions associated with sleej) (parasomnias), as well as sleep walking and enuresis, as well as sleep (hsorders which accompany agmg. Sleep disorders and sleep disturbances are generally characterized by difficulty in initiating or maintaining sleep or in obtaining restful or enough sleep.
  • certain drugs may also cause reductions in REM sleep a ⁇ a side effect and t he present invention mav be used to correct those types ol sleeping disorders as well.
  • the present invention would also be of benefit m the treatment of syndromes such as fibromvalgia which are manifested by non- restorative sleep and mu cle pain or sleej) apnoea which is associated with respiratory disturbances during sleep.
  • syndromes such as fibromvalgia which are manifested by non- restorative sleep and mu cle pain or sleej) apnoea which is associated with respiratory disturbances during sleep.
  • the present invention is not limited to just sleep disorders and sleep disturbances, but is applicable to a wide variety of con ⁇ tions which result from a diminished quality of sleep.
  • the compounds of formula (I) may be used alone or in combination with other agents which are known to be beneficial in altering circadian rhythms or in the enhancement of sleep efficiency
  • the compounds of formula (I) may be administered in conjunction with other compounds which are known in the art to be useful for suppressing or stimulating melatonin production including melatonergic agents, noradrenergic and serotonergic re-uptake blockers, alpha- 1 -noradrenergic agonists, monamine oxidase inhibitors, beta- adrenergic blockers and benzodiazepines, such as atenolol; or with other compounds which are known in the art to be useful for stimulating melatonin production including tncychc antidepressants and alpha-2-adrenerg ⁇ c antagonists; or with melatonin precursors such as tryptophan, 5- hydroxytryptophan serotonin and N-acetylserotonin, as well as melatonin analogues, mel
  • tranylcypromaine trazodone, t ⁇ azolam, trepipam, tncetamide, triclofos, trifluoperazine, t ⁇ metozine tnmipramine, uldazepam, valproate, venlafaxine, zaleplon, zolazepam, zolpidem, and salts thereof, and combinations thereof, and the like.
  • the compounds of formula (I) may be administered in conjunction with the use of physical methods such as with light therapy or electrical stimulation.
  • the compounds of formula (I) may be administered in conjunction with scheduhng bright light administration, ordinary-intensity light exposure, or exposure to dim-light or darkness (or even sleep)
  • the compound of formula (I) is administered accompanied by having an individual wear dark or red goggles at the time of administration to provide additive effects of the treatment plus darkness.
  • bright light exposure can be used in conjunction with administration of a compound of formula (1)
  • the present invention further includes within its scope the use of a compound of formula (I), alone or in combination with other agents, for altering circadian rhythms or for the prevention or treatment of sleep disorders and sleep disturbances in a mammal
  • mammals includes animals of economic importance such as bovine, ovine, and porcine animals, especially those that produce meat, as well as domestic animals, sports animals, zoo animals, and humans, the latter being preferred.
  • both the com iound of formula (I) and the other active agen si will be administered to a patient, within a reasonable period of time
  • the coir ⁇ ounds mav be in the same pharmaceutically accejitable carrier and therefore administered simultaneously They may be in separate pharmaceutical carriers such as conventional orai dosage forms which are taken simultaneously
  • the term "combination" also refers to the case where the compounds are provided in separate dosage forms and are administered sequentially. Therefore, bv way of example, one active component may be administered as a tablet and then, within a reasonable period of time, the second active component may be administered either as an oral dosage form such as a tablet or a fast-dissolving oral dosage form.
  • a “fast dissolving oral formulation” is meant, an oral delivery form which when placed on the tongue of a patient, chssolves within about 10 seconds.
  • “reasonable period of time” is meant a time period that is not in excess of about 1 hour That is, for examjde, if the firs active component is j)rovuled as a tablet, then wit hin one hour, the econd active component should be administered, either in the same type of dosage form, or another dosage form which provides effective delivery of the medicament.
  • the excellent pharmacological profile of the compounds of the present invention offers the opportunity for their use in therapy at low doses thereby minimising the risk of unwanted side effects.
  • a suitable dosage level is about 0.001 to 50 mg/kg per day, in particular about 0.01 to about 25 mg/kg, such as from about 0.05 to about 10 mg/kg per day.
  • a suitable dosage level is about 0.001 to 25 mg/kg per day, preferably about 0.005 to 10 mg/kg per day, and especially about 0.005 to 5 mg/kg per day.
  • the compounds may be administered on a regimen of 1 to 4 times per day, jireferably once or twice per day.
  • a suitable dosage level is about 0.001 to 10 mg/kg per day, preferably about 0.005 to 5 mg/kg ]>er day. and especially 0.01 to 1 mg/kg per day.
  • the compounds mav be administered on a regimen of 1 to 4 times per day, preferably once or t ice per day
  • t he amount of a compound of formula (1 ) required for use in anv treatment will vary not only wit h t he part icular compounds or composition select ed but also wit h t he rout e ot administrat ion t he nature of the condition being treated, and the age and condition of the i)at ⁇ ent, and will ultimately be at the discretion of the attendant physician
  • the compounds according to the invention in which X is -CH2- and Y is -CH2 or -CH2CI I2- may be prepared by the reduction of a corresponding compound of formula (1) in which the broken line represents a double bond, hereinafter referred to as a compound of formula (IIA)
  • Suitable reducing conditions include: catalytic hydrogenation using a metal catalyst such as palladium or platinum or hydroxides or oxides thereof, [)referably in a suitable solvent such as alcohol, e.g. methanol or ethanol. or an ester, e.g. ethyl acetate, or an organic acid e.g. acetic acid, or a mixture thereof; or reduction using tnfluoroacetic acid and t ⁇ ethylsilane.
  • a metal catalyst such as palladium or platinum or hydroxides or oxides thereof
  • a suitable solvent such as alcohol, e.g. methanol or ethanol. or an ester, e.g. ethyl acetate, or an organic acid e.g. acetic acid, or a mixture thereof
  • tnfluoroacetic acid and t ⁇ ethylsilane e.g. acetic acid, or a mixture thereof.
  • R w> is a leaving group such as t ⁇ flate (OSO2OFO or a halogen atom, for example, chlorine, bromine or iodine, especially t ⁇ flate, bromine or iodine
  • the reaction is conveniently effected in the presence of lithium chloride and a transition metal catalyst such as tetrak ⁇ s(tnphenylphosph ⁇ ne) palladium (0)
  • Suitable solvents for the reaction include aromatic hydrocarbons, for example, toluene, jiolar aprotic solvents, for example, dimethylformamide or ethers for example, dioxan, the reaction being effected at a temperature between SOT and the reflux temperature of the solvent .
  • compounds of formula (I > may be prepared from a compound of formula (V)
  • R" is a group of the formula R as defined in relation to formula (I) or a precursor therefor and LG is a leaving group such as an alkyl- or arylsulphonyloxy group (e.g. mesylate or to ylate) or a halogen atom (e.g. bromine, chlorine or iodine); and, if R' is a precursor grouj), converting it to a group R (in which process any reactive group may be protected and thereafter deprotected if desired).
  • LG is a leaving group such as an alkyl- or arylsulphonyloxy group (e.g. mesylate or to ylate) or a halogen atom (e.g. bromine, chlorine or iodine); and, if R' is a precursor grouj), converting it to a group R (in which process any reactive group may be protected and thereafter deprotected if desired).
  • This reaction may be performed in conventional manner, for example in an organic solvent, such as dimethylformamide in the presence of an acid acceptor such as potassium carbonate.
  • compounds of formula (I) may be prepared by further interconversion processes from other compounds of formula (I ) using suitable procedures.
  • processes may be used to vary the group R.
  • compounds of formula (1) wherein R is a C ualkyl group substituted by the grouj) Ar may be prepared from the corresponding compounds of formula (I) wherein R is a C ⁇ -4alkyl group substituted by the group Ar and further substitut ed by R l and R r ⁇ where R 1 and R f ' together represent an oxo group, by reduction using, for example, borane or a borohyd ⁇ de such as sodium cvanoborohydride.
  • compounds of formula (I) wherein R is a tetrazol- 1 -vl grouj) may be prepared by react ion of an intermediate of formula (VI I)
  • compounds of formula (I) may be prepared by a coupling reaction between a compound of formula (VIII) and (IX)
  • R '° and R" is B(OI fh or Sn(alkvlb or a derivative thereof, and the other is a leaving group such as a halogen atom e.g. bromine or iodine, or -
  • R 10 and R u are B(OH):.
  • the reaction is conveniently effect ed in the jiresence of a palladium (0) cafalvsl such as lel rak ⁇ .s(l r ⁇ phenylphos]>h ⁇ ne)pallad ⁇ um (0) in a suit able solvent such as an et her for example, dimefhoxyelhane at an elevated temperature
  • a suit able solvent such as an et her for example, dimefhoxyelhane at an elevated temperature
  • R l(l and ⁇ ' is Sn(alkvl) .
  • t he react ion is convenient ly effected in t he presence of palladium (I I) catalyst such as b ⁇ s(t ⁇ phenylpho.sphine) palladium (I I) chloride, in a suitable solvent such as an aromatic hydrocarbon, for example, , toluene, at. an elevated temperature.
  • palladium (I I) catalyst such as b ⁇ s(t ⁇ phenylpho.sphine) palladium (I I) chloride
  • a suitable solvent such as an aromatic hydrocarbon, for example, , toluene
  • Suitable acids of use in the reaction include mineral acids such as hydrochloric acid.
  • the reaction is conveniently effected in a suitable organic solvent, such as an alcohol, e.g. methanol, at an elevated temperature, for example, at the reflux temperature of the chosen solvent.
  • Suitable dehydrating reagents of use in the reaction include, for example, methanesulphonyl chloride or benzenesulphonyl chloride in py ⁇ dine or tnethylamine.
  • the reaction is conveniently effected at a temperature between
  • compounds of formula (1 ) may be. jirejiared by the reaction of a compound of formula (XX)
  • a compound of formula (IV) under the conditions of a reductive Heck reaction using a ])allad ⁇ um catalyst such as palladium acetate with, for example, dimethylformamide and tetrabutylammonium chloride, and a reducing agent, preferably formic acid or a salt thereof, such as potassium formate.
  • a reductive Heck reaction using a ])allad ⁇ um catalyst such as palladium acetate with, for example, dimethylformamide and tetrabutylammonium chloride, and a reducing agent, preferably formic acid or a salt thereof, such as potassium formate.
  • Cj-calkenoxy, C.3- ⁇ cycloalkoxy, C> TcycloalkylCi-ialkoxy or benzyloxy may be prepared by the interconversion of a compound of formula (I) wherein R 1 is hydroxy, hereinafter referred to as formula (XXVI)
  • reaction is conveniently effected at a temjjerature between 0°C and room temperature, using a suitable organic solvent such as dichloromethane.
  • compounds of formula (1) may be prepared from a eomjiound of formula (XXVIII)
  • reaction by reaction with lithium naphthalenide in tetrahydrofuran
  • the reaction is preferably effected at reduced temperature, for example at about -78°C.
  • Compounds of formula (I I B) may be prepared using the method of general process (K) described above.
  • I ntermediates of formula (V) may be prepared m a similar manner to the met hods of the processes described above, preferably with an am mo prot ecting Lrroup on any unprotected nitrogen atom.
  • Suitable ammo prot ect ing groups include alkoxycarbonyl groups such as _er/-hutoxycarbonyl and t ⁇ chloroethoxycarbonyl, aralkyloxycarbonyl groups such as benzyloxycarbonyl, or aralkyl groups such as benzyl.
  • Removal of the protecting group is effected by conventional procedures thus, for example, iert-butoxycarbonyl groups may be removed under acidic conditions using, for example, trifluoroacetic acid; lert- butoxycarbonyl groups, together with benzyloxycarbonyl and benzyl groups, may also be removed by hydrogenolysis in the presence of a catalyst, for example, Ijalladium; and trichloroethoxycarbonyl groujis may be removed with zinc dust.
  • a catalyst for example, Ijalladium
  • trichloroethoxycarbonyl groujis may be removed with zinc dust.
  • R 50 is as previously defined (and is preferably a triflate grouj) or a bromine or iodine atom), by reaction with a compound of the formula ( - ⁇ Sn- SnOR ⁇ K for example, hexamethyl distannane.
  • the reaction is conveniently effected in the presence of a base, for example, lithium carbonate, and a catalyst such as fr ⁇ henylphosphine
  • Suitable solvents for the reaction include ethers such as fetrahydrofuran. the reaction being effected at a temperature between room temperature and 100°C, for example, at about 60°C.
  • Compounds of formula (XI) may be prepared from a compound of formula (XII):
  • R is a benzyl grouj.
  • the reduction reaction described as process (A) above for the jireparation of compounds of formula (I) may conveniently replace the benzyl grouj) with a hydrogen atom (i.e. forming a compound of formula (V)).
  • Compounds of formula (XIV) may be prepared from the corresponding nitro compound by reduction using, for example, iron jiowder, or Raney nickel in a conventional manner.
  • the compounds of formula (XIV) or their nitro precursors are either known compounds or may be prepared using conventional methodology.
  • Comj)ounds of formula (VI 1) may also be prepared by reaction of a compound of formula (I I I) with a compound of formula (XVI )
  • a particularly preferred hydroxyl protecting group is the t ⁇ methvlsilyl grouj)
  • reaction is conveniently effected in a solvent such as an ether, e.g. tetrahydrofuran, at a reduced temeprature, for example, at -78°C.
  • a solvent such as an ether, e.g. tetrahydrofuran, at a reduced temeprature, for example, at -78°C.
  • compounds of formula (X) may be prepared by the reduction of a compound of formula (XXI)
  • a metal catalyst such as jialladium or platinum or hydroxides or oxides thereof
  • jireferablv in a suitable solvent such as an alcohol, e.g. methanol, an ester, e.g. ethyl acetate, or an organic acid. e.g. acetic acid, or a mixture thereof.
  • compounds of formula (X) may be prepared from a compound of formula (XXII I)
  • Compound of formula (XXI 11) may be prepared from a compound of formula (XIII) and, for example, a G ⁇ gnard reagent prepared from a 2-ar ⁇ l-3- bromo-1-propene using conventional methodology.
  • Compounds of formula (XX) may be prepared, for example, by the conversion of a stannane of formula (III) to the corresponding iodide by treatment with iodine at reduced temperature, for example, at about -78°C, in a suitable solvent such as dichloromethanc.
  • the iodine may then be displaced to give the compound of formula (XX) by treatment with, for example, ⁇ . '-azo- lsobutyronitnle and t ⁇ butyltin hydride in a suitable solvent, for example toluene, at an elevated temperature, for example, at about 100 o C.
  • compounds of formula (XX) may be prepared by the cvchsation of a compound of formula (XXIV)
  • Compounds of formula (XXVI 1) may be prepared by the reaction of a compound of formula (XI I) with G ⁇ gnard reagent prepared from a compound of formula (IV), preferably using magnesium and a bromide of formula (IV).
  • the coupling reaction is conveniently effected at reduced temperature, for example at about 0°C, using a suitable solvent such as an ether, for example, diethyl ether.
  • Compounds of formula (XXVI 11) may be prepared from a compound of formula (XXVI) by reaction with (l - ⁇ odo-cycloprop- l -yl)phenylsulf ⁇ de.
  • any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J F W McOmie, Plenum Press, 1973; and T.W Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley &. Sons. 1991.
  • the protecting groups may be removed at a convenient subsequent stage using methods known from t he art .
  • the exemplified compounds of this invention were tested by the methods set out at pages 36 to 39 of International Patent Specification No. WO 93/01 165.
  • the compounds were found to be active with IO. n at the NKi receptor of less than l ⁇ M on said test, met hod.
  • ( ⁇ )-(3R * ,5/T) refers to a racemic mixture of (3/?,5R) and (3S.5S).
  • T ⁇ butyl n hydride (7.8ml, 29mmol) was added dropwise t o a degassed solution of l -benzyl-3-(3-hydroxy- l-j)ropyn- ] -yl)p ⁇ pe ⁇ d ⁇ n-3-ol (Desc 1 ; 5.9 l g, 24.1mmol) and tetrak ⁇ s(tnphenylphosph ⁇ ne)pallad ⁇ um(0) (0.52g, 0.45mmol) in toluene (100ml) at -5°C.
  • reaction mixture was stirred at -5°C for 2 hours, allowed to warm up and concentrated in vacua to afford an approximately 2.5: 1 mixture of the title compound and lsome ⁇ c l-benzyl-3-(3-hydroxy- l - tr ⁇ butylstannyl- l-proj ⁇ en- l -yOp ⁇ per ⁇ d ⁇ n-3-ol.
  • the mixture was purified by flash chromatography, eluting with ethyl acetate/hexane ( 1:2), to give the title compound (8.82g, 68%); ⁇ ii (250MHz, CDCla) 0.88 (15H, m), 1.24- 1.53 (14H.
  • Diethyl azodicarboxylate (3.1ml, 19.7mmol) was added dropwise to a solution of l-benzyl-3-(3-hydroxy-2-t ⁇ butylstanny 1- 1 -propen- l-yl)p ⁇ pe ⁇ d ⁇ n-3-ol (Desc. 2, 8.72g, 16.26mmol) and t ⁇ phenylphosphine (5.12g, 19.5mmol) in tetrahydrofuran ( 100ml) at -5°C. The cooling bath was removed and the reaction mixture stirred for 45 minutes. The solvent was evaporated, the residue dissolved in acetonit ⁇ le (300ml) and extracted with hexane (3 x 150ml).
  • Acetamide (6.07g, 0.103mol) and dimethylformamide dimethyl acetal (20ml, O. lSmol) were stirred at 80°C in dioxane ( 20ml) for 2 hours
  • the reaction mixture was concentrated in vacuo, ether (50ml) added, the solution refndgerated for 30 minutes then triturated to give an orange solid
  • the solid was collected under suction and the fitrate concentrated in vacuo to a red oil (4 63g)
  • a portion of this oil (1.20g) was added to a solution of 3-bromo-4- methoxyphenylhydrazine (Desc. 14; 2.12g, 9.77mmol) in acetic acid (20ml) and the mixture stirred at 90°C for 2 hours.
  • Trifluoroacetamide (5.87g, 51.9mmol) and dimethylformamide dimethyl acetal (3.3ml, 62mmol) were stirred at 80°C in dioxane (20ml) for 30 minutes The reaction mixture was concentrated in vacuo to give a dark yellow oil (7 71g) A portion of this oil (5.04g) was added to a solution of 3-bromo-4- methoxyphenylhydrazine (Desc.
  • Trifluoroacetic anhydride (1.1ml, 1.64g, 8mmol) was added slowly to a stirred, cooled (0°C) solution of 2- ⁇ sopropoxy-5-am ⁇ no-bromobenzene (0.92g, 4mmol) and tnethylamine (1.1ml, 0.90g, 8mmol) in dichloromethane (10ml) and the mixture stirred at room temperature for 2 hours.
  • Tnphenylphosphme (7 7g, 29.4mmol) was added in portions to a stirred, heated (80°C) suspension of N-(3-biOmo-4- ⁇ sopropoxyphenvl)tr ⁇ fluoroacetam ⁇ de (8 5g, 19mmol) in carbon tetrachlo ⁇ de (100ml)
  • the mixture was stirred at 80°C for 2 days, then further t ⁇ phenylphosphine (2 5 g, 9 5 mmol) was added
  • the mixture was stirred at 80°C for 5 hours, cooled and the solvent evaporated under reduced pressure
  • the residue was triturated with hexane, filtered and the solvent evaporated under reduced pressure to give a yellow oil (6 7g).
  • Benzoyl chloride (0.10ml, 0.86mmol) was added to a solution of 3-(2- methoxy-5-(5-trifluoromethyl- lH-tetrazol- l-yl)phenyl)- l-oxa-7-azasp ⁇ ro[4,5]dec- 3-ene hydrochlonde (Desc. 11; 0.33g, 0.79mmol) in pyndine (5ml) at 0°C. The mixture was stirred at 0°C for 1 '/. hours, allowed to warm to room temperature and concentrated in vacuo. 1M Hydrochloric acid (50ml) was added to the residue and the mixture extracted with dichloromethane (2x25ml).
  • Example 1 Prepared in an analogous fashion to Example 1 1 using (1 - bromoethybbenzene. Separation of the diastereoisomers was accomplished by flash chromatography followed by preparative layer chromatography eluting with methanol/dichloromethane.
  • Diastereoisomer A [c +10° (c 1.0, MeOH); (Found: C, 57.22; H, 5.57, N, 12.64. C2GH3IC1F3N O 2 .0.5H2O requires C, 57.09; H, 5.90; N, 12.80%); ⁇ H (360MHz, CD3OD) 1.26 (3H, d, J 6.2Hz, CHCH3), 1.76 (1 ⁇ , m), 1.89 (2 ⁇ . m), 2.04 (IH, m), 2.17 (IH, m), 2.38 (IH, m), 2.73 (IH, m), 3.19 (2H, m), 3.30-3.56 (4H, m), 3.96 (211, m). 3 99 (311. s, ArOCHs), 4 31 (IH. m), 7.23-7 38 (6H. m, ArH). 7 52
  • Diastereoisomer B [ ⁇ ] D - 16° (c 1.0, MeOH); (Found- C. 56 71: H 5 78; N 12.41 C2(,H3i(TF ⁇ N-,O'_ 0 7H 2 0 requires C, 56.71. H, 5 93. N 12 72%).
  • the reaction mixture was stirred at room temperature for 4 5 hours, the phases separated and the aqueous phase extracted with ethyl acetate (10ml). The organic extracts were combined and stirred with 2-propanol (10ml) for 3 hours The mixture was filtered and concentrated in vacuo. The residue was dissolved in ethyl acetate (20ml), diluted with hexane (10ml) and stirred with basic alumina overnight. The mixture was filtered and the alumina washed with dichloromethane followed by 10% methanol in dichloromethane.

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Abstract

The present invention relates to compounds of formula (I), wherein R is C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C3-7cycloalyklC1-4alkyl, which groups are optionally substituted by hydroxy, C1-4alkoxy or NRaRb, where R?a and Rb¿ each independently represent hydrogen or C¿1-4?alkyl; or R is C1-4alkyl substituted by Ar, and optionally further substituted by one or both of R?4 and R5; R1, R2 and R3¿ represent a variety of substituents; R?9 and R10¿ are each hydrogen, halogen, C¿1-6?alkyl, CH2OR?e¿, oxo, CO¿2R?a or CONRaRb where Re represents hydrogen, C¿1-6?alkyl or phenyl; X is -CH2, or -CH2CH2-; Y is -CH=, -CH2-, -CH2CH= or -CH2CH2-, with the proviso that the sum total of carbon atoms in X+Y is 2 or 3; and when Y is -CH= or -CH2CH=, the broken line is a double bond; or a pharmaceutically acceptable salt thereof. The compounds are of particular use in the treatment or prevention of pain, inflammation, migraine, emesis and postherpetic neuralgia.

Description

SPIRO-PIPERIDINE DERIVATIVES AND THEIR USE AS
THERAPEUTIC AGENTS
This invention relates to a class of azacyclic compounds which are useful as tachykinin antagonists. More particularly, the compounds of the invention are spiro-substituted azacyclic derivatives.
International (PCT) patent specification no. WO 94/20500 (published 15th September 1994) discloses spiroazacychc derivatives as substance P antagonists. In particular, WO 94/20500 relates to spirocychc piperidine derivatives containing a l,8-dιazaspιro[5.5]undecane core.
We have now found a further class of non-peptides which are potent antagonists of tachykinins, especially of substance P
The present invention provides compounds of the formula (I).
Figure imgf000003_0001
(I) wherein
R represents Ci Galkyl, C2 calkenyl, Cz βalkynyl, C ;cycloalkyl, C3 τcycloalkylCι-^alkyl, which groups are optionally substituted by a group selected from hvdroxy, Ci lalkoxy or NRaRb, where Ra and Rb each independently represent hydrogen or Cι-4alkyl; or R represents a Ci 4alkyl group substituted by the group Λr, and optionally further substituted by one or both of the groups R4 and R\
R1 represents hydrogen, hydroxy, Ci Galkyl, C2 Galkenyl, C calkynyl C^ 7cycloalkyl, CJ τcycloalkylCι-4alkyl, Ci calkoxy, fluoroCi calkyl, fluoroCi Galkoxy, hydroxyCi 4alkyl, Ci GalkoxyCι.4alkyl, Cι-6alkoxyCι 4alkoxy, fluoroCi calkoxyC i -lalkyl, C2 βalkenyloxy, C) rcycloalkoxy, C s -cycloalkylCi galkoxy. phenoxy, benzyloxy, cyano, halogen, tπmethylsilyl, nitro, NRaRh, SRa, SORa, SO.R-1, OS02R'' COR",
Figure imgf000003_0002
or OCi ιalkylNR''Rh w here R1 and R1' each independently represent hydrogen, C i -lalkyl or fluoroCi lalkyl, R2 represents hydrogen, halogen, Ci calkyl or Ci-βalkoxy, or when Rz is adjacent to R1, they may be joined together such that there is formed a 5- or 6-membered saturated or unsaturated ring containing one or two atoms selected from nitrogen, oxygen and sulphur, which ring is optionally substituted by a group selected from Cι- alkyl, CF3, =O or =S;
R3 represents hydrogen, halogen, Ci calkyl, C2-calkenyl, C2-r>alkynyl, fluoroCi.calkyl, Ci-calkoxy, fluoroCi-calkoxy, C37cycloalkyl, C3.7cycloalkylCι 4alkyl, hvdroxy, phenoxy, benzyloxy, trimethylsilyl, nitro, cyano, SRa, SORa, S02Ra, NRaRb, CORa, CO2Ra, CONRaRb, SO2NRaRb, OCi 4alkylNRaRb, NRaCORd, or Ci 4alkyl substituted by a Cι.4alkoxy, hydroxy, cyano or CO2Ra group, where Ra and Rb are as previously defined and Rd is Ci calkyl, Ci calkoxy, fluoroCi calkyl or phenyl; or R3 represents a 5- or 6-membered aromatic heterocychc group containing 1, 2, 3 or 4 heteroatoms, selected from nitrogen, oxygen and sulphur, which group is optionally substituted by one or two groups selected from
Ci ealkyl, Ci-βalkoxy, C3-7cycloalkyl, C3-7cycloalkylCι 4alkyl, trifluoromethyl OCF3, NO2, CN, SRa, SORa, SO2Ra, CORa, CO2Ra, phenyl, -(CH2)rNRaRb, -(CH2)rNRaCORb, -(CH2)rCONRaRb, or CH2C(O)Ra, where Ra and Rb are each independently hydrogen or Cι.4alkyl and r is zero, 1 or 2; R4 and R5 each independently represent hydroxy, C1.4a.kyl,
Ci 4alkoxyCι 4alkyl, hydroxyCι-4alkyl or Cι.4alkylNRaRb where Ra and Rb are each independently hydrogen or Ci 4alkyl, or together R4 and R5 represent an oxo group or when R4 and R5 are attached to the same carbon atom, they may be joined together to form a C3 scycloalkyl ring; Ar represents phenyl optionally substituted by one or two substituents selected from halogen, Ci calkyl, Ci calkoxy, CF3, OCF3, NO2, CN, SRa, SORa, SO2Ra, CORa, CO2Ra, (CH2)rCONRaRb, (CH2)rNRaR or (CH2)rNRaCORb. where Ra and Rh are independently hydrogen or Cι-4alkyl and r is zero, 1 or 2; or Ar represents a 5-membered or 6-membered heterocychc ring containing 1, 2 or 3 nitrogen atoms optionally substituted by =0 or =S and optionally substituted by a group of the formula ZNR7R8 where Z is Ci calkylene or Ci ccycloalkyl;
R7 is hydrogen or Ci lalkyl, Cj -cycloalkyl, Ci CvcloalkvlCι lalkvl. or C. 4alkyl substituted by Ci 4alkoxy or hydroxyl, R8 is hydrogen or Cι.4alkyl, Ci -cycloalkyl, Cj 7cycloalkylCι 4alkyl, or C2 jalkyl substituted by Ci 4alkoxy, hvdroxyl or a 4, 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, O and S, or R7, R8 and the nitrogen atom to which they are attached form a he eroaliphatic ring 01 4 to 7 ring atoms, optionally substituted by one or two groups selected from hydroxy or Ci 4alkoxy optionally substituted by a Ci 4aIkoxy or hydroxyl group, and optionally containing a double bond, which ring may optionally contain an oxygen or sulphur ring atom, a group S(O) or S(O)2 or a second nitrogen atom which will be part of a NH or NRC moiety where Rc is Cι-4alkyl optionally substituted by hydroxy or Ci 4alkoxy; or R7, R8 and the nitrogen atom to which they are attached form a non-aromatic azabicychc ring system of 6 to 12 ring atoms, or Z, R" and the nitrogen atom to which they are attached form a heteroaliphatic ring to 4 to 7 ring atoms which may optionally contain an oxygen ring atom;
R9 and R10 each independently represent hydrogen, halogen, Ci Galkyl, CH2ORe, oxo, CO2Ra or CONR R where Ra and Rb are as previously defined and Re represents hydrogen, Ci calkyl or phenyl;
X represents -CH2, or -CH2CH2-, Y represents -CH=, -CH2-, -CH2CH= or -CH2CH2-, with the proviso that the sum total of carbon atoms in X+Y is 2 or 3; and when Y is -CH= or -CH2CH=, the broken line represents a double bond, and pharmaceutically acceptable salts thereof.
A preferred sub-class of compounds of formula (I) is that wherein R1 represents halogen, Ci calkyl, C2 calkenyl, C2 calkynyl, C3 7cycloalkyl,
C^ cycloalkylCi 4alkyl, Ci oalkoxy, fluoroCi βalkyl, fluoroCi calkoxy, Ci jalkyl substituted by a Ci 4alkoxy or hydroxy group, hydroxy, tπmethylsilyl, nitro, CN, SR\ SORa, SO2Ra, CORa, CO2Ra, CONRaR , NRaRb, SO2NRaRb, or OCi ιalkylNRaRb, where Ra and Rb are each independently hydrogen or Ci 4alkyl, R2 represents hydrogen, halogen, Ci calkyl or Ci Galkoxy; or when R2 is adjacent to R1, they may be joined together such that there is formed a δ- or 6-membered saturated or unsaturated ring containing one or two oxvgen atoms, R:i represents hydrogen, halogen, Ci-calkyl, C.-calkenyl, C2-6alkynyl, C.;-7cycloalkyl, C.»-7cycloalkylCι-4alkyl, Ci-calkoxy, fluoroCi-βalkyl, fluoroCi-calkoxy, substituted by a Cι.4alkoxy or hydroxy group, hydroxy, phenoxy, tπmethylsilyl. nitro, GN, SRa, SORa, SO2Ra, COR", CO2R0, CONR°R , NRaR , S()2NRaRb, OCι-ιalkylNRaRb, or a 5- or 6-membered aromatic heterocychc group containing 1 , 2, 3 or 4 heteroatoms, selected from nitrogen, oxygen and sulphur, which group is optionally substituted by one or two groups selected from Ci-calkyl, Ci-calkoxy, C.)-7cycloalkyl, C.v7cycloalkylCι.4alkyl, trifluoromethyl, OCF3, NO2. CN, SRa, SORa, S02Ra, COR", CO2Ra, phenyl, -(CH2)rNRaRb, -(CH2)rNR°CORb, -(CH2)r(X)NRaRb, or CH2C(0)Ra, where Ra and Rb are each independently hydrogen or Cι.4alkyl and r is zero, 1 or 2; and
R4 and R each independently represent Cualkyl, Cι.4alkoxyCι-4alkyl, bydroxyCι-4alkyl or Cι-4alkylNRaRb where Ra and Rb are each independently hydrogen or Ci-calkyl, or together R4 and R5 represent an oxo group or when R4 and R5 are attached to the same carbon atom, they may be joined together to form a Gn-scycloalkyl ring.
A preferred class of compound of formula (I) is that wherein R1 is hydrogen,
Figure imgf000006_0001
Ci-calkoxy, fluoroCi-calkoxy, C3-7cycloalkoxy, halogen or NRaRb; in particular a hydrogen atom or a methyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, cyclopropoxy or cyclobutoxy group; and especially a hydrogen atom or a methoxy or cyclopropoxy group.
A particularly preferred class of compound of formula (I) is that, wherein R1 is a methyl, trifluoromethyl. methoxy, ethoxy, isopropoxy or trifluoromethoxy group, especially a methoxy group. R1 is preferably in the 2'- {ortho) position on the phenyl ring drawn in formula (I).
Another preferred class of compound of formula (I) is that wherein R2 is a hydrogen, fluorine or chlorine atom, especially a hydrogen atom.
Also preferred is the class of compound of formula (I) in which R3 is halogen, Ci-calkyl, fluoroCi-calkyl, Ci-βalkoxy, fluoroCi-calkoxy, cyano or a
5-membered aromatic heterocychc group as previously defined.
Particularly preferred is the class of compound of formula (1) in which R:' is halogen or fluoroCι.ι;alkoxy, especially fluorine, trifluoromethoxy or 2.2.2- tπfluoroethoxy, or a 5-membered aromatic heterocychc group as previously defined
A further preferred class of compound of formula (I) is that wherein R ! is the group
Figure imgf000007_0001
where R11 is hydrogen, halogen, Ci-calkyl, Ci calkoxy, CF3, OCF3, NO2, CN, SRa, SOR", SO2Ra, CORa, CO2Ra, (CH2)rCONRaRb, (CH2)rNRaRb or (CH >)rNRaCOR , where Ra and Rb are hydrogen or Cι-4alkyl, and r is zero, 1 or 2
R11 is preferably hydrogen, halogen, Ci 4alkyl, especially methyl, or CF3. A particularly preferred group represented by Rn is CFj.
The group R3 is preferably m the 5'-posιtιon on the phenyl ring drawn in formula (I) (i.e R3 is para to the group R1) Another preferred class of compound of formula (I) is that wherein R represents a Ci 4alkyl group (especially a Ci 2alkyl group) substituted by the group Ar, and optionally substituted by one or both of the groups R4 and R"'
Preferablv, R4 is Ci 4alkyl, especially methyl, or R4 and R together represent an oxo group Ar preferably represents a phenyl ring, optionally substituted by one or two halogen atoms, especially chlorine or fluorine, or Ci lkoxv, especially methoxy
Another preferred class of compounds are those wherein Ar represents a pyπdyl group R9 and R10 are preferably attached at the 8- and 9- positions Preferably one of R9 and R10 is hydrogen and, more preferably, R9 and R10 are both hydrogen atoms.
Preferablv X is -CH2-
Preferablv Y' is -CH2- or -CH=. especially -CH2- One favoured group of compounds of the present invention are of the formula (la) and pharmaceutically acceptable salts thereof
Figure imgf000008_0001
(la)
wherein R, R1, R2 and R3 are as defined in relation to formula (I) and the broken line is an optional double bond
Another favoured group of compounds of the present invention are of the formula (lb) and pharmaceutically acceptable salts thereof
Figure imgf000008_0002
wherein R1, R2, R3 and R4 are as defined in relation to formula (I), the broken line is an optional double bond, and R12 and R are each independently hydrogen, halogen or Ci Galkoxy
Another favoured group of compounds of the present invention are of the formula (Ic) and pharmaceutically acceptable salts thereof
Figure imgf000009_0001
(Ic) wherein R1, R2 and R3 are defined in relation to formula (1), the broken line is an optional double bond, and R12 and R13 are each independently hydrogen, halogen or Ci-oalkoxy. Where Ar represents an optionally substituted 5- or 6-membered heterocychc ring containing 1 to 3 nitrogen atoms, suitable rings include: pyrrole, pyrazole, lmidazole, 1 ,2,3-triazole, 1 ,2,4-tπazole, pyridine, pyridaz e. pyπmidine, pyrazine and 1,3,5-triazιne.
With respect to compounds of the formula (I), Z (where present), may be a linear, branched or cyclic group. Favourably Z contains 1 to 4 carbon atoms and most favourably 1 or 2 carbon atoms. A particularly favourable group Z is CH2. With respect to compounds of the formula (I), R7 may aptly be a C;.4alkyl group or a C2.ιalkyl group substituted by a hydroxyl or Cicalkoxy group, R8 may aptly be a Gi- ialkyl group or a C^alkyl group substituted by a hydroxyl or Cicalkoxy group, or R7 and R8 may be linked so that, together with the nitrogen atom to which they are attached, they form an azetidinyl, pyrrolidinyl, piperidyl, morpholino. thiomorpholino, piperazino or piperazmo group substituted on the nitrogen atom by a Cι-4alkyl group or a C2-ιalkyl group substituted by a hvdroxy or Cicalkoxy group. Where the group NR7R8 represents a heteroaliphatic ring of 4 to 7 ring atoms and said ring contains a double bond, a particularly preferred group is 3- pyrrolme.
Where the group NR7R8 represents a non-aromatic azabicyclic ring -ystem, such a system may contain between 6 and 12, and preferably between 7 and 10, ring atoms. Suitable rings include ,r)-azabιcyclo[2.1.1]hexyl, ό-azabu:ycloi2.2.1 ]heptyl, (>-azabtcyclo[3.2.1 ]ocl.yl, 2-azabκ:yclo(2.2.2joctyi 6-azabιcyclo(3.2.21nonyl, 6-azabκ:yclo|3.3.1|nonyl, 6-azabιcy lo[3.2.2]decyl 7-azabιcyclo(4.3 l jdecyl, 7-azabιcyclo[4.4.1]undecyl and 8-azabιcyclo[5 4.1 ]dodecyl, especially 5-azabιcyclo(2.2.1|heptyl and ()-azabιcyclo[3 2 I Joctyl.
Where R8 represents a G2-4alkyl group substituted by a 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, ϋ and S, suitable rings include pyrrohdmo, pipendino, piperazino, morphohno, or thiomorphohno Particularly preferred are nitrogen containing heteroaliphatic rings, especially pyrrohdmo and morphohno rings.
In the group ZNR7R8, Z is preferably CH2 or CH2CH2, and especially CH2. The group NR7R8 preferably represents ammo, methylamino, dimethvlamino diethylamino, azetidinyl, pyrrohdmo and morphohno
Where R1 and R2 are attached to adjacent carbon atoms and are joined together such that there is formed a 5- or 6-membered saturated or unsaturated ring containing one or two oxygen atoms, there is formed a fused ring moiety uch as 2,3-dιhydrobenzofuran, benzofuran, 3,4-dιhydro-2H- l -benzopyran, 2H- 1 - benzopyran, 1 ,3-benzodιoxole or 1 ,4-benzodιoxan. Particularly preferred is 2,3- dihydrobenzofuran where the oxygen atom corresponds to the position of R1.
Where R1 and R2 are attached to adjacent carbon atoms and are joined together such that there is formed a 5-membered saturated or unsaturated ring containing one nitrogen atom and optionally one oxygen atom, there is formed a fused ring moietv such as indole, indoline, benzoxazole, benzoxazohne, benzisoxazole or benzisoxazohne
Certain particularly apt compounds of the present invention include those wherein R3 is a group selected from pyrrole, furan, thiophene, pyπdine, pyrazole, lmidazole, oxazole, isoxazole, thiazole, isothiazole, pyrazine, pyπmidine, pyπdazine, tπazole, oxadiazole, thiadiazole, tπazine, and tetrazole, each heteroaryl group being optionally substituted as previously defined.
Particularly preferred compounds of the present invention are those wherein R3 is a group selected from furan, pyπdine, pyπmidine, lmidazole, tπazole and tetrazole, each heteroaryl group being optionally substituted as previously defined.
As used herein, the term "alkyl" or "alkoxy as a group or part of a group means t hat, the group is straight or branched Examples ol' uitable alkvl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-bulyl and t-but yl Examples of uitable alkoxy groups include methoxy, ethoxy, n-propoxy. l-propoxy, n- butoxy, s-butoxy and t-butoxy.
As used herein, the terms "fluoroCi-calkyl" and "fluoroCi-calkoxy" means a Cι-ι;alky) or d.,;alkoxy group in which one or more (in particular, 1 to 3) hydrogen atoms have been replaced by fluorine atoms. Similarly, the term "fluoroCi-ialkyl" means a Cι-4alkyl group in which one or more (in particular 1 to 3) hydrogen atoms have been replaced by fluorine atoms. Particularly preferred are fluoroCi- aalkyl and fluoroCι-3alkoxy groups, for example, CF. , CF CHsF, GH2CHF2, CI I.CFJ. OGF3, OGH2GH2F, OGH2GHF2 or OCH2CF3, and most especially CFa, OCFa and OClisCFs.
As used herein, the term "hydroxyCι.4alkyl" means a Cι.4alkyl group in which one or more (in particular 1 or 2, especially 1 ) hydrogen atoms have been replaced by hydroxy groups, for example CH2OH or CH2CH2OH.
The cycloalkyl groups referred to herein may represent, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. A suitable cycloalkyialkyl group may be, for example, cyclopropylmethyl.
Similarly cycloalkoxy groups referred to herein may represent, for example, cyclopropoxy or cyclobutoxy. A suitably cycloalkylalkoxy group may be, for example, cyclopropylmethoxy. As used herein, the terms "alkenyl" and "alkynyl" as a group or part of a group means that, the group is straight or branched. Examples of suitable alkenyl groups include vinyl and ally!. A suitable alkynyl group is propargyl.
When used herein the term "halogen" means fluorine, chlorine, bromine and iodine. The most apt halogens are fluorine and chlorine of which fluorine is preferred, unless otherwise stated.
Specific compounds within the scope of this invention include: 7-benzyl-3-(2-methoxyphenyl)- l-oxa-7-azaspιro[4,5]dec-3-ene; 7-benzyl-3-(2-methoxy-5-(r)-tπfluoromethyl- lH-tetrazol- l-yl)phenyl)- l -oxa-7- azaspιro|4,5jdec-3-ene; 7-benzyl-3-(2-methoxy-r)-( lH-tetrazol- l-yl)phenyl)- l -oxa-7-azaspιro[4,51dec-3-ene;
7-benzyl-3-(2-methoxy-f)-(4-pyπdyl)phenyl)- l-oxa-7-azaspιro[4,5]dec-3-ene; 7-beιιzvl-3-(2-methoxy- )-cyanophenyl)- l -oxa-7-azaspιro(4,5]dec-3-ene; 7-l)enzyl-3-(2-methoxy-F)-t.πfluoroιτιethoxyphenyl)- 1 -oxa-7-azaspιro|4,5)dec-3-ene: 7-benzyl-3-(2-methoxy-5-(3-trιfluoromethyl-4H- l ,2,4-trιazoi-4-yl)phenyi)- l-oxa-7- azaspιro|4,5)-dec-3-ene;
7-benzyl-3-(2-methoxy-5-(2-trifluoromethyl-lll-ιmιdazol- l-yl)phenyl)- l-oxa-7- azaspιro[4,r)]-dec-3-ene; 7-benzyl-3-(2-methoxy-5-benzyloxyphenyl)- l -oxa-7-azaspιro[4,5]dec-3-ene;
7-benzoyl-3-(2-methoxy-5-(5-trifluoromethyl- lH-tetrazol- l -yl)phenyl)- l-oxa-7- azaspιro[4,5]dec-3-ene;
7-(3,4-dιchlorobenzyl)-3-(2-methoxy-5-(5-trifluoromethyl- l H-tetrazol- l-yl)phenyl)- l-oxa-7-azaspιro(4,5)dec-3-ene; 7-(4-pyridyl)-3-(2-methoxy-5-(5-trifluoromethyl- 111-tetrazol- 1 -yOphenyl)- l-oxa-7- azaspιro[4,5)dec-3-ene;
7-(3-pyrιdyl)-3-(2-methoxy-5-(5-tπfluoromethyl- l H-tetrazol- l -yOphenyl)- l -oxa-7- azaspιro|4,5]dec-3-ene;
7-(2-pyrιdyl)-3-(2-methoxy-5-(5-f rifluoromethyl- 1 H-tetrazol- 1 -yOphenyl)- 1 -oxa-7- azaspιro(4,5]dec-3-ene;
7-(2-methoxybenzyl)-3-(2-methoxy-5-(5-trifluoromethyl- l H-tetrazol- 1 -yOphenyl)- l-oxa-7-azaspiro[4,5]dec-3-ene;
7-(l -phenylethyl)-3-(2-methoxy-5-(5-thfluoromethyl- lH-tetrazol- l -yOphenyl)- 1- oxa-7-spιro[4,5]dec-3-ene; 7-(2-phenylethyO-3-(2-methoxy-f)-(5-tπfluoromethyl- lH-tetrazol- l -yOphenyl)- 1- oxa-7-azaspιro(4,5]dec-3-ene;
7-cyclohexylmethyl-3-(2-methoxy-5-(5-trifluoromethyl- 1 H-tetrazol- ) -yOphenyl)- 1 - oxa-7-azaspιro(4,5jdec-3-ene;
7-(5-thmethylamιnomethyl- lH- l,2,3-trιazol-4-yl)methyl-3-(2-methoxy-5-(5- trifluoromethyl- lH-tetrazol- 1 -yOphenyl)- l -oxa-7-azaspiro[4,5]dec-3-ene;
(±)-(3R*. 5R*)-7-benzyl-3-(2-methoxy-5-(5-trιfluoromethyl- lH-tetrazol- l - yl)phenyl)- l-oxa-7-azaspιro(4,5]decane;
(±)-(3S*. 5R*)-7-benzyl-3-(2-methoxy-5-(5-trifluoromethyl- 1 H-tetrazol- 1 - yOphenyl)- 1 -oxa-7-azaspιro|4,5Jdecane; (±)-(3R*. 5R*)-7-benzoyl-3-(2-methoxy-5-(5-tπfluoromethyl- 1 H-tetrazol- 1 - yOlihenyl)- 1 -oxa-7-azaspιro[4,5]decane;
<r)-(3R*. 5R*)-7-(2-phenylethyl)-3-(2-methoxy-r)-(r)-tπfluoromethyl- l H-tetrazol- 1 - yOphenyl)- 1 -oxa-7-azaspιro|4,5)decane; and pharmaceutically acceptable salts thereof.
In a further aspect of the present invention, the compounds of formula (1) may be prepared in the form of a pharmaceutically acceptable salt, especially an acid addition salt. For use in medicine, the salts of the compounds of formula (I) will be non- toxic pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds according to the invention or of their non-toxic pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, fumaπc acid, p-toluenesulphonic acid, maleic acid, succmic acid, acetic acid, citric acid, tartanc acid, carbonic acid, phosphoric acid or sulphuric acid. Salts of amine groups may also comprise quaternary ammonium salts in which the amino nitrogen atom carries a suitable organic group such as an alkyl, alkenyl, alkynyl or aralkyl moiety. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include metal salts such as alkali metal salts, e.g. sodium or potassium salts; and alkaline earth metal salts, e.g. calcium or magnesium salts. The salts may be formed by conventional means, such as by reacting the free base form of the product with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is removed in vacua or by freeze drying or by exchanging the anions of an existing salt for another anion on a suitable ion exchange resin. The present invention includes within its scope prodrugs of the compounds of formula (1) above. In general, such prodrugs will be functional derivatives of the compounds of formula (I) which are readily convertible in vivo into the required compound of formula (1). Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, m "Design of Prodrugs", ed. H. Bundgaard. Elsevier, 1985.
A prodrug may be a pharmacologically inactive derivative of a biologically active substance (the "parent drug" or "parent molecule") that requires t ransformation within the body in order to release the active drug, and that has improved delivery properties over the parent drug molecule. The transformation in πro may be tor example, as the result of some metabolic process, such as chemical or enzymatic hydrolysis of a carboxyhc, phosphoric or sulphate ester, or reduction or oxidation of a susceptible functionality.
The present invention includes within its scope solvates of the compounds of formula (I) and salts thereof, for example, hydrates.
The compounds according to the invention may have at least two asymmetric centres, and may accordingly exist both as enantiomers and as diastereoisomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. The compounds of the formula (I), (la), (lb), (Ic) and (Id) will have the preferred stereochemistry of the 5-posιtιon that is possessed by the late eluting enantiomer of Example 2.
According to a yet further preference, the compounds of the formula (I), (l a), (lb), (Ic) and (Id), in which Y is -GH2- or -CH2CH2-, will have the relative stereochemistry of the 3- and 5-posιtιons that is possessed by the compound of Example 22 (i.e. 3-(Λ).5-( ?) or 3-(S),5-(S)):
It will be appreciated that the preferred definitions of the various substituents recited herein may be taken alone or in combination, and apply to the generic formula for compounds of the present invention as well as to the preferred classes of compound represented by formulae (la), (lb), (Ic) and (I d) The present, invention further provides pharmaceutical compositions comprising one or more compounds of formula (1) in association with a pharmaceutically acceptable carrier or excipient.
Preferably the compositions according to the invention are in unit dosage forms such as tablets, pills, capsules, powders, granules, solutions or suspensions, or suppositories, for oral, parenteral or rectal administration, or administration by inhalation or insufflation.
For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention or a non-toxic pharmaceutically acceptable sail thereof . When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvmyl-pyrrohdone or gelatin.
Preferred compositions for administration by injection include those comprising a compound of formula (I), as the active ingredient, in association with a surface- active agent (or wetting agent or surfactant) or in the form of an emulsion (as a water-in-oil or oil-in-water emulsion)
Suitable surface-active agents include, in particular, non-ionic agents, such as polyoxyethylenesorbitans (e.g. Tween™ 20, 40, 60, 80 or 85) and other sorbitans (e.g. Span™ 20, 40, 60, 80 or 85) Compositions with a surface-active agent will conveniently comprise between 0 05 and 5% surface-active agenl , and preferably between 0 1 and 2.5% I t, will be appreciated that other ingredients may be added, for example mannitol or other pharmaceutically acceptable vehicles, if necessary Suitable emulsions may be prepared using commercially available lat emulsions, such as I ntrahpid™, Liposyn™, lnfonutrol™, Lipofundin™ and Lipiphysan™ The active ingredient may be either dissolved in a pre-mixed emulsion composition or alternatively it may be dissolved in an oil (e.g soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil or almond oil) and an emulsion formed upon mixing with a phosphohpid (e.g. egg phosphohpids, soybean phosphohpids or soybean lecithin) and water. It will be appreciated that other ingredients may be added, for example glycerol or glucose, to adjust the tonicity of the emulsion. Suitable emulsions will typically contain up to 20% oil, for example, between 5 and 20%. The fat emulsion will preferably comprise fat droplets between 0.1 and l.Oμm, particularly 0.1 and 0.5μm, and have a pH in the range of 5.5 to 8.0
Particularly preferred emulsion compositions are those prepared by mixing a compound of formula (I) with Intrahpid™ or the components thereof (soybean oil, egg phosphohpids, glycerol and water).
Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as set out above. Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect Compositions in preferablv sterile pharmaceuticallv accept able solvents may be nebulised by use of inert gases. Nebulised solutions may be breathed directly from the nebulising device or the nebulising device may be attached to a face mask, tent or intermittent positive pressure breathing machine. Solution, suspension or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.
The present invention futher provides a process for the preparation of a pharmaceutical composition comprising a compound of formula (I), which process comprises bringing a compound of formula (I) into association with a pharmaceutically accept able carrier or excipient
The compounds of formula (1) are of value in the treatment of a wide vaπetv of clinical conditions which are characterised bv the presence of an excess of t achvkinin, in particular substance P, activity Thus, for example, an excess of fachykinin, and in particular substance P, activity is implicated in a variety of (hsorders of the central nervous system. Such disorders include mood disorders, such as depression or more particularly depressive disorders, for example, single episodic or recurrent major depressive disorders and dysthymic disorders, or bipolar disorders, for example, bipolar I disorder, bipolar I I disorder and cyclothymic fhsorder; anxiety disorders, such as panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, specific phobias, for example, specific animal phobias, social phobias, obsessive-compulsive disorder, stress disorders including post-traumatic stress disorder and acute stress disorder, and generalised anxiety disorders; schizophrenia and other psychotic disorders, for example, schizophreniform disorders, schizoaffective disorders, delusional disorders, brief psychotic disorders, shared psychotic disorders and psychotic disorders with delusions or hallucinations; deleπum. dementia, and amnestic and other cognitive or neurodegenerative disorders, such as Alzheimer's disease, senile dementia. dementia of the Alzheimer's type, vascular dementia, and other dementias, for example, due to HIV disease, head trauma, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, or due to multiple aetiologies; Parkinson's disease and other extra-pyramidal movement disorders such as medication-induced movement disorders, for example, neuroleptic-induced parkinsonism. neuroleptic malignant syndrome, neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia, neuroleptic-induced tardive dvskinesia and medication-induced postural tremour; substance-related disorders arising from the use of alcohol, amphetamines (or amphetamine-hke substances) caffeine, cannabis, cocaine, hallucinogens, inhalants and aerosol propellants, nicotine, opioids, phenylglycidine derivatives, sedatives, hypnotics, and anxiolytics, which substance-related disorders include dependence and abuse, intoxication, withdrawal, intoxication deleπum, withdrawal deleπum, persisting dementia, psychotic chsorders, mood (hsorders. anxiety disorders, sexual dysfunction and sleep disorders; epilepsy; Down's syndrome; demyehnating diseases such as MS and ALS and other neuropathological disorders such as peripheral neuropathy, for example diabetic and chemotherapy-induced neuropathy, and postherpetic neuralgia, tπgeminal neuralgia, segmental or intercostal neuralgia and other neuralgias, and cerebral vascular disorders due to acute or chronic cerebrovascular damage such as cerebral infarction, subarachnoid haemorrhage or cerebral oedema.
Tachykinin. and in particular substance P. activity is also involved m nociception and pain. The compounds of the present invention will therefore be of use in the prevention or treatment of diseases and conditions in which pam predominates, including soft tissue and peripheral damage, such as acute trauma, osteoarthπtis, rheumatoid arthritis, musculo-skeletal pain, particularly after trauma, spinal pain, dental pain, myofascial pain syndromes, headache, episiotomy pam, and burns; deep and visceral pain, such as heart pain, muscle pain, eye pam, orofacial pain, for example, odontalgia, abdominal pain, gynaecological pain, for example, dysmenorrhoea, and labour pain; pain associated with nerve and root damage, such as pain associated with peripheral nerve disorders, for example, nerve entrapment and brachial plexus avulsions, amputation, peripheral neuropathies, ti douloureux, atypical facial pain, nerve root damage, and arachnoiditis; pain associated with carcinoma, often referred to as cancer pain; central nervous system pain, such as pain due to spinal cord or brain stem damage; low back pain; sciatica; ankylosing spondylitis, gout; and scar pain.
Tachykinin, and in particular substance P, antagonists may also be of use in the treatment of respiratory diseases, particularly those associated with excess mucus secretion, such as chronic obstructive airways disease, bronchopneumonia, chronic bronchitis, cystic fibrosis and asthma, adult respiratory distress syndrome, and bronchospasm; inflammatory diseases such as inflammatory bowel disease, psoriasis, fibrositis, osteoarthπtis, rheumatoid arthritis, pruritus and sunburn; allergies such as eczema and rhinitis; hypersensitivity disorders such as poison ivy; ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, and the like; ophthalmic conditions associated with cell proliferation such as proliferative vitreoretinopathy; cutaneous diseases such as contact dermatitis, atopic dermatitis, urticaria, and other eczemato l dermatitis. Tachykinin, and in particular substance P. antagonists may also be of use in the treatment of neoplasms, including breast tumours, neuroganghoblastomas and small cell carcinomas such as small cell lung cancer.
Tachykinin. and in particular substance P, antagonists may also be of use in the treatment, of gastrointestinal (GI) disorders, including inflammatory disorders and diseases of the Gl tract such as gastritis, gastroduodenal ulcers, gastric carcinomas, gastric lymphomas, disorders associated with the neuronal control of viscera, ulcerative colitis, Crohn' disease, irritable bowel syndrome and emesis, including acute, delayed or anticipatory emesis such as emesis induced by chemotherapy, radiation, toxins, viral or bacterial infections, pregnancy, vestibular disorders, for example, motion sickness, vertigo, dizziness and Meniere's disease, surgery, migraine, variations in intercranial pressure gastro-oesophageal reflux disease, acid indigestion, over indulgence in food or drink, acid stomach, waterbrash or regurgitation, heartburn, for example, episodic, nocturnal or meal-induced heartburn, and dyspepsia.
Tachykinin, and in particular substance P, antagonists may also be of use in the treatment of a variety of other conditions including stress related
Figure imgf000019_0001
disorders; reflex sympathetic dystrophy such as shoulder/hand synchOnie, adverse immunological reactions such as rejection of transplanted tissues and disorders related to immune enhancement or suppression such as systemic lupus erythematosus; plasma extravasation resulting from cytokine chemotherapy, (hsorders of bladder function uch as cystitis, bladder detrusor hyper-re flexia and incontinence; fibrosing and collagen diseases such as scleroderma and eosinophihc fasciohasis; (hsorders of blood flow caused by vasodilation and vasospastic (hseases such as angina, vascular headache, migraine and Revnaud's disease; and pain or nociception attributable to or associated with any of the foregoing conditions, especially the transmission of pam in migraine.
The compounds of formula (I) are also of value in the treatment of a combination of the above conditions, in particular in the treatment of combined post-operative pain and post-operative nausea and vomiting.
The compounds of formula (1) are particularly useful in the treatment of emesis, including acute, delayed or anticipatory emesis, such as emesis induced by chemotherapy, radiation, toxins, pregnancy, vestibular disorders, motion, surgery, migraine, and variations in intercranial pressure. Most especially, the compounds of formula (I) are of use in the treatment of emesis induced by antineopla tic (cytotoxic) agents including those routinely used in cancer chemotherapy, and emesis induced by other pharmacological agents fur example rohpram. Examples of such chemotherapeutic agents include alkylating agents, for example, nitrogen mustards, ethyleneimine compounds, alkyl sulphonates and other compounds with an alkylating action such as nitrosoureas, cisplatm and dacarbazine; antimetabohtes, for example, folic acid, puπne or pyπmidine antagonists; mitotic inhibitors, for example, vmca alkaloids and derivatives of podophyllotoxin; and cytotoxic antibiotics.
Particular examples of chemotherapeutic agents are described, for instance, by D. J. Stewart in Nausea and. Vomiting: Recent. Research and Clinical Advances, Eds. Λ. Kucharczyk el al, CRC Press Inc., Boca Raton, Florida. USA ( 1991) pages 177-203, especially page 188. Commonly used chemotherapeutic agents include cisplatm, dacarbazine (DTIC), dactinomycin, mechlorethamine (nitrogen mustard), streptozocin, cyclophosphamide, carmustine (BGNU), lomustme (CCNU), doxorubicin (adriamycin), daunorubicin, procarbazine, mitomycin, cytarabine, etoposide, methotrexate, 5-fluorouracιl, vinblastine, vincπstine, bleomycm and chlorambucil [R. J . Gralla et al in Cancer Treatment
Reports (1984) 68(1), 163- 172].
The compounds of formula (I) are also of use in the treatment of emesis induced by radiation including radiation therapy such as m the treatment of cancer, or radiation sickness; and in the treatment of post-operative nausea and vomiting.
I t will be appreciated that the compounds of formula (1 ) may be presented together with another therapeutic agent as a combined preparation for simultaneous, separate or sequential use for the relief of emesis. Such combined preparations may be, for example, in the form of a twin pack. A further aspect of the present invention comprises the compounds of formula (I) in combination with a 5-HT.ι antagonist, such as ondansetron, granisetron or tropisetron, or other anti-emetic medicaments, for example, a dopamine antagonist such as metoclopramide or domperidone, or GABAB receptor agonists such as baclofen. Additionally, a compound of formula (1) either alone or in combination with one or more other anti-emetic therapeutic agents, may be administered in combination with an anti-inflammatory corticosteroid. such as dexamethasone. betamethasone, triamcinolone, tπamcinolυne acetonide, flunisohde, budesonide, or others such as those disclosed m US patent nos 2,789, 1 18, 2,990.401, 3,048,581 , 3, 126.375, 3,929,768, 3,996.359, 3,928,326 and 3, 749, 712. Dexamethasone (Decadron™) is particularly preferred. Furthermore, a compound of formula (I) may be administered in combination with a chemotherapeutic agent such as an alkylating agent, antimetabohte, mitotic inhibitor or cytotoxic antibiotic, as described above. In general, the currently available dosage forms of the known therapeutic agents for use in such combinations will be suitable.
When tested in the ferret model of cisplatin-induced emesis described by F. D. Tattersall et al, in Eur. J. pharmacoi, (1993) 250. R5-R6. the compounds of the present invention were found to attenuate the retching and vomiting induced by cisplatm.
The compounds of formula (1) are also particularly useful in the treatment of pain or nociception and or inflammation and disorders associated therewith such as, for example, neuropathy, such as diabetic and chemotherapy-induced neuropathy, postherpetic and other neuralgias, asthma, osteroarthπtis, rheumatoid arthritis and headache including migraine, acute or chronic tension headache, cluster headache, temporomandibular pain and maxillary sinus pain.
The compounds of formula (I) are also particularly useful in the treatment of depression including depressive disorders, for example, single episodic or recurrent mapr depressive disorders, and dysthymic disorders, depressive neurosis, and neurotic depression; melancholic depression including anorexia, weight loss, insomnia and early morning waking, and psychomotor retardation; atypical depression (or reactive depression) including increased appetite, hypersomnia, psychomotor agitation or irritability, anxiety and phobias; seasonal affective disorder; or bipolar (hsorders or manic depression, for example, bipolar I disorder, bipolar 11 disorder and cyclothymic disorder.
The present invention further provides a compound of formula (1) for use in therapy.
According to a further or alternative aspect, the present invention provides a compound of formula (I) for use in the manufacture of a medicament for the treatment of physiological disorders associated with an excess of tachykinins, especially substance P.
The present invention also provides a method for the the treatment or prevention oi physiological disorders associated with an excess of tachykinins, especially sub-t ance P, which method comprises administrat ion to a patient in need thereof of a tachykinin reducing amount of a compound of formula (I) or a composition comprising a compound of formula (1).
According to a further aspect of the present invention, it may be desirable to treat any of the aforementioned conditions with a combination of a compound according to the present invention and one or more other pharmacologically active agents suitable for the treatment of the specific condition. The compound of formula (1) and the other pharmacologically active agent(s) may be administered to a patient simultaneously, sequentially or in combination. Thus, for example, for the treatment of respiratory diseases such as asthma, a compound of formula (I) may be used in conjunction with a bronchodilator, such as a p2-adrenergιc receptor agonist or tachykinin antagonist which acts at NK-2 receptors. The compound of formula (i) and the bronchodilator may be administered to a patient simultaneously, sequentially or in combination. Likewise, a compound of the present invention may be employed with a leukotriene antagonists, such as a leukotriene D antagonist such as a compound selected from those disclosed in European patent specification nos. 0 480 717 and 0 604 1 14 and in US patent nos. 4,859,692 and 5,270,324. This combination is particularly useful in the treatment of respiratory diseases such as asthma, chronic bronchitis and cough.
The present invention accordingly provides a method for the treatment of a respiratory disease, such as asthma, which method comprises administration to a patient in need thereof of an effective amount of a compound of formula (I) and an effective amount of a bronchodilator. The present invention also provides a composition comprising a compound of formula (I), a bronchodilator, and a pharmaceutically acceptable carrier.
It will be appreciated that for the treatment or prevention of migraine, a compound of the present invention may be used in conjunction with other anti- migraine agents, such as ergotamines or 5-HTι agonists, especially sumatπptan, naratπptan, zolmatπptan or πzatπptan.
Likewise, for the treatment of behavioural hyneralgesia, a compound of the present invention may be used in conjunction with an antagonist of N-methvl D-aspartate (NMI)Λ), such as dizocilpine. For the treatment or prevention of inflammatory conditions in the lower urinary tract, especially cystitis, a compound of the present invention may be used in conjunction with an antnnflammatory agent such as a bradykinin receptor antagonist. It will be appreciated that for the treatment or prevention of pain or nociception, a compound of the present invention may be used in conjunction with other analgesics, such as acetaminophen (paracetamol), aspirin and other NSAIDs and, in particular, opioid analgesics, especially morphine. Specific anti- inflammatory agents include diclofenac, lbuprofen, lndomethacin, ketoprofen, naproxen, piroxicam and suhndac. Suitable opioid analgesics of use in conjunction with a compound of the present invention include morphine, codeine, dihydrocodeine, diacetylmorphine, hydrocodone, hydromorphone, levorphanυl, oxymorphone, alfentanil, buprenorphine, butorphanol, fentanyl, sufentanyl, mepeπdine, methadone, nalbuphine, propoxyphene and pentazocine; or a pharmaceutically acceptable salt thereof. Preferred salts of these opioid analgesics include morphine sulphate, morphine hydrochloπde, morphine tartrate, codeine phosphate, codeine sulphate, dihydrocodeine bitartrate, diacetylmorphine hydrochloπde, hydrocodone bitartrate, hydromorphone hydrochlonde, levorphanol tartrate, oxymorphone hydrochloπde, alfentanil hydrochlonde, buprenorphine hydrochlonde, butorphanol tartrate, fentanyl citrate, mependine hydrochlonde. methadone hydrochlonde. nalbuphine hydrochlonde, propoxyphene hydrochlonde, propoxyphene napsylate (2-naphthalenesulphonιc acid (1: 1) monohydrate), and pentazocine hydrochlonde Therefore, in a further aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the present invention and an analgesic, together with at least one pharmaceutically acceptable carrier or excipient.
In a further or alternative aspect of the present invention, there is provided a product comprising a compound of the present invention and an analgesic as a combined preparation for simultaneous, separate or sequential use in the treat ment or prevention of pain or nociception
It will be appreciated that for the treatment of depression or anxiet y, a compound of t he present invention may be used in conjunction with ot her ant i- depressant or anti-anxiety agents. Suitable classes of anti-depressant agent include norepinephπne reuptake inhibitors, selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamine oxidase (RIMAs) serotonin and noradrenahne reuptake inhibitors (SNRIs), corticotropin releasing factor (GRF) antagonists α-adrenoreceptor antagonists and atypical anti- depressants
Suitable norepinephnne reuptake inhibitors include tertiary amine tricychcs and secondary amine tricychcs Suitable examples of tertiary amine tricychcs include amitriptyhne, clomipramine, doxepin, lmipramine and tnmipramine and pharmaceutically acceptable salts thereof Suitable examples of secondary amine tricychcs include amoxapine desipramine maprotihne nortnptyhne and protnptyhne, and pharmaceutically acceptable salts thereof
Suitable selective serotonin reuptake inhibitors include fluoxetine fluvoxamine paroxetine and sertrahne and pharmaceutically acceptable salts thereof
Suitable monoamine oxidase inhibitors include isocarboxazid phenelzine tranylcypromine and selegihne, and pharmaceutically acceptable salts thereof
Suitable reversible inhibitors of monoamine oxidase include moclobemide and pharmaceutically acceptable salts thereof Suitable serotonin and noradrenahne reuptake inhibitors of use in the present invention include venlafaxine and pharmaceutically acceptable salts thereof
Suitable CRF antagonists include those compounds described in International Patent Specification Nos WO 94/1 643, WO 94/13644 WO 94/13661 WO 94/13676 and WO 94/13677
Suitable atypical anti-depressants include bupropion lithium nefazodone, trazodone and viloxazine, and pharmaceutically acceptable salts thereof
Suitable classes of anti-anxiety agent include benzocbazepmes and 5-HTn agonists or antagonists especially 5-HTIA partial agonists and corticotropin releasing factor (CRF) antagonists
Suitable benzodiazepines include alprazolam, chlordiazejioxide ι lonazepam < hlorazepate diazepam halazepam lorazepam oxazepam and prazepam and jiharmaceutically accej)table salts thereof Suitable 5- HT IΛ receptor agonists or antagonists include, in particular, the 5-HTIΛ receptor partial agonists buspirone, flesinoxan, gepirone and ipsapirone, and pharmaceutically acceptable salts thereof.
Therefore, in a further aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the present invention and an anti-depressant or anti-anxiety agent, together with at least one pharmaceutically acceptable carrier or excipient.
In a further or alternative aspect of the present invention, there is provided a product comprising a compound of the present invention and an anti- depressant or anti -anxiety agent as a combined preparation for simultaneous, separate or sequential use for the treatment or prevention of depression and/or anxiety.
It will be appreciated that for the. treatment or prevention of eating disorders, including obesity, bulimia nervosa and compulsive eating disorders, a compound of the present invention may be used in conjunction with other anorectic agents.
The present invention accordingly provides the use of a compound of formula (1) and an anorectic agent for the manufacture of a medicament for the treatment or prevention of eating disorders. The present invention also provides a method for the treatment or prevention of eating (hsorders, which method comprises administration to a patient m need of' sucn treatment an amount of a compound of formula (I ) and an amount of an anorectic agent, such that together they give effective relief.
In a further aspect of the jiresent invention, there is provided a pharmaceutical composition comprising a compound of formula (1) and an anorectic agent, together with at least one pharmaceutically acceptable carrier or excipient.
It will be appreciated that the compound of formula (1) and anorectic agent may be present as a combined prej)aratιon for simultaneous, separate or sequential use for the treatment or prevention of eating (hsorders. Such combined preparations may be, for example, in the form of a twin pack.
In a further or alternative aspect of the present invention, there is t herefore provided a product comprising a compound of formula (i) and an anorectic agent as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of eating disorders.
In a further embodiment of the present invention there is provided the use of a compound of formula (I) and an anorectic agent for the manufacture of a medicament for the treatment or prevention of obesity.
The present invention also provides a method for the treatment or prevention of obesity, which method comprises administration to a patient in need of such treatment an amount of a compound of formula (I) and an amount of an anorectic agent, such that together they give effective relief. In an alternative embodiment of the present invention there is provided the use of a compound of formula (I) and an anorectic agent for the manufacture of a medicament for the treatment, or prevention of bulimia nervosa.
The present invention also provides a method for the treatment or prevention of bulimia nervosa, which method comprises administration to a j)atιent in need of such treatment an amount of a compound of formula (I) and an amount of an anorectic agent, such that together they give effective relief.
In a further embodiment of the present invention there is provided the use of a compound of formula (I) and an anorectic agent for the manufacture of a medicament for the treatment or prevention of compulsive eating disorders. The present invention also provides a method for the treatment or prevention of compulsive eating disorders, which method comprises administration to a patient in need of such treatment an amount of a compound of formula (I) and an amount of an anorectic agent, such that together they give effective relief. In an alternative embodiment of the present invention there is provided the use of a compound of formula (I) and an anorectic agent for the manufacture of a medicament for reducing the total body fat mass m an obese mammal, especially a human.
The present invention also provides a method for reducing the total body fat mass in an obese mammal, especially a human, which method comprises administration to a patient in need of such treatment an amount of a compound of formula (I) and an amount of an anorectic agent, such that together they give effective relief. Suitable anoretic agents of use in combination with a compound of t he present invention include, but are not limited to, aminorex, amphechioral amphetamine, benzphetamine, chlorphentermine, clobenzorex, cloforex clominorex, clortermme, cyclexednne, dexfenfluramine, dextroamphetamine. diethylpropion, diphemethoxidine, N-ethylamphe famine, fenbutrazate fenfluramine, femsorex, fenproporex, fludorex, fluminorex, furfurylmethylamphetamme, levamfetamine, levophacetoperane. mazindol, mefenorex, metamfepramone, methamphetamine, norp.seudoephedrme. pentorex, phendi etrazine, jihenmetrazine, phentermine, jihenylpropanolamine picilorex and sibutramine; and pharmaceutically acceptable salts thereof.
Particularly jireferred anorectic agents include amphetamine and derivatives thereof such as amphetamine, benzphetamine, chlorphentermine, clobenzorex, cloforex, clotermine, dexfenfluramine, dextroamphetamine diethvlpropion, Λ'-ethylamphetamine, fenfluramine, fenproporex, furfurylmethylamphetamme, levamfetamine, mefenorex, metamfepramone, methamphetamine, norp.seudoephedrme, pentorex, phendimetrazine, phenmetrazine, jihentermme, phenylpropanolamine, picilorex and sibutramine, and pharmaceutically acceptable salts thereof.
A jiarticularly suitable class of anorectic agent are the halogenated amphetamine derivatives, including chlorphentermine. cloforex. clortermme, dexfenfluramine. fenfluramine, picilorex and sibutramine, and pharmaceutically acceptble salts thereof;
Particularly preferred halogenated amphetamine derivatives of use in combination with a compound of the present invention include, fenfluramine and dexfenfluramine, and pharmaceutically acceptable salts thereof.
I t will be ajipreciated that for the treatment or prevention of obesity the compounds of the pre.sent invention may also be used in combination w ith a selective serotonin reuptake inhibitor (SSRI).
The present invention accordingly provides the use of a compound of formula (I) and an SSRI for the manufacture of a medicament for the t reatment or prevention of obesitv
The present invention also provides a method for the t eatment or prevent ion of obesit v, which method comprises administ rat ion t o a jiat ient in need of such treatment an amount of a compound of formula (1) and an amount of an SSRI , such that together t hey give effective relief
In a further aspect of the present invention, there is provided a pharmaceutical composition for the treatment or prevention of obesity comprising a compound of formula (I) and an SSRI, together with at least one pharmaceutically acceptable carrier or excipient
It will be appreciated that the compound of formula (I) and SSRI may be present as a combined preparation for simultaneous, separate or sequential use for the treatment or prevention of obesity. Such combined preparations may be, for example, in the form of a twin pack
In a further or alternative aspect of the present invention, there is t herefore provided a product comprising a compound of formula (I) and an SSRI as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of obesity In an alternative embodiment of the present invention, there is provided the use of a compound of formula (I) and an SSRI for the manufacture of a medicament for reducing the total body fat mass in an obese mammal, especially a human
The present invention also provides a method for reducing the total body fat mass in an obese mammal, especially a human, which method comprises administration to the mammal an amount of a compound of formula (I ) and an amount of an SSRI, such that together they give effective relief
In a further aspect of the present invention, there is provided a pharmaceutical composition for reducing the total body fat mass in an obese mammal, especially a human, comprising a compound of formula (I) and an
SSRI together with at least one pharmaceutically acceptable carrier or excipient Suitable selective serotonin reuptake inhibitors of use in combination with a compound of the present invention include: fluoxetine, fluvoxamine, paroxetine and sertrahne and pharmaceutically acceptable salts thereof As used herein "obesity" refers to a condition wherebv a mammal has a
Body Mass I ndex (BM1 ) which is calculated as weight per height quar (kg/m2), of al least 25 9 Conventionally, those persons with normal weight , have a BMI of 19 9 to less than 25 9 The obesitv herein may be due to any cause, whether genetic or environmental Examples of disorders that may result in obesity or be t he cause of obesity include overeating and bulimia, polycystic ovarian disease, cranioj aryngioma, the Prader-Wilh Syndrome, Frohhch's svndrome Type I I diabetes, GH -deficient subjects, normal variant short stature, Turner s syndrome, and other pathological conditions showing reduced metabolic activitv or a decrease in resting energy expenditure as a percentage of total fat-free mass, e.g, children with acute lymphoblastic leukemia
"Treatment" (of obesity) refers to reducing the BMI of the mammal to less than about 25 9 and maintaining that weight for at least 6 months The treatment suitably results in a reduction in food or calorie intake by the mammal
"Prevention" (of obesity) refers to preventing obesitv from occurring if the treatment is administered prior to the onset of the obese condition Moreover, if treatment is commenced in already obese subjects, such treatment is expected to prevent or to prevent the progression of, the medical sequelae of obesity, such as, e g , arteriosclerosis Type II diabetes, polycycstic ovarian disease, cardiovascular diseases, osteoarthritis, dermatological disorders, hypertension, insulin resistance, hypercholesterolemia, hypertnglyceridemia, and cholelithiasis Thus in one aspect this invention relates to the inhibition and/or complete suppression of l ogenesis in obese mammals, i e . the excessive accumulation of hpids in fat cells, which is one of the major features of human and animal obesity, as well as loss of total body weight In another aspect the invention ameliorates the conditions that are a consequence of the disease such as preventing or arresting the progression of polycystic ovarian disease so that the patient is no longer infertile, and increasing the insulin sensitivity and/or decreasing or eliminating the need or usage of insulin in a diabetic patient e.g , one with adult -onset diabetes or Type II diabetes
A further aspect of the present invention comprises the use of a compound of formula (1) for achieving a chronobiologic (circadian rhythm phase-shifting) effect and alleviating circadian rhythm disorders in a mammal The present invention is f urther directed to the use of a compound of formula ( I) for blocking t he phase-shifting effect s of light in a mammal The present invention further relates to the use of a compound of formula (i) for enhancing or improving sleep quality, in particular by increasing sleep efficiency and augmenting sleep maintenance, as well as for preventing and treating sleep disorders and sleep disturbances, in a mammal. In a preferred embodiment, the present invention provides a method for the phase advance or phase delay in the circadian rhythm of a subject which comprises administering to the subject an appropriate amount of a compound ol' formula (I) or a pharmaceutically acceptable salt thereof.
The administration to a subject of an appropriate amount of a compound of formula (I) is useful, for example, in the prevention or treatment of the following conditions to achieve chronobiologic effects and/or to alleviate circadian rhvthm phase disturbances: disorders of the sleep-wake schedule; jet lag; shift work; people who have a maladaption to work and off-work schedules; medical residents, nurses, firemen, policemen or those whose duties require alertness and wakefulness at evening or nighttime hours, or those deprived of sleep for various periods because of their duties or responsiblities; animal workers; the infantry, or other members of the armed forces whose duties require extreme levels of alertness and wakefulness, and those who may be sleep deprived in the performance of these duties; submariners, or people confined for research. exploration or industrial purposes below the seas; miners, spelunkers, researchers or those confined beneath the Earth; astronauts in orbit around the Earth, on missions in space to the Earth's moon or to the planets or out of the solar system, or in training for uch missions; the blind or sight-impaired or those persons whose ability to distinguish differences in light and dark may be permanently or temporarily impaired; psychiatric patients; insomniacs; the comatose, or those who need to be maintained in a state of unconsciousness for medical, psychiatric or other reasons; residents of the far North or Antartica. or those persons who live in a climate or climates which possess abnormal amounts of light or darkness; those suffering from seasonal affective disorder (SAD), winter depression, or other forms of depression; the aged; Alzheimer's disease patients, or those suffering from other forms of dementia, patients who require dosages of medication at appropriate times in the circadian cycles, patients suffering from delayed sleep phase syndrome, advanced sleep phase syndrome, or non-24 hour sleep phase syndrome; and patients suffering from primary or secondary insomina or circadian rhythm-related insomnia. The present invention is useful, for example, in the prevention or treatment, of conditions associated with circadian rhyfhmicity as well as mental and physical disorders associated with travel across time zones and with rotating shift-work schedules. In a preferred embodiment, the present invention provides a method for the prevention or treatment of a circadian rhythm disorder in a mammal, including time-zone change (jet-lag) syndrome, shift-work sleep disorder, delayed sleep-phase syndrome, advanced sleep-phase syndrome, and non-24-hour sleep- wake disorder, which comprises administering to the mammal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
In another preferred embodiment, the present invention provides a method for shortening the time of remtrainment of circadian rhythms in a subject following a shift, in the sleep-wake cycle which comprises administering to the subject an appropriate amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
In a more preferred embodiment, the pre.sent invention provides a method for alleviating the effects of jet lag in a traveller, especially a mammal, which comprises administering to the traveller an alertness increasing amount of a compound of formula (I) or a pharmaceutically acceptable alt thereof. The purpose of this embodiment is to assist the body to adjust physiologically to the changes in sleep and feeding patterns when crossing several time zones.
In another more preferred embodiment, the present invention provides a method for resetting the internal circadian clock in a subject, for example shift workers changing from a day to a night shift or vice versa, which comprises administering to the subject an appropriate amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
The pre.sent invention is further directed to the use of a compound of formula (1) or a pharmaceutically acceptable salt thereof, for enhancing or improving sleep quality as well as preventing and treating sleep disorders and sleep disturbances in a mammal. In particular, the pre.sent invention provides a method for enhancing or improving sleep quality by increasing sleep efficiency and augmenting sleep maintenance. I n addition, the present invention provides a method for preventing and treating sleep disorders and sleep disturbances m a mammal which comprising the administration of a compound of formula ( I) or a pharmaceut ically acceptable salt thereof. The present invention is useful for the treatment of sleeji disorders, including Disorders of Initiating and Maintaining Sleep (insomnias) ("DIMS") which can arise from psychophysiological causes, as a consequence of psychiatric disorders (particularly related to anxiety), from drugs and alcohol use and abuse (particularly during withdrawal stages), childhood onset DIMS, nocturnal myoclonus and restless legs and non specific REM disturbances as seen in ageing.
The following outcomes in a subject which are provided by the present invention may be correlated to enhancement in sleep quality: an increase in the value which is calculated from the time that a subject sleeps divided by the time that a subject is attempting to sleep; a decrease in sleep latency (the time it takes to fall asleep); a decrease in the number of awakenings during sleep; a decrease in the time spent awake following the initial onset of sleep; an increase in the total amount of sleep; an increase the amount and percentage of REM sleep: an increase in the duration and occurrence of REM sleep; a reduction in the fragmentation of REM sleep; an increase in the amount and percentage of slow- wave (i.e. stage 3 or 4) sleep; an increase in the amount and percentage of stage 2 sleep; a decrease in the number of awakenings, especially in the early morning; an increase in daytime alertness; and increased sleep maintenance. Secondary outcomes which may be provided by the pre.sent invention include enhanced cognitive function and increased memory retention.
The present invention is further useful for the prevention and treatment of sleep disorders and sleej) disturbances including sleep problems associated with insomnia, hypersomnia, sleep apnea, narcolepsy, nocturnal myoclonus, REM sleep interruptions, jet-lag, shift workers' sleep disturbances, dysomnias, night terror, insomnias associated with depression or with emotional/mood disorders, dysfunctions associated with sleej) (parasomnias), as well as sleep walking and enuresis, as well as sleep (hsorders which accompany agmg. Sleep disorders and sleep disturbances are generally characterized by difficulty in initiating or maintaining sleep or in obtaining restful or enough sleep.
I n addition, certain drugs may also cause reductions in REM sleep a< a side effect and t he present invention mav be used to correct those types ol sleeping disorders as well. The present invention would also be of benefit m the treatment of syndromes such as fibromvalgia which are manifested by non- restorative sleep and mu cle pain or sleej) apnoea which is associated with respiratory disturbances during sleep. It will be clear to one skilled in the art that the present invention is not limited to just sleep disorders and sleep disturbances, but is applicable to a wide variety of conώtions which result from a diminished quality of sleep.
The compounds of formula (I) may be used alone or in combination with other agents which are known to be beneficial in altering circadian rhythms or in the enhancement of sleep efficiency For example, the compounds of formula (I) may be administered in conjunction with other compounds which are known in the art to be useful for suppressing or stimulating melatonin production including melatonergic agents, noradrenergic and serotonergic re-uptake blockers, alpha- 1 -noradrenergic agonists, monamine oxidase inhibitors, beta- adrenergic blockers and benzodiazepines, such as atenolol; or with other compounds which are known in the art to be useful for stimulating melatonin production including tncychc antidepressants and alpha-2-adrenergιc antagonists; or with melatonin precursors such as tryptophan, 5- hydroxytryptophan serotonin and N-acetylserotonin, as well as melatonin analogues, melatonin agonists and melatonin antagonists In addition, the compounds of formula (I) may be administered in conjunction with other compounds which are known in the art to be useful for enhancing sleep quality and preventing and treating sleej) disorders and sleep disturbances, including e.g., sedatives, hypnotics, anxiolytics, antipsychotics, antianxiety agents, minor tranquihzers, melatonin agonists and antagonists, melatonin, melatonergic agents, benzodiazepines, barbituates, 5HT-2 antagonists, and the like, such as ddinazolam, allobarbital alonimid, alprazolam, amitnptvhne, amobarbital, amoxapine, bentazepam, benzoctamine, brotizolam bupropion, buspnone, butabarbital, butalbital, capunde, carbocloral, chloral betaine, chloral hydrate, chlordiazepoxide, clomipramine, clopeπdone, clorazepate. clorethate, clozapine, cvprazepam, desipramine, dexclamol, diazepam, dichloralphenazone, divalproex, diphenhydramine, doxepin, estazolam, ethchlorvynol, etomidate, fenobam flumtrazepam flurazepam, fluvoxamine tluoxetine fυsazepam, glutetbimide halazepam, hvdroxvzine, lmφramme lithium, lorazejiam lormet azepam maprotihne, mecloqualone melatonin. mephobarbital, mejirobamate. methaqualone midaflur, midazolam, nefazodone, nisobamate nifrazepam nortriptyhne, oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine jierphenazine, phenelzine, phenobarbital, prazepam, promethazine, propofol, protπptyhne, quazepam, reclazepam, roletamide, secobarbital sertrahne, suproclone, temazepam, thioπdazine, tracazolate. tranylcypromaine, trazodone, tπazolam, trepipam, tncetamide, triclofos, trifluoperazine, tπmetozine tnmipramine, uldazepam, valproate, venlafaxine, zaleplon, zolazepam, zolpidem, and salts thereof, and combinations thereof, and the like.
The compounds of formula (I) may be administered in conjunction with the use of physical methods such as with light therapy or electrical stimulation. In particular, the compounds of formula (I) may be administered in conjunction with scheduhng bright light administration, ordinary-intensity light exposure, or exposure to dim-light or darkness (or even sleep) In one embodiment of the present invention, the compound of formula (I) is administered accompanied by having an individual wear dark or red goggles at the time of administration to provide additive effects of the treatment plus darkness. In another embodiment of the present invention, the individual wears dark goggles at times other than the time of administration of the compound of formula (I) to avoid the occurrence of an external zeitgeber with respect to the jihase shift resulting from the compound of formula (I). Similarly, bright light exposure can be used in conjunction with administration of a compound of formula (1)
Accordingly, the present invention further includes within its scope the use of a compound of formula (I), alone or in combination with other agents, for altering circadian rhythms or for the prevention or treatment of sleep disorders and sleep disturbances in a mammal
As used herein the term "mammals" includes animals of economic importance such as bovine, ovine, and porcine animals, especially those that produce meat, as well as domestic animals, sports animals, zoo animals, and humans, the latter being preferred.
It will be appreciated that when using any combinat ion described herein, both the com iound of formula (I) and the other active agen si will be administered to a patient, within a reasonable period of time The coirψounds mav be in the same pharmaceutically accejitable carrier and therefore administered simultaneously They may be in separate pharmaceutical carriers such as conventional orai dosage forms which are taken simultaneously The term "combination" also refers to the case where the compounds are provided in separate dosage forms and are administered sequentially. Therefore, bv way of example, one active component may be administered as a tablet and then, within a reasonable period of time, the second active component may be administered either as an oral dosage form such as a tablet or a fast-dissolving oral dosage form. By a "fast dissolving oral formulation" is meant, an oral delivery form which when placed on the tongue of a patient, chssolves within about 10 seconds. By "reasonable period of time" is meant a time period that is not in excess of about 1 hour That is, for examjde, if the firs active component is j)rovuled as a tablet, then wit hin one hour, the econd active component should be administered, either in the same type of dosage form, or another dosage form which provides effective delivery of the medicament. The excellent pharmacological profile of the compounds of the present invention offers the opportunity for their use in therapy at low doses thereby minimising the risk of unwanted side effects.
In the treatment of the conditions associated with an excess of tachykinins, a suitable dosage level is about 0.001 to 50 mg/kg per day, in particular about 0.01 to about 25 mg/kg, such as from about 0.05 to about 10 mg/kg per day.
For example, in t he treatment of conditions involving the neurotransmi.ssion of pain sensations, a suitable dosage level is about 0.001 to 25 mg/kg per day, preferably about 0.005 to 10 mg/kg per day, and especially about 0.005 to 5 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day, jireferably once or twice per day.
In the t reatment of emesis using an ln ectable formulation, a suitable dosage level is about 0.001 to 10 mg/kg per day, preferably about 0.005 to 5 mg/kg ]>er day. and especially 0.01 to 1 mg/kg per day. The compounds mav be administered on a regimen of 1 to 4 times per day, preferably once or t ice per day
I f will be appreciated that, t he amount of a compound of formula (1 ) required for use in anv treatment will vary not only wit h t he part icular compounds or composition select ed but also wit h t he rout e ot administrat ion t he nature of the condition being treated, and the age and condition of the i)atιent, and will ultimately be at the discretion of the attendant physician
According to a general process (A. 1), the compounds according to the invention in which X is -CH2- and Y is -CH2 or -CH2CI I2-, may be prepared by the reduction of a corresponding compound of formula (1) in which the broken line represents a double bond, hereinafter referred to as a compound of formula (IIA)
Figure imgf000036_0001
(HA)
wherein Y' is -CH= or -CH3CH=
Suitable reducing conditions include: catalytic hydrogenation using a metal catalyst such as palladium or platinum or hydroxides or oxides thereof, [)referably in a suitable solvent such as alcohol, e.g. methanol or ethanol. or an ester, e.g. ethyl acetate, or an organic acid e.g. acetic acid, or a mixture thereof; or reduction using tnfluoroacetic acid and tπethylsilane.
Similarly, according to a general process (A.2), compounds of formula (I ) in which X is -CH2- and Y is -CH2CH2-. may be prepared by the reduction of a compound of formula (IIB)
Figure imgf000036_0002
(I I B) herein Y" is -OH2- or -CI LCI l - using t he reaction conditions described in proc ss (A I ), above
According to another general process (B), compounds of formula (1 ) in w hich \ is -CH2- and Y is -011= or -CH2CH= and the broken line is a double bond (l e compounds of formula (I IA)), may be jirepared by the reaction of a compound of formula (I I I)
Figure imgf000037_0001
(II I)
w herein Y' is -C1 I= or -CHjCH≡ and each R'5 is a 'ι-4alkyl group, preferablv methyl or n-butyl groups, with a compound of formula (IV)
Figure imgf000037_0002
(IV) herein Rw> is a leaving group such as tπflate (OSO2OFO or a halogen atom, for example, chlorine, bromine or iodine, especially tπflate, bromine or iodine The reaction is conveniently effected in the presence of lithium chloride and a transition metal catalyst such as tetrakιs(tnphenylphosphιne) palladium (0) Suitable solvents for the reaction include aromatic hydrocarbons, for example, toluene, jiolar aprotic solvents, for example, dimethylformamide or ethers for example, dioxan, the reaction being effected at a temperature between SOT and the reflux temperature of the solvent . according to another general process (C), compounds of formula (I > may be prepared from a compound of formula (V)
Figure imgf000038_0001
(V) wherein R1, R2. R3, X, Y and the broken line are as defined in relation to formula (I) by reaction with a compound of formula (VI):
LG-R2 (VI)
where R" is a group of the formula R as defined in relation to formula (I) or a precursor therefor and LG is a leaving group such as an alkyl- or arylsulphonyloxy group (e.g. mesylate or to ylate) or a halogen atom (e.g. bromine, chlorine or iodine); and, if R' is a precursor grouj), converting it to a group R (in which process any reactive group may be protected and thereafter deprotected if desired).
This reaction may be performed in conventional manner, for example in an organic solvent, such as dimethylformamide in the presence of an acid acceptor such as potassium carbonate.
Suitable alternative methods for introducing the grouj) Rh are described, for instance, in I nternational Patent Specification No. WO 95/ 18124.
According to another process (D), compounds of formula (I) may be prepared by further interconversion processes from other compounds of formula (I ) using suitable procedures. In particular, processes may be used to vary the group R. For example, compounds of formula (1) wherein R is a C ualkyl group substituted by the grouj) Ar may be prepared from the corresponding compounds of formula (I) wherein R is a Cι-4alkyl group substituted by the group Ar and further substitut ed by Rl and Rrι where R1 and Rf' together represent an oxo group, by reduction using, for example, borane or a borohydπde such as sodium cvanoborohydride. According to another general process (E), compounds of formula (I) wherein R is a tetrazol- 1 -vl grouj) may be prepared by react ion of an intermediate of formula (VI I)
Figure imgf000039_0001
(VII)
with ammonium chloride and sodium azide at, elevated temperature, conveniently in a solvent such as dimethylformamide.
According to another general process (F), compounds of formula (I) may be prepared by a coupling reaction between a compound of formula (VIII) and (IX)
Figure imgf000039_0002
(VIII) (IX)
wherein one of R '° and R" is B(OI fh or Sn(alkvlb or a derivative thereof, and the other is a leaving group such as a halogen atom e.g. bromine or iodine, or -
OSO.CFs. Where one of R10 and Ru is B(OH):. the reaction is conveniently effect ed in the jiresence of a palladium (0) cafalvsl such as lel rakι.s(l rιphenylphos]>hιne)palladιum (0) in a suit able solvent such as an et her for example, dimefhoxyelhane at an elevated temperature Where one of Rl(l and \ ' is Sn(alkvl) . t he react ion is convenient ly effected in t he presence of palladium (I I) catalyst such as bιs(tπphenylpho.sphine) palladium (I I) chloride, in a suitable solvent such as an aromatic hydrocarbon, for example,, toluene, at. an elevated temperature.
According to another general process (G), compounds of formula (I) may be jirepared from a compound of formula (X)
Figure imgf000040_0001
(X) whereinY" is -C1 L- or -CH2CH2-, by an acid catalysed intramolecular cychsation reaction or by a dehydration reaction. Suitable acids of use in the reaction include mineral acids such as hydrochloric acid. The reaction is conveniently effected in a suitable organic solvent, such as an alcohol, e.g. methanol, at an elevated temperature, for example, at the reflux temperature of the chosen solvent.
Suitable dehydrating reagents of use in the reaction include, for example, methanesulphonyl chloride or benzenesulphonyl chloride in pyπdine or tnethylamine. The reaction is conveniently effected at a temperature between
0°C and 100°C. preferably al. between room temperature and 80°C, using a suitable organic solvent uch as dichloromethane. where necessary.
Intermediates of formula (X) are particularly preferred for controlling the stereochemistry of the 3-position in compounds of formula (I), especially where t he 'λ(R) epi er is desired.
According to another general process (H), compounds of formula (1 ) may be. jirejiared by the reaction of a compound of formula (XX)
Figure imgf000041_0001
R
(XX)
with a compound of formula (IV), under the conditions of a reductive Heck reaction using a ])alladιum catalyst such as palladium acetate with, for example, dimethylformamide and tetrabutylammonium chloride, and a reducing agent, preferably formic acid or a salt thereof, such as potassium formate.
According to another general process (J), compounds of formula (I) in which R1 is Cι-ι;alkoxy, fluoroCi-calkoxy. Cj-calkenoxy, C.3-τcycloalkoxy, C> TcycloalkylCi-ialkoxy or benzyloxy, may be prepared by the interconversion of a compound of formula (I) wherein R1 is hydroxy, hereinafter referred to as formula (XXVI)
Figure imgf000041_0002
R
(XXVI)
by reaction with an appropriate alkyl-. fluoroalkyl-, alkenyl-, cycloalkyl-, cvcloalkylalkyl- or aralkyl-hahde, especially the iodide, in the presence of a base. Suitable bases include alkali metal hydrides such as sodium hydride, in a suitable solvent such as dimethylformamide. The reaction is conveniently effected at about, room temperature. According to a further general process (K) comjjounds of formula ( I) in which Y is -CH= or -CI (i.e. a compound of formula ( I IA), above), may be lirepared by t he dehydrat ion of a compound of formula (XXVI I)
Figure imgf000042_0001
R
(XXVII)
usmg an acid uch as trifluoroacetic acid. The reaction is conveniently effected at a temjjerature between 0°C and room temperature, using a suitable organic solvent such as dichloromethane.
According to another general process (L), compounds of formula (1) may be prepared from a eomjiound of formula (XXVIII)
Figure imgf000042_0002
(XXVII 1)
by reaction with lithium naphthalenide in tetrahydrofuran The reaction is preferably effected at reduced temperature, for example at about -78°C.
Further details of suitable procedures will be found in the accompanying Examples.
Compounds of formula (I I B) may be prepared using the method of general process (K) described above.
I ntermediates of formula (V) may be prepared m a similar manner to the met hods of the processes described above, preferably with an am mo prot ecting Lrroup on any unprotected nitrogen atom. Suitable ammo prot ect ing groups include alkoxycarbonyl groups such as _er/-hutoxycarbonyl and tπchloroethoxycarbonyl, aralkyloxycarbonyl groups such as benzyloxycarbonyl, or aralkyl groups such as benzyl. Removal of the protecting group is effected by conventional procedures thus, for example, iert-butoxycarbonyl groups may be removed under acidic conditions using, for example, trifluoroacetic acid; lert- butoxycarbonyl groups, together with benzyloxycarbonyl and benzyl groups, may also be removed by hydrogenolysis in the presence of a catalyst, for example, Ijalladium; and trichloroethoxycarbonyl groujis may be removed with zinc dust.
Compounds of formula (III) may be prepared from a compound of formula (XI)
Figure imgf000043_0001
(XI) wherein R50 is as previously defined (and is preferably a triflate grouj) or a bromine or iodine atom), by reaction with a compound of the formula ( -^Sn- SnOR^K for example, hexamethyl distannane. The reaction is conveniently effected in the presence of a base, for example, lithium carbonate, and a catalyst such as frψhenylphosphine |)alladium(0). Suitable solvents for the reaction include ethers such as fetrahydrofuran. the reaction being effected at a temperature between room temperature and 100°C, for example, at about 60°C. Compounds of formula (XI) may be prepared from a compound of formula (XII):
Figure imgf000043_0002
(XII) by enυhsafion of the ketone m the presence of a base, for examj)lo, sodium hexamefhyldisilazide. followed by reaction with a reagent capable of int roducing a suitable leaving group, for instance, where R""'; is -OSO2CF , usmg 2-[N'.N- bιs(tπfluoromethylsulphonyl)amιno|-5-chloropyrιdιne or triflic anhydride. The reaction is conveniently effected in a suitable solvent such as an ether, for example, tetrahydrofuran at a reduced temperature, for instance, -80°C.
Compounds of formula (XII) may be prepared from a compound of formula (XII I) by the following reaction sequence (Scheme A) or by methods analogous thereto(wιth the proviso that Ry and R10 are not oxo):
Scheme A
0)
Figure imgf000044_0001
(XII)
Compounds of formula (III), wherein Y' is -CH=, may also be jirepared from a compound of formula (XI II) by the following reaction sequence (Scheme B) or by methods analogous thereto (with the proviso that R9 and R10 are not oxo): Scheme B
Figure imgf000045_0001
fXI II)
TBAF nBugSnH
Pd(PhgP)4 toluene
Figure imgf000045_0002
Figure imgf000045_0003
(i l l )
In anot her pref rred embodiment of the aforementioned processes. R is a benzyl grouj). The reduction reaction described as process (A) above for the jireparation of compounds of formula (I) may conveniently replace the benzyl grouj) with a hydrogen atom (i.e. forming a compound of formula (V)).
Compounds of formula (IV) in which RΛ is an N-linked heterocychc group may be prepared by conventional methodology, for example from a comjiound of formula (XIV)
Figure imgf000046_0001
(XIV) by reaction with a suitable anhydride of the formula R60CO)2θ, where Rβ0 is hydrogen or a desired substituent for the heterocycle, followed by reaction with tπphenylphosphine in carbon tetrachloπde, followed by the further step of (l) reaction with an azide such as sodium azide to effect the formation of a tetrazole ring; or (ii) reaction with hydrazine hydrate to effect the formation of a 1,2,4- tnazole ring; or (in) reaction with aminoacetaldehyde diethyl acetal to effect the formation of an lmidazole ring.
Compounds of formula (XIV) may be prepared from the corresponding nitro compound by reduction using, for example, iron jiowder, or Raney nickel in a conventional manner.
The compounds of formula (XIV) or their nitro precursors are either known compounds or may be prepared using conventional methodology.
Compounds of formula (VI I) niay be prepared by reacting a compound of formula (XV)
Figure imgf000046_0002
(XV)
with any suitable reagent for completing the R moiety as described in the jireceding jirocesses.
Comj)ounds of formula (VI 1) may also be prepared by reaction of a compound of formula (I I I) with a compound of formula (XVI )
Figure imgf000047_0001
Figure imgf000047_0002
according to the method described m process (B), above
Intermediates of formula (X) wherein Y" is -CH2CH2- may be prepared by the reduction of a compound of formula (XVII)
Figure imgf000047_0003
(XVII) or a protected derivative thereof, using conventional methodology, for instance, by cat alytic hvdrogenation using a metal catalyst such as palladium or platinum or oxides thereof, jireferably in a solvent such as an alcohol e g et hanol or an ester, e.g. ethyl acetate
A particularly preferred hydroxyl protecting group is the tπmethvlsilyl grouj)
Compounds of formula (XVI I) may be prepared by the reaction of a compound of formula (XIII) with a compound of formulae (XVI I I)
Figure imgf000048_0001
(XVII I)
or a protected derivative thereof, by lithiation using n-butyl lithium followed by quenching with, for example, sodium dihydrogen orthυphosphate. The reaction is conveniently effected in a solvent such as an ether, e.g. tetrahydrofuran, at a reduced temeprature, for example, at -78°C.
Compounds of formula (XIII) may be prepared by methods described in European Patent Specification No. 0 577 394-A. or by analogous methods.
Compounds of formula (XVIII) are known compounds (see Ckemisc e Berichte, (1988) 121, 1315- 1320) or may be prepared by methods analogous to those described therein.
Compounds of formula (IX) and (XVI) are known compounds or may be prepared by conventional methods or using techniques analogous to those taught herein.
In an alternative method, compounds of formula (X) may be prepared by the reduction of a compound of formula (XXI)
Figure imgf000048_0002
(XXI)
using, for example, catalytic hvdrogenation in the presence of a metal catalyst such as jialladium or platinum or hydroxides or oxides thereof, jireferablv in a suitable solvent such as an alcohol, e.g. methanol, an ester, e.g. ethyl acetate, or an organic acid. e.g. acetic acid, or a mixture thereof.
Compounds of formula (XXI) wherein Y' is -CH= may be prepared from a compound of formula (XXII)
Figure imgf000049_0001
(XXII)
bv reaction with a compound of formula (IV) using reductive Heck conditions as described in A Arcadi et al, Tetrahedron, 1 88, 44, 481 Compounds of formula (XXII) may be prepared from compounds of formula (XIII) and, for example, a Grignard reagent prepared from
O-trimethylsilylpropargyl alcohol using conventional methodology, followed by removal of the hvdroxy protecting group.
According to another method, compounds of formula (X) may be prepared from a compound of formula (XXII I)
Figure imgf000049_0002
(XXIII)
by reaction with borane in tetrahydrofuran, followed by an oxidative work-up using, for example, hydrogen peroxide and sodium hydroxide Compound of formula (XXI 11) may be prepared from a compound of formula (XIII) and, for example, a Gπgnard reagent prepared from a 2-arγl-3- bromo-1-propene using conventional methodology.
Compounds of formula (XX) may be prepared, for example, by the conversion of a stannane of formula (III) to the corresponding iodide by treatment with iodine at reduced temperature, for example, at about -78°C, in a suitable solvent such as dichloromethanc. The iodine may then be displaced to give the compound of formula (XX) by treatment with, for example, α. '-azo- lsobutyronitnle and tπbutyltin hydride in a suitable solvent, for example toluene, at an elevated temperature, for example, at about 100oC.
Alternatively, compounds of formula (XX) may be prepared by the cvchsation of a compound of formula (XXIV)
(XXIV)
using the dehydrating conditions described above for general process (G) or using tπphenylphosphine and diethylazodicarboxylate in a suitable solvent such as tetrahydrofuran.
Compounds of formula (XXIV) wherein Y' is -CH= may be prepared by the partial reduction of an acetylene compound of formula (XXI I) The reaction is conveniently effected by catalytic hydrogenation using a metal catalyst such as palladium on calcium carbonate in the presence of a lead poison (e.g. Lindlar catalyst) Other suitable methods will be readily ajiparent to a person of ordinary skill in the art . Further useful methodology for the preparation of compounds in which Ar is a heterocychc group is described, for exaπψle, in International Patent Significat ion No WO 95/18124 ( '(impounds of formula (XXVI) may be prepared from the appropriate phenolic precursor (or a protected (e.g. benzyloxy) derivative thereof) using, for example, the methods of processes (A), (B) or (C).
Compounds of formula (XXVI 1) may be prepared by the reaction of a compound of formula (XI I) with Gπgnard reagent prepared from a compound of formula (IV), preferably using magnesium and a bromide of formula (IV). The coupling reaction is conveniently effected at reduced temperature, for example at about 0°C, using a suitable solvent such as an ether, for example, diethyl ether.
Compounds of formula (XXVI 11) may be prepared from a compound of formula (XXVI) by reaction with (l -ιodo-cycloprop- l -yl)phenylsulfιde.
I t will be appreciated that compounds of the formula (I) wherein Ar contains an =0 or =S substituent can exist in tautomeric forms All such tautomeric forms and mixtures thereof are included within this invention. Most aptly the =O or =S substituent in Ar is the =0 substituent. Where they are not commercially available, the intermediates of formula
(VI) above may be prepared by the procedures described in the accompanying Examples or by alternative procedures which will be readily apparent to one skilled in the art.
During any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J F W McOmie, Plenum Press, 1973; and T.W Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley &. Sons. 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from t he art .
The exemplified compounds of this invention were tested by the methods set out at pages 36 to 39 of International Patent Specification No. WO 93/01 165. The compounds were found to be active with IO.n at the NKi receptor of less than l μM on said test, met hod.
For the avoidance of doubt. I he nomenclature adhered to throughout this specification follows the1 general principles illust rated below
Figure imgf000052_0001
As used herein, (±)-(3R*,5/T) refers to a racemic mixture of (3/?,5R) and (3S.5S).
The following non-limiting Examples serve to illustrate the preparation of compounds of the present invention:
DESCRIPTION 1
1 -Benzyl-3-(3-hvdroxy- 1 -propyn- 1 -yl)pineπdιn-3-ol 0-Tπmethylsιlylpropargyl alcohol (15.4ml, lOOmmol) was added slowly at
0 to 5°C to a cooled (0°C) solution of ethylmagnesium bromide (1M in tetrahydrofuran, 100ml, l OOmmol) in tetrahydrofuran. The reaction mixture was stirred at 0°C for 15 minutes and then allowed to warm to room temperature over 30 minutes (exotherm and gas evolution observed), before recoohng to 0°C. To this was added a olution of l-benzyl-3-pιpeπdone (l δ. IGg, 80. l m.moD in tetrahydrofuran (30ml), keeping the temperature below 5°C The reaction mixture was stirred at room temperature overnight, quenched by addition of water/saturated aqueous ammonium chloride (50ml/50ml) and extracted with ethyl acatate (2 x 100ml). The organic phases were washed with brine (100ml), combined, dried (MgS()4) and evaporated to an amber oil (25.55g). This oil was dissolved in tetrahydrofuran (50ml), the solution cooled to 0°C and treated with a solution of tetrabutylammonium fluoride (1.1M in tetrahydrofuran, 100ml,
1 lOmmol). After stirring at room temperature for 20 minutes the solution was concentrated in vacuo, diluted with water (250ml) and extracted with ethyl acatate (2 x 100ml). The extracts were washed with brine (100ml), combined, dried (MgS(>4 ) and evaporated to give the title product as an oil (18 65g, 95%); m/z (ES+) 246 ([M+H]+). DESCRIPTION 2
1 -Benzyl-3-(3-hvdroxy-2-tnbutylstannyl- 1 -propen- 1 -yl)pιpendιn-3-ol
Tπbutyl n hydride (7.8ml, 29mmol) was added dropwise t o a degassed solution of l -benzyl-3-(3-hydroxy- l-j)ropyn- ] -yl)pιpeπdιn-3-ol (Desc 1 ; 5.9 l g, 24.1mmol) and tetrakιs(tnphenylphosphιne)palladιum(0) (0.52g, 0.45mmol) in toluene (100ml) at -5°C. The reaction mixture was stirred at -5°C for 2 hours, allowed to warm up and concentrated in vacua to afford an approximately 2.5: 1 mixture of the title compound and lsomeπc l-benzyl-3-(3-hydroxy- l - trιbutylstannyl- l-projιen- l -yOpιperιdιn-3-ol. The mixture was purified by flash chromatography, eluting with ethyl acetate/hexane ( 1:2), to give the title compound (8.82g, 68%); δii (250MHz, CDCla) 0.88 (15H, m), 1.24- 1.53 (14H. m), 1.78 (2H, m), 1 .98 (1H, m), 2.11 (111, d, J 11.1 Hz), 2.69-2.80 (211, m), 3.51 ( H I, d, J 13.2Hz, NC /ACHBP1I), 3.57 (1 H, d, J 13.2Hz, NCHACHBPh), 4.44 (2H, br s, CH2OH), 5.38 ( 1H. br s, CH=C), 7.26-7.34 (511, m, Aril).
DESCRIPTION 3 7-Benzyl-3-trιbutylstannyl- l-oxa-7-azaspιrol4,51dec-3-ene
Diethyl azodicarboxylate (3.1ml, 19.7mmol) was added dropwise to a solution of l-benzyl-3-(3-hydroxy-2-tπbutylstanny 1- 1 -propen- l-yl)pιpeπdιn-3-ol (Desc. 2, 8.72g, 16.26mmol) and tπphenylphosphine (5.12g, 19.5mmol) in tetrahydrofuran ( 100ml) at -5°C. The cooling bath was removed and the reaction mixture stirred for 45 minutes. The solvent was evaporated, the residue dissolved in acetonitπle (300ml) and extracted with hexane (3 x 150ml). The combined hexane extracts were evaporated and the residue chromatographed on silica, eluting with ethyl acetate/hexane (1:9 then 1 :4), to afford the title compound as a colourless oil (5.00g, 59%); 5n (250MHz, CDCb) 0.87-0.96 (15H, m). 1.25- 1.35 (GH. m), 1.45- 1.60 (1 1 I I, m), 1.79 G H, m), 2.29-2.48 ( 1H, m), 3.48 ( 1H. d. J 13.3Hz NCHACI IβPh), 3.59 (1H, d, J 13.3Hz, NCHAC//BP1I), 4.67 (2H, m. 2-CH2), 6.03 ( 1H, br s, 4-CH=), 7.22-7.30 (511, m, ArH) DESCRIPTION 4 2-Bromo-4-(5-trιfluoromethyl- lH-tetrazol-l -yl)aniβole
(a) 4-amιno-2-bromoanisoIe A mixture 2-bromo-4-mtroanιsole (15g, 64.6mmol) and iron powder (27.3g,
0.49mol) in water (100ml) and glacial acetic acid (25ml) was stirred at reflux for 2 hours. The mixture was allowed to cool to ambient temperature and filtered through a pad of Hyflo™ (washed with 25% acetic acid/water). The filtrate was extracted with ethyl acetate (2 x 250ml) and the organic layer was dried over sodium sulphate. Removal of the solvent in vacuo left an oil which was chromatographed on silica eluting with 40% ethyl acetate/hexane to give the title compound as a brown solid (10.32g, 79%); m/z (ES+) 202 ([M+H]+).
(b) 2-Bromo-4-(trifluoroacetamido)anisole 4-Amιno-2-bromoanisole (5g, 24.7mmol) was dissolved in dichloromethane
(50ml) containing triethylamine (3.44ml, 24.7mmol). The solution was cooled to 0°C and trifluoroacetic anhydride (3.5ml, 24.7mmol) was added slowly. The reaction was stirred at ambient temperature for 2 hours, diluted with dichloromethane (200ml) and washed with water (2 x 200ml). The organic layer was dried over sodium sulphate and the solvent was removed in vacuo leaving an oil. Chromatography on silica eluting with 15-25% ethyl acetate/hexane gave the title compound as white solid (4.4g); δn (250MHz, CDClj) 7.79 (1H, d, J 2.6Hz, 3- H), 7.58 (1H, dd, J 8.9, 2.6Hz, 5-H), 6.90 (1H, d, J 8.9Hz, 6-H). 3.90 (3H, s. ArOCHs).
(c) 2-Bromo-4-(5-trifluoromethyl-lH-tetrazol- l-yl)anιsole 2-Bromo-4-(trifluoroacetamido)anisole (4.3g, 14.4mmol) was suspended in carbon tetrachlonde (80ml). The suspension was heated to 80°C and tπphenylphosphine (4.54g, 17.3mmol) was added in portions over 4 hours The reaction was stirred at 80°C for 16 hours. The solvent was removed in vacuo and hexane (100ml) was added to the residue and heated to reflux temperature. The suspension was allowed to cool to ambient temperature and filtered (tπphenylphosphine oxide). The solvent was removed from the filtrate in vacuo leaving an oil (4.6g). The oil in /V,/V-dιmethylformamιde (20ml) was added to a suspension of sodium azide (1.24g, 19.1mmol) in iV,N-dιmethylformamιde (20ml) at ambient temperature. The mixture was stirred for 2 hours and poured into water (200ml). The mixture was extracted with ethyl acetate (2 x 200ml) and the combined organics were washed with water (200ml), dried over sodium sulphate and the solvent was removed m vacuo leaving a yellow oil. Chromatography on silica eluting with 25% ethyl acetate/hexane gave the title compound as a clear oil (4.9g); δn (250MHz, CDCh) 7.72 (1H, d, J 2.6Hz, 3-H), 7.44 (1H, dd, J 8.9, 2.6Hz, 5-H), 7.08 (1H, d, J 8.9Hz, 6-H), 4.02 (3H, s, ArOCHa).
DESCRIPTION 5
2-Bromo-4-(lH-tetrazol- l-yl)amsole
4-Amιno-2-bromoanisole (Desc. 4(a); 4.7g) was dissolved in triethylorthoformate (50ml), trifluoroacetic acid (1.8ml) was added and the mixture heated at reflux for 48 hours. The solvent was removed in vacuo to afford a brown solid. Sodium azide (2.25g) and acetic acid (25ml) were added and the mixture heated at reflux for 6 hours. The product was purified on flash silica eluting with dichloromethane containing increasing proportions of methanol (0.25%, 0.5 and 0.75%) to give the title compound as a brown solid (3.98g, 67% yield); δH (250MHz, DMSO-d6) 4.07 (3H, s, ArOCHs), 7.50 (1H. d, J 9Hz, 6-H), 8.03 (1H. dd, J 3, 9Hz. 5-H), 8.32 (1H, d, J 3Hz. 3-H), 10.16 ( 1H. s, 5'- H).
DESCRIPTION β 2-Bromo-4-(4l-pyrιdyl)anisole
a ) 4-(4f-Pyridyl)amsole
4-Methoxybenzene boronic acid (2g, 13.15mmol) and 4-bromo-pyrιdιne hydrochlonde were suspended in dimethoxyethane (50ml). A 2M solution of sodium carbonate (30ml) was added followed by dιphenylphosphιnobutanepalladιum(II) chloride (lOOmg). The mixture w as stirred at 85°C for 1.5 hours under an atmosphere of nitrogen. The reaction mixture was allowed to cool to ambient temperature, was diluted with ethvl acetate (150ml) and washed with water (2x50ml) The aqueous layer was extracted with ethyl acetate (2x100ml) and the combined organic lavers were dried over sodium sulphate Removal of the solvent in vacuo gave an off white solid which was chromatographed on silica gel in 70- 100% ethyl acetate/hexane as eluent The title compound was obtained as a white solid (1 95, 80%) δH
(250MHz, CDC13) 8 62-8 60 (2H, dd, J 6 2, 1 6Hz), 7 03-7 57 (2H, dd, J 9 0 2 2Hz), 7 50-7 47 (2H, dd, J 6 2, 1 6Hz), 7 04-6 98 (2H, dd, J 9 0, 2 2Hz) 3 87 (3H s), m/z (ES+) 186 ([M+H]+)
b) 2-Bromo-4-(4'-pyπdyl)anιsole
4-(4'-Pyndyl)anιsole (lg, 5 4mmol) was dissolved in acetic acid (6ml) with stirring Iron powder (30mg, 0 54mmol) was added Bromine (0 33ml, 6 3mmol) in acetic acid (4ml) was added dropwise over 5 mm at ambient temperature The reaction was then stirred at 60°C for one hour Bromine (0 16ml, 3 lmmol) in acetic acid (2ml) was added and the solution was stirred at 60°C for a further
1 5 hours and then allowed to cool to ambient temperature Water (25ml) was added and excess bromine was destroyed by adding solid sodium bisulphate until the colour disappeared Solid sodium carbonate was added to basify the solution which was then extracted with ethyl acetate (2x30ml) The combined organic lavers were dried over sodium sulphate and removal of the solvent in vacuo gave an oil which was chromatographed on silica in diethyl ether as eluent giving the title compound as a white solid (772mg, 54%), δH (250MHz, CDCI3) 8 64-8 62 (2H dd J 6 2, 1 7Hz), 7 85 (IH, d, J 2 2Hz), 7 61-7 56 (IH, dd, J 8 6, 2 2Hz) 7 18 7 46 (2H dd, J 6 2, 1 7Hz), 7 02-6 99 (IH, d, J 8 6Hz), m/z (ES+) 266/264 ([M+H]+)
DESCRIPTION 7 2-Bromo-4-trιfluoromethoxyanιsole
(a) 2-Bromo-4-tnfluoromethoxyphenol To a cooled (0 C) solution of 4-tπfluoromethoxyphenol (35 6g, 0 2mol) in chloroform (280ml) was added dropwise a solution of bromine (32g, 0 2mol) m chloroform (50ml) The solution was stirred at 0°C for 1 hour and at room temperature for 2 hours Dichloromethane (200ml) and water (400ml) weie added and the organic phase was washed with water (400ml), brine (200ml) and dried (M SO > The solvent was removed and the residue purified by distύlation at reduced pressure to give the title compound, δH (250MHz, CDCI3) 7 38 ( IH, d, J 2 lHz, 3-H), 7 13 (IH, dd, J 9 1, 2 1Hz, 5-H), 7.03 (IH, d, J 9 1Hz, 6-H), 5.53 ( IH, s. ArOH)
(b) 2-Bromo-4-trιfluoromethoxyamsoIe
To a solution of 2-bromo-4-trιfluoromethoxyphenol (7 2g) and potassium carbonate (11.6g, 0.084mol) in dimethylformamide (60ml) was added methyl iodide (14.94ml, 0.24mol). The solution was stirred for 15 hours at room temperature under nitrogen whereupon water (400ml) and diethyl ether (200ml) were added The organic phase was washed with water (4 x 200ml), saturated NaHCO3 (2 x 200ml), brine (200ml), and the solvent removed in vacuo The residue was purified by chromatography on silica gel eluting with ethyl acetate in hexane (0-2%), to give the title compound; 6H (250MHz, CDCI3) 7.45 (IH, d, J 2.8Hz, 3-H), 7.16 (IH, dd, J 9.0, 2.8Hz, 5-H), 6.88 (IH, d, J 9.0Hz, 6-H), 3.90 (3H, s, ArOCHs).
DESCRIPTION 8 2-Bromo-4-(3-tπfluoromethyl-4H-l,2.4-tnazol-4-yl)anιsole
2-Bromo-4-(trιfluoroacetamιdo)anιsole (Desc. 4(b), 4 3g, 14 4mmol) was suspended in carbon tetrachlonde (80ml). The suspension was heated to 80°C and tπphenylphosphine (4.54g, 17.3mmol) was added in portions over 4 hours The reaction was stirred at 80°C for 16 hours. The solvent was removed in vacuo and hexane (100ml) was added to the residue and heated to reflux temperature
The suspension was allowed to cool to ambient temperature and filtered (tπphenylphosphine oxide). The solvent was removed from the filtrate in vacuo leaving an oil (4 6g). A portion of this oil (2.04g) was dissolved in tetrahydrofuran (25ml), cooled to 0°C and treated with hvdrazine hydrate (1 0ml 21mmol) The mixture was stirred at 0°C for 30 minutes then concentrated in l acuo The residue was dissolved in acetic acid (100ml) containing triethvl orthoformate (25ml) and the solution heated at reflux for 4 hours The mixture as evaporated, treated with 1M sodium hydroxide solution ( 100ml) and extracted with ethyl acetate (2 x 50ml) The extracts were washed with brine (50ml), combined, dried (MgSU4) and evaporated to a orange solid which was purified by tπturation with diethyl ether/hexane to afford the title compound as a pale cream solid (2 21g), δH (250MHz, CDC13) 3 99 (3H, s, ArOCH . 02 (IH, d, J 8 8Hz, 6-H), 7 32 (IH, dd, J 8 8, 2 6Hz, 5-H), 7 58 (IH, d J 2 6Hz, 3-H) 8 32 (IH, s 5'-H)
DESCRIPTION 9
2-Bromo-4-(2-trιfluoromethyl- lH-imidazol- l-yl)amsole 2-Bromo-4-(trιfluoroacetamιdo)anιsole (Desc 4(b), 4 3g, 14 4mmol) was suspended m carbon tetrachlonde (80ml) The suspension was heated to 80°C and tπphenylphosphme (4 54g, 17 3mmol) was added in portions over 4 hours The reaction was stirred at 80°C for 16 hours The solvent was removed m vacuo and hexane (100ml) was added to the residue and heated to reflux temperature The suspension was allowed to cool to ambient temperature and filtered
(triphenylphosphine oxide) The solvent was removed from the filtrate in vacuo leaving an oil (4 6g) A portion of this oil (3.63g) was dissolved in tetrahydrofuran (40ml) and treated with aminoacetaldehyde diethyl acetal (5 0ml, 34mmol) The mixture was stirred at room temperature for 3 hours, concentrated in vacuo, redissolved in acetic acid (100ml) and heated at reflux for 1 hour The mixture was evaporated, treated with 1M sodium hydroxide solution (250ml) and extracted with ethyl acetate (2 x 100ml) The extracts were washed with brine (100ml), combined, dried (MgSO- and evaporated to an amber oil Purification by flash chromatography, eluting with ethyl acetate/hexane (1.2 then 2 3), gave the title compound (2 60g); 6H (250MHZ, CDCI3) 3 97 (3H, s,
ArOCHi), 6 98 (IH, d J 8 7Hz, 6-H), 7 12 (IH, d, J 1 1Hz), 7 21 (IH, d, J 1 1Hz), 7 31 (IH, dd, J 8 7, 2 6Hz, 5-H), 7 58 (IH, d, J 2 6Hz, 3-H) DESCRIPTION 10
4-Benzyloxy-2-bromoanιsole
a) 4-Benzyloxy-2-bromophenol To a suspension of 4-benzyloxyphenol (30g, lδOmmol) in chloroform
(400ml) was added, dropwise, a solution of bromine (24g, lδOmmol) in chloroform (150ml). After stirring for 1 hour the mixture was washed with 0.1M NaHSOs (500ml), then water (500ml). The chloroform layer was separated, dried (MgS04), filtered and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 5, 10, 20% ethyl acetate/hexane.
Recrystallisation from hexane afforded the title compound (20.5g, 49%); OH (250MHz, CDCb) 4.98 (2H, s, OCH2), 6.82-6.99 (2H, m, ArH), 7.09-7.12 (IH, d, J 2.75Hz, ArH), 7.30-7.42 (5H, m).
b) 4-Benzyloxy-2-bromoanιsole
To a solution of 4-benzyloxy-2-bromophenol (20g, 71.6mmol) in N,N- dimethylformamide (65ml) was added potassium carbonate (12.4g, 89.6mmol) and methyl iodide (12.7g, 89.6mmol). The mixture was stirred at room temperature for 18 hours, poured into water (250ml) and extracted with ethyl acetate (2x100ml). The organic layer was separated, dried (MgSOt), filtered and concentrated in vacuo to give the title compound (20.15g, 96%), δH (250MHz, CDCU) 3.84 (3H, s, ArOCHj), 4.99 (2H, s, OCH2), 6.80-6.94 (2H, m, ArH). 7.21 (IH, d, J 2.75Hz, ArH), 7.28-7.43 (5H, m).
DESCRIPTION 11
3-(2-Methoxy-5-(5-trifluoromethvI-lH-tetrazol- l-yl)phenyl)- l-oxa-7- azaspιro|4,51dec-3-ene hvdrochloride
1-Chloroethyl chloroformate (1.9ml, 17.6mmol) was added dropw ise at - 4°C to a solution of 7-benzyl-3-(2-methoxy-5-(5-trifluoromethyl-lH-tetrazol- l - yOphenyl)- l-oxa-7-azaspιro[4,5]dec-3-ene (free base of Ex. 2. 6.16g, 13 07mmol) in dichloromethane (60ml). The reaction mixture was stirred at -4°C for 30 minutes, allowed to warm to room temperature over 30 minutes and stirred at room temperature for 15 minutes. The reaction mixture was concentrated in vacuo, the residual red oil dissolved in methanol (60ml) and heated at reflux for 40 minutes. The mixture was allowed to cool, concentrated in vacuo and the residue triturated with ether to give a title compound in two crops (3.54g, 65%), m.p. 203-205°C; (Found: C, 48.33; H, 4.44; N, 16.31. C17H19CIF3N5O2. 0.25H2O requires C, 48.35; H, 4.65; N, 16.58%); δn (360MHz, DMSO-d6) 1.72- 1.96 (4H, m),
2.85 (IH, m), 3.11 (3H, m), 4.00 (3H, s, ArOCHs), 4.99 (2H, m, 2-CHj), 6.64 (IH, br s. 4-CH=), 7.38 (IH, d, J 8.9Hz, 3'-H), 7.65 (IH, d, J 2.5Hz, 6'-H), 7.76 (IH, dd, J 8.9, 2.5Hz, 4'-H); m/z (ES+) 382 (fM+H]+).
DESCRIPTION 12
(±)-(3R*. 5R*)-3-(2-Methoxy-5-(5-trifluoromethyl-lH-tetrazol- l -yl)phenyl)- l-oxa- 7-azaspιrol4,5ldecane and (±)-(3S*. 5R*)-3-(2-methoxy-5-(5-trιfluoromethyl- lH- tetrazoI- l-yl)phenyl)- l-oxa-7-azaspirof4,51decane
A mixture of 7-benzyl-3-(2-methoxy-5-(5-tπfluoromethyl- lH-tetrazol- l- yl)phenyl)-l-oxa-7-azaspιro[4,5jdec-3-ene (free base of Ex. 2; 1.73g, 3.67mmol),
20% palladium hydroxide on carbon (0.39g), and acetic acid (5ml) in methanol (45ml) was hydrogenated at 50psi for 5 hours, during which time two further portions of catalyst were added (0.35g and 0.39g). The catalyst was filtered off and replaced by fresh catalyst (0.98g) and the mixture hydrogenated at 50psι overnight (14 hours). The reaction mixture was filtered, concentrated in vacuo, treated with saturated sodium hydrogen carbonate (250ml) and extracted with dichloromethane (100ml then 2x50ml). The combined extracts were dried ( gSO.ι) and concentrated in vacuo to afford the title products as an approximately 7: 1 mixture (1.26g, 90%). The structure of the major diasterisomer [(3R*, 5R*)] was assigned on the basis of 500MHz ID proton,
COSY and NOESY NMR experiments; proton data for major isomer, δH (DMSO- dc) 1.35 (IH, m, 9-Heq), 1.58 (2H, m, 9-Hax, 10-H.x), 1.66 (2H. m, 4-Heq, 10-Heq), 2.35 (IH, dd, J 12.5, 8.1Hz, 4-Hax), 2.53 (2H, m, 6-Haχ, 8-H» . 2.65 (2H, m. 6-Heq, 8-Heqj, 3.59 (IH, t, 8.4Hz, 2-Hcq), 3.72 (IH, m, 3-H), 3.91 (3H. s, A1OCH3). 4.10 ( IH. m. 2-Ha . 7.24 (IH, d, J 8.7Hz, 3'-H), 7.61 (IH, dd, J 8 7. 2 5Hz. 4'-H). 7.70
O H. d. J 2.5Hz. O'-H). DESCRIPTION 13
(±)-(3R*. 5R*)-3-(2-Methoxy-5-(5-trιfluoromethyl- lH-tetrazol-1 -yl)phenv - l -oxa- 7-azaspιror4.51decane hydrochlonde
3-(2-Methoxy-5-(5-trιfluoromethyl- lH-tetrazol- l-yl)phenyl)-l-oxa-7- azaspιro[4,5]dec-3-ene hydrochlonde (Desc. 11; 2.23g, 5.34mmol) was hydrogenated in analogous fashion to Description 12, followed by recrystallisation from isopropanol/diethyl ether to afford the title compound (1.04g, 46%); δH (360MHz, D2O) 1.85 (3H, m), 2.01 (2H, m), 2.38 (IH, m), 2.98- 3.09 (2H, m), 3.38 (I H, m), 3.44 (IH, d, J 12.8Hz), 3.94 (2H, m), 3.97 (3H, s, ArOCHs), 4.32 (IH, m), 7.26 (IH, d, J 8.8Hz, 3'-H), 7.53-7.58 (2H, m, ArH): m/z
(ES+) 384 ([M+H]+).
DESCRIPTION 14
3-Bromo-4-methoxyphenylhvdrazιne A solution of sodium nitrite (3.16g, 45.8mmol) in water 30ml was added dropwise over 30 minutes to a stirred suspension of 4-amιno-2-bromoanιsole (Desc. 4(a); 7.31g, 36.2mmoι) in concentrated hydrochloric acid (50ml), maintaining the temperature below 0°C. The mixture was stirred at ca. 0°C for 30 minutes then added portionwise to a suspension of tιn(II) chloride dihydrate (36.87g, 163mmol) in concentrated hydrochloric acid (50ml) at -10°C. The resulting thick paste was stirred at -2°C for 15 minutes, allowed to warm to room temperature over 20 minutes and stirred at room temperature for a further 20 minutes. The reaction mixture was recooled, basified with 10M sodium hydroxide solution and extracted with ethyl acetate (2 x 250ml) The extracts were washed with brine (250ml), combined, dried (MgSO<ι) and concentrated in vacuo to afford 3-bromo-4-methoxyphenylhydrazιne (7.27g, 93%); δn (250MHz, CDCI3) 3.84 (3H, s, ArOCHs), 6.75 (IH, dd, 8.8, 2.6Hz, 6-H), 6.83 (IH, d, 8 8Hz, 5-H), 7.11 ( lH. d, 2.6Hz, 2-H).
DESCRIPTION 15
2-Bromo-4-(5-methyl-lH- 1.2.4-trιazol- l-yl)amsole
Acetamide (6.07g, 0.103mol) and dimethylformamide dimethyl acetal (20ml, O. lSmol) were stirred at 80°C in dioxane ( 20ml) for 2 hours The reaction mixture was concentrated in vacuo, ether (50ml) added, the solution refndgerated for 30 minutes then triturated to give an orange solid The solid was collected under suction and the fitrate concentrated in vacuo to a red oil (4 63g) A portion of this oil (1.20g) was added to a solution of 3-bromo-4- methoxyphenylhydrazine (Desc. 14; 2.12g, 9.77mmol) in acetic acid (20ml) and the mixture stirred at 90°C for 2 hours. The reaction mixture was concentrated, treated with saturated sodium hydrogen carbonate (150ml) and extracted with dichloromethane (2 x 50ml). The combined extracts were dried (MgSO-i), evaporated and the residue purified by flash chromatography, eluting with 1.1 then 3: 1 ethyl acetate/hexane then ethyl acetate, to give the title compound
(0 33g, 13%), δn (250MHz, CDCls) 2.51 (3H, s, 5'-CH3), 3 97 (3H, s, ArOCHs), 7 00 ( IH, d J 8 7Hz 6-H), 7 37 (IH, dd, J 8 7, 2.6Hz, 5-H), 7 67 (IH, d, J 2 6Hz, 3-H). 7 92 (IH, s, 3'-H)
DESCRIPTION 16
2-Bromo-4-(5-trιfluoromethvI-lH-1.2.4-trιazol- l-yl)anιsole
Trifluoroacetamide (5.87g, 51.9mmol) and dimethylformamide dimethyl acetal (3.3ml, 62mmol) were stirred at 80°C in dioxane (20ml) for 30 minutes The reaction mixture was concentrated in vacuo to give a dark yellow oil (7 71g) A portion of this oil (5.04g) was added to a solution of 3-bromo-4- methoxyphenylhydrazine (Desc. 14; 4 29g, 19.8mmol) in acetic acid (40ml) and the mixture stirred at 90°C overnight The reaction mixture was concentrated m vacuo, the residue dissolved in ethyl acetate (50ml) and stirred with saturated sodium hydrogen carbonate solution (150ml) for 15 minutes The phases were separated and the aqueous phase extracted with ethyl acetate (2 x 50ml) The extracts were washed with brine (50ml), combined and dried (MgSO.ι) The residue after evaporation was purified by flash chromatography (gradient elution with 1 4, 1 2, 2 1 then 3.1 ethyl acetate hexane) to afford 2-bromo-4-(5- trιfiuoromethyl- lH-trιazol- l-yl)anιsole (0.194g, 3%), δH (360MHz, CDCI3) 3 98 (3H, s, ArOCHi), 7 00 (IH, d, J 8.8Hz, 6-H), 7 40 (IH, dd, J 8 8. 2 6Hz 5-H) 7 69 ( I H, d, J 2 6Hz 3-H), 8 11 (IH, s, 3'-H) DESCRIPTION 17
2-Bromo-4-(N-methyltrifluoroacetamιdo)amsole
Sodium hydride (60% dispersion in mineral oil, 0.48g, 12mmol) was added to a stirred, cooled (0°C) solution of 2-bromo-4-(trifluoroacetamιdo)anιsole (Description 4(b); 2.98g, lOmmol) in dimethylformamide (30ml). The mixture was stirred at 0 °C for 30 minutes, then methyl iodide (0.75ml. 1.70g, 12mmol) was added. The mixture was stirred at 0°C for 30 minutes, then at room temperature for 3 hours. Water (50ml) was added and the mixture was extracted with ethyl acetate (3 x 50ml). The combined organic extracts were washed with water (4 x 50ml) then brine (50ml), dried (MgSO-i) and the solvent evaporated under reduced pressure. The residue was purified by flash chromatography, elutmg with hexane/CH2Cl2 (50:50 increasing to 30:70), to give the title compound as a colorless solid (2.72 g, 87%); δH (250MHz, CDC ) 3.32 (3H, s, N-CH ?), 3.94 (3H, s, ArOCH3), 6.91 (IH, d, J 8.7Hz. 6-H), 7.18 (IH, dd. J 8.7, 2.4Hz, 5-H), 7.46 (IH, d, J 2.4Hz, 3-H).
DESCRIPTION 18
1 -(3-Bromo-4-ιsopropoxyphenyl)-2-trifluoromethyl- lH-imidazole
(a) 2-Bromo-4-nιtrophenol
Bromine (27 ml) was added dropwise to a solution of 4-nιtrophenol (50g) in glacial acetic acid (400ml) and the mixture stirred at room temperature for 18 hours. The solvent was evaporated under reduced pressure and the residue was crystallised from dichloromethane/hexane. The solid was collected and dried m vacuo to give the title compound as a colorless solid (67 g); OH (250MHz, CDCb)
7 13 (IH, d, J 8.9 Hz, 6-H), 8.16 (IH, dd, J 2.6, 8.9 Hz, 5-H). 8.44 (IH, d, J 2.6 Hz, 3-H).
(b) 2-Isopropoxy-5-nitrobromobenzene 2-Iodopropane (2.2g) was added to a mixture of 2-bromo-4-nιtrophenol
( 2.5g) and potassium carbonate (5g) in acetone (30ml) and the mixture heated under reflux for 18 hours. The mixture was cooled and the solvent was evaporated under reduced pressure. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried (MgSO4) and the solvent evaporated under reduced pressure The residue was purified by flash chromatography, eluting with hexane/EtOAc (90: 10), to give the title compound (2.8 g, 94%); δH (250MHz, CDC ) 1 42 (6H, d, J 5.7Hz, OCH(CH3)2), 4.75 (1Η, m, OCH(CΗ3)2), 6.93 (IH, m, ArH), 8.20 (IH, m,
ArH), 8.46 (IH, s, ArH)
(c) 3-Bromo-4-ιsopropoxyanιlιne
Platinum oxide (50mg) was added to a solution of 2-ιsopropoxy-5- mtrobromobenzene (1.7g, 6.5mmol) in ethyl acetate (50ml) and the mixture was stirred under hydrogen (50psι) for 1 hour. The mixture was filtered, further platinum oxide (50mg) was added and the mixture was stirred under hvdrogen (50psι) for 1 hour. The mixture was filtered and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography, eluting with hexane/EtOAc (80:20), to give the title compound (0.92 g, 62%); δH
(360MHz, CDCb) 1.32 (3H, d, J 5.6Hz, OCH(CH3)2), 4.33 (1Η, m, OCH(CΗ3)2), 6.57 (IH, dd, J 8.7, 2.8Hz, 6-H), 6.78 (IH, d, J 8.7Hz, 5-H), 6.91 (IH, d, J 2.8 Hz, 2-H).
(d) N-(3-Bromo-4-ιsopropoxyphenyl)tπfluoroacetamιde
Trifluoroacetic anhydride (1.1ml, 1.64g, 8mmol) was added slowly to a stirred, cooled (0°C) solution of 2-ιsopropoxy-5-amιno-bromobenzene (0.92g, 4mmol) and tnethylamine (1.1ml, 0.90g, 8mmol) in dichloromethane (10ml) and the mixture stirred at room temperature for 2 hours. The mixture was diluted with dichloromethane (30ml) and washed with water (30ml) and brine (30ml), dried (M SO4) and the solvent evaporated under reduced pressure to give the title compound as a beige solid (1.28 g, 100%); δH (360MHz, CDCb) 1 37 (3H, d, J 5.6Hz, OCH(CH3)2), 4 54 (IH, m, OCH(CH3)2), 6.91 (IH, d. J 8.9Hz, 5'-H). 7 46 (IH, dd, J 8.9, 2.7Hz, 6'-H), 7 74 (IH, d, J 2.7Hz. 2*-H).
(e) l-(3-Bromo-4-ιsopropoxyphenyl)-2-trιfluoromethvI- lH-ιmιdazole
Tnphenylphosphme (7 7g, 29.4mmol) was added in portions to a stirred, heated (80°C) suspension of N-(3-biOmo-4-ιsopropoxyphenvl)trιfluoroacetamιde (8 5g, 19mmol) in carbon tetrachloπde (100ml) The mixture was stirred at 80°C for 2 days, then further tπphenylphosphine (2 5 g, 9 5 mmol) was added The mixture was stirred at 80°C for 5 hours, cooled and the solvent evaporated under reduced pressure The residue was triturated with hexane, filtered and the solvent evaporated under reduced pressure to give a yellow oil (6 7g). A portion (3g) was dissolved in tetrahydrofuran (40ml), cooled in ice and aminoacetaldehyde diethyl acetal (3 9ml, 27mmol) was added The mixture was stirred at 0°C for 30mmutes, the solvent was evaporated under reduced pressure and the residue was dissolved in acetic acid (50ml) The mixture was heated under reflux for 3 hours, cooled and the solvent evaporated under reduced pressure. Aqueous sodium hydroxide solution (1M, 2 x 150 ml) was added and the mixture extracted with ethyl acetate (2 x 150ml) The combined organic extracts were washed with brine (100ml), dried (MgSO-i) and the solvent evaporated under reduced pressure. The residue was purified by flash chromatography, eluting with hexane/EtOAc (80:20), to give the title compound as an oil (1.3g); δH (360MHz, CDCb) 1 43 (6H, d, J 6.0Hz, OCH(CH3)2), 4 63 (IH sept. J 6.0Hz, OCH(CH3)2), 6.96 (IH, d, J 8.7Hz, 5'-H), 7 10 (IH, d, J 1 1Hz 4-H or 5-H), 7 20 (IH, d, J 1 1Hz, 5-H or 4-H), 7.25 (IH, dd, J 8.7, 2 6Hz, 6'-H) 7 56 (IH, d, J 2.6Hz, 2'-H); m/z (ES+) 349, 351 ([M+H]+)
DESCRIPTION 19 2-Bromo-4-(5-trιfluoromethyl-lH-tetrazol-l -yl)methylanιsole
a) 2-Bromo-4-amιnomethylanιsole Borane-tetrahydrofuran complex (1 0 M solution in tetrahydrofuran 250 ml) was added to a solution of 2-bromo-4-cyanoanιsole (17g) in tetrahvdrofuran ( 150ml) The mixture was heated at reflux for 2 hours then cooled to - 10°C and carefully quenched with 6N HC1 (130ml) The mixture was basified with 4N NaOH then extracted with ethyl acetate The organic layer was separated dried NIgSO.t), filtered and concentrated in vacuo The residue was purified by flash chromatography, eluting with 120-8 1 dichloromethane methanol ammonia to give the title compound (12 3 g, 71 ..). 6n (250MHz CDCb) 3 80 (2H. s CH_NH2) 3 92 (3H, s, ArϋCRi), 6 85 (IH, d, J 8 4Hz 6-H), 7 20 ( III, dd J 8 4, 2 1Hz 5-H), 7 51 (1H, d, J 2 1Hz, 3-H)
b) 2-Bromo-4-(trιfluoroacetamιdo)methylanιsole Tnethylamine (14 4g, 142mmol) was added to a solution of 2-bromo-4- methylaminoamsole (12 3g, 57mmol) in dichloromethane (30ϋml) The solution was cooled with an ice-acetone bath and trifluoroacetic anhvdπde (11 9g, 57mmol) was added slowly The mixture was stirred at ambient temperature for 18 hours then washed with water (2 x 100ml) The organic laver was separated, dried (MgSO4), filtered and concentrated in vacuo Chromatography on silica gel, eluting with 30% ethyl acetate in hexane, gave the title compound (12 2g, 69%), δH (250MHz, CDCb) 3 88 (3H, s, ArOCHi), 4 42 (2H, d, J 5 9Hz, CH_), 6 87 (IH d, J 8 4Hz, 6-H), 7 21 (IH, dd, J 8 4, 2.1Hz, 5-H), 7 47 (IH, d, J 2.1Hz, 3-H)
c) 2-Bromo-4-(5-trιfluoromethyl-lH-tetrazol- l-yl)methvIanιsole
2-Bromo-4-(tπfluoroacetamιdo)methylanιsole (5g, lβmmol) was suspended in carbon tetrachloπde (125ml) Tπphenylphosphine (8g, 30 δmmol) was added and the mixture stirred at 80°C for 16 hours Solvent was removed in vacuo and the residue poured into hexane (100ml) and stirred at reflux for 30 minutes The suspension was filtered through Hyflo™ and the filtrate concentrated to an oil The oil in N.N-dimethylformamide (15 ml) was added to a stirred solution of sodium azide (lg, lδmmol) in N N-dimethylformamide at 0°C The mixture was stirred at ambient temperature for 2 hours then poured into water (200ml) and extracted with ethyl acetate (2 x 100ml) The combined organics were washed with water (3 x 200ml), dried over sodium sulfate and the solvent was removed in vacuo leaving a vellow oil Chromatography on silica gel, eluting with 10-50% ethyl acetate in hexane, gave the title compound as a yellow oil (230mg, 5%, δH (360MHz, CDCb) 4 90 (IH, d, J 7 6Hz, NCHAHBAr), 4 9δ (IH, d, J 7 6Hz, NCHAHBAr), 7 00 (1Η, d, J 8 6Ηz, 6-H), 7 52 (IH dd, J 2 2, 8 5Hz, 5- H), 7 80 (IH, d, 2 2Hz. 3-H), m/z (ES4) 337, 339 ([M+H]+) DESCRIPTION 20
(±)- (3R*. 5R*)-3-(2-Methoxy-5-(2-trιfluoromethyl-lH-ιmιdazol- l-yl)phenyl)- l-oxa- 7-azaspιro[4 δldecane oxalate
7-Benzyl-3-(2-methoxy-5-(2-tnfluoromethyl- lH-imidazol- lyl)phenyl)- 1- 5 oxa-7-azaspιro[4.5]-dec-3-ene (4.2g), 20% palladium hydroxide on carbon (0 5g) in methanol (40ml) was hydrogenated at 50psι for 5 days during which time the catalyst was filtered off and replaced by fresh twice. The reaction mixture was filtered through Hyflo™ then concentrated in vacuo. The residue was purified by flash chromatography eluting with 90:8- 1
10 dichloromethane. methanol. ammonia. Treatment with oxalic acid afforded the oxalate salt which was recrystallised from isopropanol/diethvl ether ( 1 97g, 49%), δH (360MHz, D.O) 1 77-1 99 (5H, m), 2.31-2 36 (IH, m), 2 97 -3 07 (2H. m), 3.35- 3.43 (2H, m), 3 88-3.93 (5H, m), 4.25-4.32 (IH, m), 7 12-7 14 (IH, d, J 9 5Hz, 3'- H). 7.24-7.25 (IH, d, J 1.2Hz, imidazole H), 7.35-7 36 (2H. m), 7 37-7 38 ( IH, d, J
15 1.2Hz. imidazole H); m/z (ES+) 382 ([M+H]+)
DESCRIPTION 21
(2R)- l-Phenyl-2-(p-toluenesυlfonyIoxy)propane
(2R)- l-Phenyl-2-propanol (0.5ml, 3.65mmol) was added dropwise to a
20 solution of p-toluenesulfonyl chloride (0.73g, 3.83mmol) m pyπdine (3ml) at 0°C The mixture was stirred at 0°C under nitrogen for 30 minutes then at room temperature overnight. The reaction mixture was poured into 2M hydrochloric acid (75ml) and extracted with diethyl ether (2 x 50ml) The extracts were washed with 2M hydrochloric acid (50ml), saturated sodium hydrogen carbonate
25 (50ml) and brine (50ml), combined, dried (M SO4) and concentrated in vacuo to give the title compound as a white solid (0.95g, 90%); δH (250MHz, CDCb) 1 30 (3H, d, J 6.2Hz, CHCH , 2.42 (3H, s, ArCHs), 2.77 (IH, dd, J 13 8, 6 6Hz CH(OTs)CHιHBPh), 2.92 (IH, dd, J 13.8, 6.6Hz, CH(OTs)CHAHβPh), 4 74 (IH, m, CHOTs), 7 03 (2H, m. ArH), 7.20 (5H, m, ArH), 7 62 ( IH m. ArH) n 0 EXAMPLE 1
7-Benzyl-3-(2-methoxyphenyl)-l-oxa-7-azaspιroI4,51dec-3-ene hydrochlonde
A mixture of 7-benzyl-3-tnbutylstannyI-l-oxa-7-azaspιro[4.5]dec-3-ene (Desc. 3; 1.68g, 3.24mmol), 2-bromoamsole (0.80ml, 6 42mmol), lithium chloride (0.94g, 22mmol) and tetrakιs(triphenylphosphιne)palladιum(0) (0 37g, 0 32mmol) in toluene (40ml) was degassed then heated at reflux overnight (17 hours) The mixture was allowed to cool, filtered and concentrated in vacuo The residue was dissolved in ether (100ml) and extracted with 2M hydrochloric acid (100ml then 25ml). The aqueous phases were washed with more ether (100ml), combined, basified with 4 M sodium hydroxide (70ml) and extracted with ethyl acetate
(2x50ml). The organic phases were washed with brine (50ml), dried (MgSU4) and concentrated The residue was purified by flash chromatography, eluting with ethyl acetate hexane (1:2 then 1: 1), to give 7-benzyl-3-(2-methoxyphenyl)-l-oxa-7- azaspιro[4,5]dec-3-ene (0.67g, 62%). This oil was dissolved in isopropanol and treated with excess ethereal hydrogen chloride. The mixture was concentrated m vacuo and recrystallised from lsopropanol/diethyl ether to afford the title compound, m.p. 198-201°C; (Found: C, 69.61; H, 6.85; N, 3.62 C22H2GC1NO2.0 4H2O requires C, 69.70; H, 7.13; N, 3.69%), δH (360MHz, D2O) 1.78-2.22 (4H, m), 2.98-3.26 (3H, m), 3.58 (IH, m), 3.89 (3H, s, ArOCH3), 4.29 (IH, br d, NCHAHBPh), 4.43 (IH, d, J 13.1Hz, NCHAHEPh), 5 00 (2Η, m, 2-CH2),
6.33 (IH, br s, 4-H), 7 02 (IH, t, J 7.5Hz, ArH), 7.11 (IH, d, J 8 4Hz, ArH), 7 16 ( IH, m, ArH), 7.39 (IH, m, ArH), 7.53 (5H, m, PhH); m/z (EST) 336 ([M+H]+)
EXAMPLE 2 7-Benzyl-3-(2-methoxy-5-(5-trιfluoromethyl-lH-tetrazol-l-yl)phenyl)-l-oxa-7- azaspιro[4,51dec-3-ene hydrochlonde
Prepared in an analogous fashion to Example 1 using the bromide of Description 4
M.p. 221-223°C (IPA/Et2θ); (Found. C, 56.35; H, 4.83, N, 13.33 C24H25CIF3N5O2.O.2H2O requires C, 56.35, H, 5.01 , N, 13 69%), δH (360MHz,
D9θ) 1.80-2.12 (4H, m), 3 03 (IH, m), 3 15 (I H. br d), 3 24 (IH br d). 3 56 (IH, m). 3 96 (3H, s, ΛrOCH3), 4.32 (IH. br d, NCHAHBPh), 4 12 ( III. d. J 13 1Hz, XCHAHβPh). 4 97 (211, m. 2-CΗ2), 6 45 (III, br s, 4-CH=) 7 25 ( IH d J 9 OHz 3'-H), 7.33 (IH, br s, 6'-H), 7.49 (5H. br s. PhH), 7.54 (IH, m, 4'-H); m/z (ES"1") 472 ([M+H]+)
Separation of the enantiomers of the title compound was carried out by chiral HPLC on a Chiralcel OD-H δμm column (250 x 4mm i.d.), eluting with 5% ethanol in hexane ( 1.5ml/mιn). Peaks observed for enantiomers at 10 8 and 16.8 minutes.
EXAMPLE 3
7-Benzyl-3-(2-methoxy-5-(lH-tetrazol-l-yl)phenyl)-l-oxa-7-azaspιro[4.51dec-3-ene hvdrochloridc
Prepared in an analogous fashion to Example 1 using the bromide of Description 5. δH (360MHz, DMSO-dc) 1.60- 1.92 (4H, m), 2.δ8-2.96 (4H, m), 3.98 (3H, s, ArOCHs), 4.02-4.10 (2H, br d, NCH.Ph), 4.96-5.04 (2H, m, 2-CH_), 6.59 ( IH, s, 4- CH=), 7.32-7.43 (7H, m), 7.65 (IH, m) 7.83 (IH, d, J 6.55Hz, ArH), 10.00 (IH, s, tetrazole H); m/z (ES+) 404 ([M+H]+).
EXAMPLE 4
7-Benzyl-3-(2-methoxy-5-(4-pyrιdyl)phenyl)-l-oxa-7-azaspιro[4.5ldec-3-ene dihvdrochloride
Prepared in an analogous fashion to Example 1 using 2-bromo-4-(4'- pyndyOanisole (Description 6). δH (360MHz, D2O) 1.78-2.09 (4H, m), 3.01-3.26 (3H, m), 3.56-3.61 (IH, m), 3.88 (3H, s, ArOCH3), 4.22-4.50 (2H, m), 5.00-5.10 (2H, m), 6.38 ( IH, s), 7.22 (IH, m), 7.38-7.56 (6H, m), 7.91 (IH, m), 8.06 (2H, m), 8.62 (2H, m); m/z (ES+) 414
([M+H]+).
EXAMPLE 5
7-Benzyl-3-(2-methoxy-5-cvanophenyl)- l-oxa-7-azaspιrol4.5|dec-3-ene hvdrogen oxalate
Prepared in an analogous fashion to Example 1 using 2-bromo-4- cvanoamsole. δH (360MHz, DMSO-de) 1.63-1.87 (4H, m), 2.62-2.87 (4H, m), 3.94 (3H, s, ArOCHj), 3.97 (2H, s, NCH2Ph), 4.95 (2H, m), 6.55 (IH, s), 7.26 (IH, d. J 8.75Hz, ArH), 7.38-7.43 (δH, m), 7.63 (IH, d, J 1.9Hz), 7.77-7.80 (IH, m); m/z (ES-) 360 ([M+H] *).
EXAMPLE 6 7-Benzyl-3-(2-methoxy-5-trifluoromethoxyphenyl)- l -oxa-7-azaspιro[4,5]dec-3-ene hvdrochloride
Prepared in an analogous fashion to Example 1 using the bromide of Description 7. δH (360MHz, DMSO-dr.) 1.69-1.85 (3H, m), 2.02-2.18 (IH, m), 2.87-2.94 ( IH, m), 3.05 (2H, s), 3.35-3.45 (IH, m), 3.78 (3H, s, ArOCHs), 4.15-4.32 (2H, m), 4.86-4.95 (2H, m), 7.11-7.13 (IH, m), 7.37-7.42 (5H, m); m/z (ES1) 420 ( M+H]+).
EXAMPLE 7
7-Benzyl-3-(2-methoxy-5-(3-trifluoromethyl-4H-l,2,4-triazol-4-yl)phenyl)- l-oxa-7- azaspιro!4,51-dec-3-ene hvdrochloride
Prepared in an analogous fashion to Example 1 using the bromide of Description 8. M.p. 221-224°C (IPA/Et2O); (Found: C, 57.21; H, 5.02; N, 10.27.
C 5H2GClF3N4θ2.1.0H2θ requires C, 57.20; H, 5.38; N, 10.67%); δH (360ιMHz, DaO) 1.84-2.16 (4H, m), 3.04-3.30 (3H, m), 3.58 (IH, m), 3.98 (3H, s, ArOCIl3), 4.35 ( IH, br d, NCHAHBPh), 4.45 (IH, d, J 13.1Hz, NCHAHBPh), 5.00 (2Η, m. 2-CH2), 6.48 (IH, br s, 4-CH=), 7.26 (IH, d, J 9.0Hz, 3'-H), 7.30 (IH, d, J 2.5Hz. 6'-H). 7.49-7.53 (6H, m, ArH); m/z (ES+) 471 ([M+H]+).
EXAMPLE 8
7-Benzyl-3-(2-methoxy-5-(2-trifluoromethyl- lH-imιdazol-l-yl)phenyl)- l -oxa-7- azaspιrol4.δl-dec-3-ene hvdrochloride Prepared in an analogous fashion to Example 1 using the bromide of
Description 9.
(Found: C, 57.43; H, 5.60; N, 7.39. C2GH27CIFΛN3O2.2H2O requires C, 57.62; H, 5.77; N. 7.75%); δH (360MHz, D--0) 1.78-2.14 (4H, m), 3.05 ( IH. m ). 3 I S (2H, m), 3.60 ( IH, ), 3.93 (3H, s, ArOClb), 4.29 (IH, d, J 13.2Hz. NCH.vHnPh), 4.45 (IH, d, J 13.1Hz, NCHAHBPh), 4.94 (2H, m, 2-CH2), 6.42 (111, s, 4-CH=), 7.15 (IH, d, J 8.9Hz, 3'-H), 7.19 (IH, d, J 2.5Hz, 6'-H), 7.26 (IH, d, J 1.2Hz, imidazole H), 7.37 (2H, m, imidazole H and 4'-H) 7.49 (δH, br s, PhH); m/z (ES+) 470 ([M+H]+).
EXAMPLE 9
7-Benzyl-3-(2-methoxy-5-benzyloxyphenyl)- l-oxa-7-azaspiro[4,51dec-3-ene Prepared in an analogous fashion to Example 1 using 4-benzyloxy-2- bromoanisole (Description 10). δH (250MHz, CDCb) 1.60- 1.75 (3H, m), 1.79-1.91 ( IH, m), 2.38-2.59 (4H, m). 3.57 (2H, s), 3.83 (3H, s), 4.91-5.03 (4H, m), 6.60 (IH, s), 6.73-6.86 (3H, m), 7.20-7.45 (10H, m); m/z (ES ) 442 ([M+H]+).
EXAMPLE 10
7-Benzoyl-3-(2-methoxy-5-(5-trifluoromethyl- lH-tetrazol- 1 -vDphenyl)- l-oxa-7- azaspιro[4,51dec-3-ene
Benzoyl chloride (0.10ml, 0.86mmol) was added to a solution of 3-(2- methoxy-5-(5-trifluoromethyl- lH-tetrazol- l-yl)phenyl)- l-oxa-7-azaspιro[4,5]dec- 3-ene hydrochlonde (Desc. 11; 0.33g, 0.79mmol) in pyndine (5ml) at 0°C. The mixture was stirred at 0°C for 1 '/. hours, allowed to warm to room temperature and concentrated in vacuo. 1M Hydrochloric acid (50ml) was added to the residue and the mixture extracted with dichloromethane (2x25ml). The combined extracts were dried (MgSOj), concentrated and the residue purified by flash chromatography, eluting with 2'/2% methanol in dichloromethane, to afford the title compound as a white foam (0.26g, 68%), which was recrystallised frδtn ethyl acetate/hexane, m.p. 154-156°C; (Found: C, 59.29; H, 4.45; N, 14.15. C2.1H22F3N5O3 requires C, 59.38; H, 4.57; N. 14.43%); δH (360MHz, DMSO-dr„ 353K) 1.62 (IH, m), 1.75-1.85 (3H, m), 3.19 (IH, m), 3.39 (IH, br d. J 12Hz), 3.49 (IH, m), 3.80 (IH, m), 3.94 (3H, s, ArOCH.0, 4.74 (IH, m, 2-CHAHB), 4.89 ( IH. dd. J 12.6. 1.9Hz, 2-CHAHB), 6.52 (IH. br s, 4-CH=), 7.30 (IH, d, J 8.8Hz. 3'-H). 7.37 (5H, m, PhH), 7.55 (IH. d, J 2.6Hz. 6'-H), 7.63 ( IH, dd, J 8.8. 2.6Hz. 4'-H); m/z (ES*) 486 ([M+Hp). EXAMPLE 11
7-(3.4-Dichlorobenzyl)-3-(2-methoxy-5-(5-trifluoromethyl- lH-tetrazol- l- vI)phenyl)- l-oxa-7-azaspιrof4.51dec-3-ene hydrochlonde 3,4-Dichlorobenzyl bromide was added to a mixture of 3-(2-methoxy-5-(5- trifluoromethyl- lH-tetrazol-l-yl)phenyl)- l-oxa-7-azaspιro[4,5]dec-3-ene hydrochloπde (Desc. 11; 200 mg, 0.48mmol) and potassium carbonate (200mg, 1.44mmol) in dimethylformamide (10ml) at room temperature. After stirring for one hour the mixture was poured into water (100ml) and extracted with ethyl acetate (2x50ml). The organic layer was separated, dried (MgSC ), filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with 2, 2.5 and 5% methanol/dichloromethane. Treatment with ethereal hydrogen chloride afforded the hydrochlonde salt which was recrystallised from isopropanol/diethyl ether (58mg, 22%); δn (360MHz, MeOD), 1.81-2.05 (3H, m), 2.17-2.30 (IH, m), 3.04-
3.δ8 (4H, m), 4.05 (3H, s, ArOCHs), 4.37 (2H, m), 5.11 (2H, s), 6.52 (IH, s), 7.35 (IH, m), 7.50 (2H, m), 7.60 (IH, m), 7.68 (IH, m), 7.81 (IH, m); m/z (ES+) 540 ([M+H]+).
EXAMPLE 12
7-(4-Pyrιdyl)-3-(2-methoxy-5-(5-trifluoromethyf-lH-tetrazol- l -yl)phenyl)- l-oxa-7- azaspιro[4,δldec-3-ene dihvdrochloride
Prepared in an analogous fashion to Example 11 using 4-pιcolyl chloride. δH (360MHz, D20) 1.82-2.24 (4H, m), 3.18-3.24 (IH, m), 3.30-3.42 (2H, m), 3.59-3.63 (IH, m), 4.01 (3H, s, ArOCH3), 4.68-4.82 (2H, m), 5.07 (2H, s, NCH2Py), 6.52 (IH, s), 7.31 (IH, d, J 9.0Hz, 3'-H), 7.41 (IH, d, J 2.6Hz, δ'-H), 7.62 (IH, m), 8.16 (2H, d, J 6.5Hz), 8.90 (2H, d, J 6.35Hz); m/z (ES+) 473 ([M+H]+).
EXAMPLE 13 7-(3-Pyrιdyl)-3-(2-methoxy-5-(5-trifluoromethyl-lH-tetrazol- l-yl)phenyl)- l-oxa-7- azaspιrof4,51dec-3-ene dihvdrochloride
Prepared in an analogous fashion to Example 11 using 3-pιcolyl chloride δn (360MHz. D20) 1.88-2.20 (4H, m), 3.07-3.60 (4H, m), 4.00 (3H. s. ArOCH.3), 4.65 (2H, s), 5.05 (2H, s), 6.52 (IH, s), 7.32 (IH, d. J 9.0Hz. 3'-H), 7.43 (IH, m, ArH), 7.61 (IH, m, ArH), 8.11 (IH, m), 8.65 (IH, m) 8.89 (IH, m), 8.98 (IH, m); m/z (ES+) 473 ([M+H]+).
EXAMPLE 14 7-(2-Pyridyl)-3-(2-methoxy-5-(5-trifluoromethvI-lH-tetrazol- l-yl)phenyl)- l-oχa-7- azaspiro [4.5] dec-3-ene dihvdrochloride
Prepared in an analogous fashion to Example 11 using 2-picolyl chloride. M.p. 119-122°C; (Found: C, 50.40; H, 4.91; N, 14.95. C23H25CI2F3N6O2 requires C, 50.65; H, 4.62; N, 15.41%); δH (360MHz, D2O) 1.84-2.22 (4H, m), 3.16- 3.22 (IH, m), 3.28-3.41 (2H, m), 3.58-3.61 (IH, m), 4.00 (3H. s, ArOCH3), 4.54 (2H, q, J 13.8Hz, N-CH2), 5.05 (2H, s, O-CH2), 6.53 (IH, s), 7.29 (IH, d, J 9.1Hz), 7.41 (IH, d, J 2.6Hz), 7.58-7.60 (2H, m), 7.67 (IH, d, J 7.8Hz), 8.00-8.04 (IH, m), 8.68 (IH, m); m/z (ES+) 473 ([M+H]+).
EXAMPLE 15
7-(2-Methoxybenzyl)-3-(2-methoxy-5-(5-trifluoromethyl-lH-tetrazol- l-yl)phenyl)- l-oxa-7-azaspirpr4.51dec-3-ene hvdrochloride Prepared in an analogous fashion to Example 11 using 2-methoxybenzyl chloride.
M.p. 210-214°C; (Found: C, 56.07; H, 4.84; N, 12.90. C25H27CIF3N5O3 requires C, 55.82; H, 5.06; N, 13.02%); δH (360MHz, D2O), 1.82-2.20 (4H. m),
3.01-3.10 (IH, m), 3.21 (2H, m), 3.60-3.64 (IH, m), 3.93 (3H, s), 3.95 (3H, s), 4.40 (2H, q, J 13.4Hz), 5.00-5.08 (2H, m), 6.49 (IH, s), 7.06-7.10 (IH, m), 7.12-7.14
(IH, m), 7.26-7.28 (IH, m), 7.36-7.37 (IH, m), 7.37-7.40 (IH, m), 7.48-7.57 (2H, m); m/z (ES+) 520 ([M+H]+).
EXAMPLE 16 7-(l-Phenylethyl)-3-(2-methoxy-5-(5-trifluoromethyl- lH-tetrazol-l-yl)phenyl)- l - oxa-7-spirof4,51dec-3-ene diastereoisomers A and B
Prepared in an analogous fashion to Example 1 1 using (1 - bromoethybbenzene. Separation of the diastereoisomers was accomplished by flash chromatography followed by preparative layer chromatography eluting with methanol/dichloromethane.
Diastereoisomer A: δH (360MHz, CDCb) 1.38 (3H, d, J 6.8Hz, NCH(Ph)CH ), 1.56-1.78 (4H, m), 2.30-2.42 (2H, m), 2.δ0-2.δ8 (2H, m), 3.δδ (IH, q, J 6.8Hz, NCH(Ph)CH3), 4.00 (3H, s, ArOCH3), 4.98 (2H, , 2-CH2), 6.74 (IH, br s, 4-CH=), 7.08 (IH, d, J 8.9Hz, 3'-H), 7.22-7.37 (7H, m, ArH); m/z (ES+) 486 ([M+H]+).
Diastereoisomer B: δH (360MHz, CDCb) 1.37 (3H, d, J 6.8Hz, NCH(Ph)CH3), 1.56-1.68 (3Η, m), 1.82 (IH, m), 2.46 (4H, m), 3.3δ (IH, q, J 6.8Hz, NCH(Ph)CH3), 3.99 (3H, s, ArOCHs), 4.98 (2H, m, 2-CH2), 6.69 (IH, br s, 4-CH=), 7.07 (IH, d, J 8.9Hz, 3'-H), 7.21-7.36 (7H, m, ArH); m/z (ES+) 486 (fM+H]+).
EXAMPLE 17 7-(2-Phenylethyl)-3-(2-methoxy-δ-('δ-trifluoromethyl-lH-tetrazol- l-yl)phenyl)- l- oxa-7-azaspiro[4,51dec-3-ene hvdrochloride
Prepared in an analogous fashion to Example 11 using (2- bromoethyl)benzene.
(Found: C, 55.62; H, 5.20; N, 12.60. C25H27CIF3N5O2. I.OH2O requires C, 55.61; H, 5.41; N, 12.97%); δH (360MHz, D2O) 1.88-2.10 (4H, m), 3.02-3.13 (3H, m), 3.20 (IH, d, J 12.6Hz), 3.45 (3H, m), 3.60 (IH, m), 4.02 (3H, s. ArOCHs), 5.07 (2H, m, 2-CH2), 6.52 (IH, br s 4-CH=), 7.32-7.35 (4H, m, ArH), 7.40-7.44 (3H, m, ArH), 7.62 (IH, m, ArH); m/z (ES+) 486 ([M+H]+),
EXAMPLE 18
7-Cvclohexyimethyl-3-(2-methoxy-5-(5-trifluoromethyl- lH-tetrazol- l-yl)phenyl)- l-oxa-7-azaspirol4.51dec-3-ene hvdrochloride
Prepared in an analogous fashion to Example 11 using bromomethylcyclohexane. M.p. 213-215°C (IPA/Et2O); δn (360MHz. MeOD) 1.06- 1.39 (5H, m). 1.61-
1.98 (8H, m). 2.16-2.34 (IH, m), 2.84-3.08 (3H, m), 3.10-3.20 (IH, m), 3.36-3.45 (2H, m), 4.02 (3H, s, ArOCH.3), 5.11 (2H. s, OCH2), 6.51 ( IH. s). 7.30-7.3S ( I H, m, ArH), 7.49 ( IH. m, ArH), 756-7.61 (IH, m, ArH): m/z (ES') 478 (M+H)\ EXAMPLE 19
7-(5-Dιmethylamιnomethyl- lH-l,2,3-trιazol-4-yl)methyl-3-(2-methoxy-5-(5- trifluoromethyl- lH-tetrazol-l-yl)phenyl)- l-oxa-7-azaspιro[4,δ]dec-3-ene dihvdrochloride
3-(2-Methoxy-5-(5-tnfluoromethyl-lH-tetrazol-l-yl)phenyl)- l-oxa-7- azaspιro[4,5]dec-3-ene hydrochlonde (Desc 11; 322. Omg, 0.795mmol) in dimethylformamide (5ml) was added dropwise over 15 minutes to a mixture of l,4-dιchloro-2-butyne (0.41ml, 4.1mmol) and potassium carbonate (0.88g, 6 4mmol) in dimethylformamide (5ml) at 65°C. The reaction mixture was stirred at 65°C for 2 hours, allowed to cool and poured into water (100ml) The mixture was extracted with ethyl acetate (2x50ml), the extracts washed with brine (δOml), combined and dried (MgSO4). The residue after evaporated was purified by flash chromatography, eluting with ethyl acetate/hexane (T l, 2 1 then 3 1) to give an oil (151.2mg) This oil (145.3mg) was dissolved in dimethylsulfoxide
(3ml), sodium azide (27.9mg) was added and the mixture stirred at room temperature overnight (16 hours). The reaction mixture was diluted with saturated ammonium chloride solution (40ml) and extracted with ethyl acetate (2x20ml). The extracts were washed with brme (20ml), combined, dried (MgSO4) and evaporated under high vacuum at room temperature The residual brown oil
( 145 6mg) was dissolved in 1,4-dιoxane (2ml) and added to dimethvlamine ( 1.5ml) at -78°C The mixture was sealed in a tube and heated at 85°C overnight (18 hours) The reaction mixture was concentrated m vacuo and the residue purified by flash chromatography elutmg with dichloromethane/methanoP ammonia (90:8 1, 60:8 1 then 45-8- 1) to give a pale brown foam (94 6mg, 24% over 3 steps) The foam was dissolved in methanol/diethyl ether and treated with 1M ethereal hydrogen chloride (0.4ml) The mixture was concentrated in vacuo and triturated with diethyl ether to give a solid which was recrystallised from lsopropanol/diethyl ether to afford the title compound as a buff solid, m.p > 170°C, (Found. C, 45.2δ, H, 5.31, N, 20 34
Figure imgf000075_0001
1 0H2O requires C, 45 25, H, 5.28, N, 20.65%), δH (360MHz. D2O) 1 82-2 12 (4H, m), 2 96 (6H, s. NMe >), 3 09 (IH, m). 3.26 (IH, br d, J 12 4Hz), 3 45 (IH m), 3.56 ( IH. m), 4 02 (3H, s, A1OCH3), 4 56 (2H, s, CH2N), 4 58 (2H, s CH.N). 5 07 (2H, m, 2-CH2), 5.54 (IH, br s, 4-CH=), 7.33 (IH. d, J 9 0Hz, 3'-H), 7 43 (IH. d J 2.6Hz, 6'-H), 7.63 (IH, dd, J 9.0, 2.6Hz, 4'-H); m/z (ES+) 520 ([M+H]4)
EXAMPLE 20 (±)-(3R*. 5R*)-7-Benzyl-3-(2-methoxy-δ-(δ-trιfluoromethyl-lH-tetrazol- l- yl)phenyI)-l-oxa-7-azaspiro[4,δldecane hydrochlonde and (+H3S*. δR*)-7- BenzvI-3-(2-methoxy-5-(5-trifluoromethvI- lH-tetrazol-l -yl)phenyl)- l -oxa-7- azaspιro[4,51decane hvdrochloride
Prepared in an analogous fashion to Example 11, using the mixture of diastereoisomers of Description 12 and benzyl bromide The diastereoisomers were separated by flash chromatography, eluting with ethyl acetate/hexane (1:2, 2:3 then 1: 1), to afford pure major diastereomer [(3R*, 5R*)] followed by preparative layer chromatography, eluting three times with 1:4 ethyl acetate hexane, to affect purification of the minor diastereoisomer [(3S*,δR*)] Hvdrochloride salts were prepared as before
Data for (±)-(3R*, 5R*)-7-benzyl-3-(2-methoxy-5-(5-tπfluoromethyl- lH- tetrazol-l-yl)phenyl)- l-oxa-7-azaspiro[4,5]decane hydrochlo de: δH (500MHz, MeOD) 1.66 (IH, m, 10-Hax), 1.85 (2H, m, 9-Heq, 10-Heq), 1.98 (IH, dd, J 13.9Hz, 4-H ), 2.17 (IH, m, 9-Hax), 2.28 (IH, m, 4-Heq), 2.97 (2H, m, 8- Has, 6-Hax), 3.33 (IH, m, 6-He„), 3.47 (IH, m, 8-Heq), 3.80 (IH. m, 3-H), 3 89 (IH. m, 2-Haχ), 3.95 (3H, s, ArOCH.0, 4.19 (IH, t, J 7 8Hz, 2-IIeq), 1.27 (IH. d. J 13Hz, NCHAHBPh), 4.39 (IH, d, J 13Hz, NCHAHBPh), 7.22 (1Η, d, J 8.4Ηz, 3'-H), 7.5δ (7H, m, ArH); m/z (ES*) 474 ([M+H]+)
Data for (±)-(3S*, 5R*)-7-benzyl-3-(2-methoxy-5-(δ-trifluoromethyl- lH- tetrazol- l-yl)phenyl)-l-oxa-7-azaspιro[4,5]decane hydrochlonde: δH (500MHz, MeOD) 1.64 (IH, dt, J 4, 13 5Hz, 10-Hax), 1.90 (IH. m, 9-Heq), 1 94 (IH, m, 4-Hax), 2.01 (IH, m, 10-Heq), 2.17 (IH, m, 9-Heq), 2.22 (IH. m. 4-Heq), 3.01 (2H, m, 8-Haλ, 6-Hax), 3.50 (IH, m, 8-Heq), 3 71 (IH, t, J 9.0Hz. 2-Hax), 3.87 (3H, s, ArOCH3), 3.89 (IH, m, 3-H), 4.24 (2H, m, NCHAHβPh. 2-Hoq), 4.40 ( IH, d, J 13.1Hz, NCH
Figure imgf000076_0001
7.20 (IH, d, J 8 4Hz, 3'-H), 7 42 (IH, d, J 2.5Hz 6'-H),
7.50 (6H, m, ArH), m/z (ES+) 474 (PM+H]+) EXAMPLE 21
(+)-(3R*. 5R*)-7-BenzovI-3-(2-methoxy-5-(5-trιfluoromethyl- lH-tetrazol- l- yl)phenyl)- l-oxa-7-azaspιrof4.51decane
Prepared in an analogous fashion to Example 10 using the piperidine of Description 13 δH (360MHz, DMSO-dc, 353K) 1 49 (IH, m), 1 75 (4H m), 2 19 (IH, m), 3 28 (IH, m), 3 44 (2H, m), 3 65 (3H, m), 3 92 (3H, s, ArOCH3), 4 03 (2H, m) 7 23 (IH, d, J 8 7Hz, 3'-H), 7 37 (2H, m, PhH), 7 44 (3H, m, PhH) 7 57 (IH, dd J 8 7, 2 6Hz, 4'-H), 7 62 (IH, d, J 2 6Hz, 6'-H), m/z (ES+) 488 ([M+H]+)
EXAMPLE 22
(±)-(3R*. 5R*)-7-(2-Phenylethyl)-3-(2-methoxy-5-(5-tnfluoromethyl-lH-tetrazol- l- yl)phenyl)- l -oxa-7 azaspιro[4.5ldecane hvdrochloride
Prepared in an analogous fashion to Example 11 using the piperidine of Description 13 and (2-bromoethyl)benzene
M p 187- 189°C (IPA/Et2O), δH (360MHz,D2O) 1 75-2 10 (5H, m), 2 28-2 39 (IH, m), 3 00-3 09 (2H, m), 3 10-3 22 (2H, m), 3.41-3 49 (2H, m), 3 50-3 59 (2H, m), 3 81-3 99 (2H, m), 3 99 (3H, s, ArOCH3), 4 20-4 33 (IH, m), 7 25 (IH, d J 8 8Hz, 3'-H), 7 37-7 56 (7H, m), m/z (ES+) 488 ([M+H1+)
EXAMPLE 23 7-Benzyl-3-(2-methoxy-5-(5-methyl- lH-l,2,4-trιazol- l-yl)phenyl)-l-oxa-7- azaspιro!4.51-dec-3-ene hvdrochloride
Prepared in an analogous fashion to Example 1 using the bromide of Description 15
M p >130°C (amorphous solid), 6H (360MHz, D2O) 1 82-2 10 (4H, m) 2 38 (3H, s, 5"-CH ), 3 00-3 26 (3H, m), 3 54 (IH, m), 3 93 (3H, s ArOCH , 4 30 (IH, br d NCHAHBPh), 4 41 (IH, d, J 13 1Hz, NCHAHBPh), 4 97 (2Η, m, 2-CH.) 6 42 (IH, br s, 4-CH=), 7 19 (2H, m, 3'-H, 6'-H), 7 41 (IH, dd, J 8 9 2 5Hz, 4'-H) 7 50 (5H, br s, PhH) 8 01 (IH, s, 3"-H), m/z (ES+) 417 f[M+H]+) EXAMPLE 24
7-Benzyl-3-(2-methoxy-5-(5-trifluoromethyl-lH- l,2,4-trιazol- l-yl)phenyl)- l -oxa-7- azaspiro[4,51-dec-3-ene hydrogen oxalate
Prepared in an analogous fashion to Example 1 using the bromide of Description 16. δH (360MHz, D2O) 1.78-2.12 (4H, m), 3.03 (IH, m), 3.15 (IH, d, J 12.5Hz), 3.26 (IH, d, J 12.5Hz), 3.56 (IH, m), 3.96 (3H, s, ArOCHs), 4.30 (IH, d, J 13.2 Hz, NCHAHBPh), 4.42 (IH, d, J 13.2Hz, NCHAHBPh), 4.98 (2Η, m, 2-CH2), 6.44 (IH, br s, 4-CH=), 7.22 (IH, d, J 8.9Hz, 3'-H), 7.31 (IH, d, J 2.6Hz, 6'-H), 7.51 (6H, m, ArH), 8.30 (IH, s, 3"-H); m/z (ES+) 471 ([M+H]+).
EXAMPLE 25
7-Benzyl-3-(2-methoxy-5-(N-methyltrifluoroacetamido)-l-oxa-7-azaspirol4.51dec-
3-ene hvdrochloride Prepared in an analogous manner to Example 1 using 2-bromo-o-(N- methyltrifluoroacetamido)anisole (Desc.17).
5H (360MHz, D2O) 1.78-2.05 (4H, m), 3.01-3.19 (3H, m), 3.27 (3H, s, N-
CH ), 3.50 (IH, m), 3.88 (3H, s, ArOCHa), 4.29 (IH, br d, NCHAHBPh), 4.40 (IH, d, J 13.0Hz, NCHAHBPh), 4.97 (2Η, , 2-CH2), 6.37 (IH, br s, 4-H), 7.10 (IH, d J 8.9Hz, ArH), 7.15 (IH, m, ArH), 7.31 (IH, m, ArH), 7.48 (5H , br s, PhH); m/z
(ES+) 461 ([M+H]+).
EXAMPLE 26
7-Benzyl-3-(2-ιsopropoxy-5-(2-trifluoromethyl-lH-imιdazol- l-yl)phenyl)- l-oxa-7- azaspirol4.51dec-3-ene hvdrochloride
Prepared in an analogous fashion to Example 1 using l-(3-bromo-4- ιsopropoxyphenyl)-2-trifluoromethyl-l//-imidazole (Desc. 18). δH (360 MHz, D2O) 1.23 (3H, d, J 5.9Hz), 1.24 (3H, d, J 5.9Hz), 1.80-2.06
(4H, m), 3.02-3.12 (3H, ra), 3.57 (IH, m), 4.19 (IH, d, J 13.1 Hz, NCHACHBPh), 4.43 (IH, d. J 13.2 Hz, NCHACHβPh), 4.80-4.91 (2Η, m, 2-CHz), 6.28 (IH. s, 4-H),
7.00 (IH, d. J 9.0 Hz, 3'-H), 7.12 (IH, m, ArH), 7.18 (IH, d, J 1.15Hz. lmidazole-
H), 7.20-7.24 (2H, m, ArH, lmidazole-H), 7.37-7.44 (5H, m, Ph-H); m/z (ES") 498
( [M+H]+). EXAMPLE 27
7-Benzyl-3-(2-methoxy-5-(5-trifluoromethyl- lH-tetrazol- l-yl)methyIphenvI)- l- oxa-7-azaspiro[4.δ1dec-3-ene hvdrochloride Prepared in an analogous fashion to Example 1 using the bromide of
Description 19. δH (360 MHz, D2O) 1.72-2.14 (4H, m), 3.01-3.23 (3H, m), 3.δ6 (IH, m), 3.91 (3H, s, ArOCHs), 4.2δ (IH, d, J 13.2Hz, NCHACHBPh), 4.40 (IH, d, J 13.2 Hz, NCHACHBPh), 4.88-4.97 (2Η, m, 2-CH2), δ.26-δ.33 (2H, m), 6.39 (IH, s. 4-H), 7.18 (IH, d, 8.7 Hz, 3'-H), 7.29 (IH, d, J 2.1Hz, 6'-H), 7.46 (5H, s, Ph-H), 7 55 ( IH, dd,
J 8.7, 2.1Hz, 4'-H); m/z (ES+) 486 ([M+H]+).
EXAMPLE 28
(±)-(3R*. 5R* -7-Benzyl-3-(2-methoxy-5-(2-trifluoromethyl-lH-imιdazol- l- yl)phenyl)- l-oxa-7-azaspiro[4.5ldecane hydrogen oxalate
Prepared in an analogous fashion to Example 11 using the piperidine of Description 20 and benzyl bromide.
(Found: C, δ9.38; H, 5.11; N, 7.12. C26H28F3N3θ2.C2H2θ .0.25H2O requires C, 59.41; H, 5.43; N, 7.42%); δH (360MHz, D2O) 1.68 (IH, m), 1.80-2.07 (4H. m), 2.25 (IH, m), 2.98 (2H, m), 3.40 (IH, br d, J 12.6Hz), 3.52 (IH, m), 3.76 (IH, m),
3.87 (IH, m), 3.89 (3H, s, ArOCHs), 4.13 (IH, m), 4.29 (IH, d. J 13.2 Hz. NCHAHBPh), 4.41 (IH, d, J 13.2Hz, NCHAHBPh), 7.12 (1Η, d, J 8.7Ηz, 3'-H), 7.23 (IH, d, J 1.1Hz, imidazole H), 7.35 (3H, m, ArH), 7.54 (5H, m. PhH); m/z (ES+) 472 ([M+H]+).
EXAMPLE 29 (±)-(3R*. 5R*. l lR*/S*)-3-(2-Methoxy-5-(2-trifluoromethyl-lH-ιmιdazol- l- yl)phenyl)-7-(l-phenyl)ethyl- l -oxa-7-azaspιro[4,51decane hvdrochloride
Prepared in an analogous fashion to Example 11 using the piperidine of Description 20 and 1-bromoethylbenzene.
OH (360MHZ, D2O) 1.63-2.27 (8H. m), 2.80-2.95 (2H, m), 3 40-3 94 (7H, m), 1 18 (IH, m), 4.58 (IH, m), 7.15 (IH, dd. 8.7, 3.2Hz, 4'-H), 7.26 ( IH, d. J 1.2Hz, lmidazole-H), 7.37-7.41 (3H. m. ArH), 7 58 (5H, s. PhH): m/z (ES" ) 486 i [M^H]+) EXAMPLE 30
(+)-(3R*. 5R*)-3-(2-Methoxy-5-(2-trifluoromethyl-lH-imιdazol- l-yl)phenyl)-7-(2- phenyl)ethyl- l-oxa-7-azaspιrof4,δldecane hvdrochloride Prepared in an analogous fashion to Example 11 using the piperidine of
Description 20 and 2-bromoethylbenzene. δH (360 MHz, D2O) 1.71-2.10 (5H, m), 2.27 (IH, m), 3.00-3.17 (4H, m), 3.39-3.55 (4H, m), 3.86-3.88 (2H, m), 3.92 (3H, s, ArOCHs), 4.24 (IH, m), 7.14 (IH, m, ArH), 7.23 (IH, d, J 1.2Hz, imidazole-H), 7.35-7.43 (8H, m, ArH); m/z (ES+) 486 ([M+H]+).
EXAMPLE 31
(+)-(3R*. 5R*)-3-(2-Methoxy-5-(2-trifluoromethvI-lH-ιmidazol-l-yl)phenyl)-7- phenylacetyl- l-oxa-7-azaspiror4,51decane Prepared in an analogous fashion to Example 10 using the piperidine of
Description 20 and phenylacetyl chloride. δH (360MHz, CDCb; mixture of rotamers) 1.18-1.80 (9H, m), 1.90-1.99 and 2.14-2.19 (IH, dd, J 12.4, 7.8 Hz), 3.21-4.27 (10H, m), 6.82 (IH, m), 7.03-7.25 (9H, m); m/z (ES+) 500 ([M+H]*).
EXAMPLE 32 (±)-(3R*. 5R*)-7-(2-Oxo-2-phenyl)ethyl-3-(2-methoxy-5-(2-trifluoromethyl- lH- imidazol-l-yl)phenyl)-l -oxa-7-azaspiro[4,51decane hydrogen oxalate
Prepared in an analogous fashion to Example 11 using the piperidine of Description 20 and phenacyl bromide. δH (360MHz, D2O) 1.82 (2H, m), 1.93 (2H, m), 2.10 (IH, m), 2.22 (IH, m), 3.03 (IH, m), 3.22 (IH, m), 3.48 (IH, m), 3.68 (IH, m), 3.84 (4H, m), 3.97 (IH, m), 4.39 (IH, m). 4.81 (IH, d, J 17.9Hz, NCHAHBCOPh), 4.97 (IH, d, J 17.9Hz, NCHAHBCOPh), 7.07 (1Η, d J 9.4Ηz, 3'-H), 7.17 (IH, d, J 1.0Hz, imidazole H), 7.33 (3H, m, ArH), 7.54 (2H, m, ArH), 7.71 (IH, t, J 7.5Hz, ArH), 7.93 (2H. d, J
7.5Hz, ArH); m/z (ES+) 500 ([M+H]+). EXAMPLE 33
(±)-(3R*. 5R*. 12S*/R*)-7-(2-Hvdroxy-2-phenyl)ethyl-3-(2-methoxy-5-(2- trιfluoromethyl- lH-ιmιdazol- l-yl)phenyl)- l-oxa-7-azaspιro[4,δldecane hydrogen oxalate Sodium borohydride (12mg, 0.32mmol) was added to a solution of (±)-(3R*,
5R*)-7-phenacyl-3-(2-methoxy-5-(2-trιfluoromethyl-lH-ιmιdazol- l-yl)phenyl)- l- oxa-7-azaspιro[4,5]decane (105.9mg, 0.212mmol) in ethanol (2ml) and the mixture stirred at room temperature for 4 hours The mixture was poured into water (50ml) and extracted with ethyl acetate (2 x 20ml). The extracts were washed with brine (20ml), combined, dried (MgSO4) and concentrated. The residue was purified by flash chromatography, eluting with 5% then 7.5% methanol m dichloromethane to give (±)-(3R*, 5R*. 12S*/R*)-7-(2-hydroxy-2- phenylethyl)-3-(2-methoxy-5-(2-trιfluoromethyl-lH-ιmιdazol- l-yl)phenyl)- l-oxa- 7-azaspιro[4,5]decane_(86.0mg, 81%). The free base was dissolved in ether and treated with oxalic acid (lδ.7mg) in ether. The resulting precipitate was collected under suction, washed with ether and dried in vacuo to afford the title compound (75 lmg); (Found: C, 58.89; H, 5.11; N, 6.87. C27H30F3N3O3 C2H2O4 requires C, 58.88, H, 5.45; N, 7 10%), δH (360MHz, D2O) 1 72-2.37 (6H, m), 3 11 (2H, m), 3.34-3.96 (10H, m), 4.27 (IH, m), 5.25 (IH, m), 7.13 (IH, d, J 9.3Hz, 3'- H), 7.22 (IH, br s, imidazole H), 7 36 (3H, m, ArH), 7 47 (5H m, ArH), m/z (ES+)
502 (1M+H]+)
EXAMPLE 34
(±)-(3R*. 5R*. l lS*/R*)-3-(2-Methoxy-5-(2-trιfluoromethyl- lH-ιmιdazol- l- yl)phenyl)-7-(l-methyl-2-phenyl)ethyl- l-oxa-7-azaspιrof4.5f decane hydrochlonde
Prepared in an analogous fashion to Example 11 using the piperidine of Description 20 and 2-bromo-l-phenylpropane δH (360MHz, D2O) 0.74-0.81 (3H, m), 1 55 (IH, m), 1.79-2.31 (7H, m), 2.62- 2 94 (2H, m), 3 40-3.60 (2H, m), 3 88-3.91 (5H, m), 4 11-4 28 (2H, m), 7 11-7.13 (IH. m), 7.22 (lH,d, J 1.2Hz, imidazole-H), 7 33-7 37 (SH, m) 7 54 (5H, m) m/z
(ES*) 500 ([M+Hn EXAMPLE 35
(±)-(3R*. 5R*)-7-(Indan-2-\d)-3-(2-methoxy-5-(2-trιfluoromethyl- lH-imidazol- 1 - yl)phenyl)- l-oxa-7-azaspirol4,5]decane
(±)-(3R*,5R*)-3-(2-Methoxy-5-(2-trifluoromethyl- lH-ιmιdazol- l-yl)phenyl)- l-oxa-7-azaspιro[4.5]-decane (free base of Desc.20; 180mg, 0.47mmol) and mdan-
2-one (75 mg, 0.57mmol) were stirred at reflux in toluene (20ml) for 18 hours, under Dean-Stark conditions. The mixture was concentrated in vacuo then redissolved in methanol (30ml) and glacial acetic acid (1ml). Sodium cyanoborohydride (35mg, 0.55mmol) was added portionwise. The mixture was stirred at room temperature for 72 hours, concentrated in vacuo and the residue partitioned between 2N NaOH and ethyl acetate. The organic layer was separated, dried (MgSO4), filtered and concentrated. Chromatography on silica gel eluting with 120:8: 1 dιchloromethane:methanol:ammonia gave the title compound as a tan solid (22mg); δH (360MHz CDCb) 1.58- 1.95 (7H, m), 2 48 (4H, m), 2.99-3.22 (4H, m), 3.73-3.82 (2H, m), 3.91 (3H, s, ArOCHs), 4.27 (IH, m), 6.90
(IH, d, J 8.6Hz, 3'-H), 7.11-7.26 (8H, m, ArH); m/z (ES+) 498 ([M+H]+).
EXAMPLE 36
(3R. 5R. l lS)-7-(l-Methyl-2-phenyl)ethyl-3-(2-methoxy-5-(5-trifluoromethyl- lH- tetrazol- l-yl)phenylV l-oxa-7-azaspιrof4.51decane hydrochlonde and (3S. 5S, l lS)-7-( l-methvI-2-phenyl)ethyl-3-(2-methoxy-δ-(5-trιfluoromethyl- lH-tetrazol- l- vQphenyl)- l-oxa-7-azaspιro[4.δf decane hvdrochloride
A mixture of (±)-(3R*, δR*)-3-(2-methoxy-5-(δ-trifluoromethyl-lH-tetrazol- l-yl)phenyl)- l-oxa-7-azaspιro[4,5]decane (Desc. 13; 167. Omg, 0.436mmol), (2R)- 1 - phenyl-2-0 -toluenesulfonyloxy)propane (Desc.21; 238.6mg, 0.822mmol) and potassium carbonate (186.8mg, 1.35mmol) in dimethylformamide (4ml) was stirred at room temperature overnight (24 hours). Further portions of (2R)- 1- phenyl-2-0 -toluenesulfonyloxy)propane (231. δmg, 0.797mmol) and potassium carbonate (182. lmg, 1.32mmol) were added and the mixture stirred at 60°C for 24 hours. Finally, more (2R)- l-phenyl-2- toluenesulfonyloxy)propane
( 128.2mg, 0.442mmol) was added and the mixture stirred at 80°C for 5 hours The reaction mixture was poured into water (50ml) and extracted with ethyl acetate (2 x 25ml). The extracts were washed with brine (δϋml), combined, dried (MgSO4) and concentrated. The residue was purified by flash chromatography, eluting with 1:2 then 1: 1 ethyl acetate/hexane, to give a partial separation of the two diastereoisomers. These were further purified by preparative layer chromatography and the hydrochlonde salts prepared to afford the title compounds, diastereoisomer A (20.1mg); [α]π -9° (c 1.0, MeOH); (Found: C, 57.13;
H, 5 69; N, 12.56. C2GHHCIF3N5O2.O.5H2O requires C, 57.09: H, 5.90; N, 12 80%); δH (500MHz, D.O) 1.30 (3H, d, J 6.7Hz, CHCH3), 1.82 (2Η, m), 2.03 (3H, m), 2.39 (IH, m), 2.86 (IH, m), 3.21 (2H, m), 3.30 (IH, m), 3.51 (2H, m), 3.67 (IH, m), 3.95 (2H, m), 3.98 (3H, s, AJ-OCH3), 4.28 (IH, m), 7.27 (IH, d, J 8.8Hz, 3'-H), 7.38 (3H, m, ArH), 7.45 (2H, m, ArH), 7.55 (2H, m, ArH); m/z (ES+) 502 ([M+H]+) and diastereoisomer B (17 7mg); [α]n +19° (c 1.0, MeOH); (Found- C, 56.25: H. 5.62; N. 12.16. C2r,H3iClF3N5θ2.H2θ requires C, δ6.16; H, δ.98; N, 12.60%); δH (δOOMHz, D2O) 1.14 (3H, d, J 6.7Hz, CHCH3), 1.66 (2Η, m), 1 78 (IH, m), 1.91 (2H, m), 2.24 (IH, m), 2.84 (IH, m), 3.05 (3H, m), 3.22 (IH, br d, J 10.7Hz), 3.35 (IH, d, J 12.4Hz), 3.56 (IH, m), 3.79 (2H, m), 3.84 (3H, s, ArOCHs), 4.13 (IH, m),
7.12 (IH, d, J 8.8Hz, 3'-H), 7.24 (3H, m, ArH), 7.31 (2H, m, ArH), 7.49 (2H, m, ArH); m/z (ES+) 502 ([M+H]+).
EXAMPLE 37 (3R. 5R. l lR)-7-( l-MethvI-2-phenyl)ethyl-3-(2-methoxy-5-(5-trιfluoromethyl- lH- tetrazol- l-yl)phenyl)-l-oxa-7-azaspιro[4,δ1decane hvdrochloride and (3S. 5S. llR)-7-(l-methyl-2-phenyl)ethyl-3-(2-methoxy-5-(5-trιfluoromethyl- lH-tetrazol- l-yl)phenyl)- l-oxa-7-azaspιroI4,51decane hvdrochloride
Prepared in an analogous manner to Example 36, using (2S)- l-phenyl-2- ( -toluenesulfonyloxy)propane (prepared as Description 21)
Diastereoisomer A: [c +10° (c 1.0, MeOH); (Found: C, 57.22; H, 5.57, N, 12.64. C2GH3IC1F3N O2.0.5H2O requires C, 57.09; H, 5.90; N, 12.80%); δH (360MHz, CD3OD) 1.26 (3H, d, J 6.2Hz, CHCH3), 1.76 (1Η, m), 1.89 (2Η. m), 2.04 (IH, m), 2.17 (IH, m), 2.38 (IH, m), 2.73 (IH, m), 3.19 (2H, m), 3.30-3.56 (4H, m), 3.96 (211, m). 3 99 (311. s, ArOCHs), 4 31 (IH. m), 7.23-7 38 (6H. m, ArH). 7 52
(211, m, ArH). m/z (EST) 502 (fM+H]+).
Diastereoisomer B: [α]D - 16° (c 1.0, MeOH); (Found- C. 56 71: H 5 78; N 12.41 C2(,H3i(TFιN-,O'_ 0 7H20 requires C, 56.71. H, 5 93. N 12 72%). OH (500MHz, CDsOD) 1.26 (3H, d, J 6.4Hz, CHCH3), 1 77 (1 Η, m), 1.92 (2Η, m), 2.07 (IH, m), 2.26 (IH, m), 2.42 (IH, m), 2.94 (IH, m), 3.21 (311, ra), 3.36 (IH, m), 3 51 (IH, m), 3.61 (IH, m), 3.98 (2H, m), 4.02 (3H, s, ArOCH3), 4 35 (IH, m), 7 27 (IH, d, J 8.7Hz, 3'-H), 7.33 (3H, m, ArH), 7.39 (2H, m, ArH), 7 54 ( IH, dd, J 8 7, 2.6Hz, 4'-H), 7.58 (IH, d, J 2.6Hz, 6'-H); m/z (ES+) 502 ([M+H]+).
EXAMPLE 38
(±)-(3R*. 5R*)-7-Benzyl-3-(2-methoxy-5-(3-trifluoromethvI-4H- 1.2.4-trιazol-4- yl)phenyl)-8-oxo-l-oxa-7-azasριro[4,51decane A mixture of (±)-(3R*, 5R*)-3-(2-methoxy-5-(3-trιfluoromethyl-4H- 1,2,4- tnazol-4-yl)phenyl)-l-oxa-7-azaspιro[4,5]decane and (±)-(3S*. 5R*)-3-(2-methoxy- 5-(3-trιfluoromethyl-4H-l,2,4-trιazol-4-yl)phenyl)-l-oxa-7-azaspιro[4,5]decane [1.5: 1 ratio; prepared by hydrogenation 7-benzyl-3-(2-methoxy-5-(3- tπfluoromethyl-4H- l,2,4-trιazol-4-yl)phenyl)-l-oxa-7-azaspιro[4,5]-dec-3-ene (Ex 7) in an analogous manner to Desc. 12] (295.9mg, 0.706mmol) in dichloromethane (10ml) was treated with tnethylamine (0.30ml, 2.15mmol) and acetyl chloride (0.06ml, 0.84mmol) The mixture was stirred at room temperature for 20 hours, diluted with dichloromethane (10ml) and washed with 1M hydrochloric acid (40ml) then saturated sodium hydrogen carbonate (40ml) The dichloromethane phase was dried (MgSO4) and concentrated in vacuo to afford a crude mixture of acetyl pipendines, m/z (ES ) 42δ (PM+H] ) This mixture was dissolved in ethyl acetate (10ml) and treated with 10% aqueous sodium periodate (10ml) and ruthemum(IV) oxide hydrate (lOmg). The reaction mixture was stirred at room temperature for 4 5 hours, the phases separated and the aqueous phase extracted with ethyl acetate (10ml). The organic extracts were combined and stirred with 2-propanol (10ml) for 3 hours The mixture was filtered and concentrated in vacuo. The residue was dissolved in ethyl acetate (20ml), diluted with hexane (10ml) and stirred with basic alumina overnight. The mixture was filtered and the alumina washed with dichloromethane followed by 10% methanol in dichloromethane. The filtrate w as evaporated and the residue purified by preparative layer chromatography eluting with 5% methanol in dichloromethane, to afford a mixture of pipeπdones (34 6mg), m/z (ES*) 397 ([M+H]+) This material was dissolved in THF (5ml) and treated successively with 1.0M sodium bιs(tnmethylsιlyl)amιde in THF (0 11ml 0 llmmol) and benzyl bromide (12μl, 0 lOmmoi) The mixture was stirred at roo temperature for 3 hours, at reflux for 2 hours and then at room temperature overnight The reaction mixture was poured into water (50ml) and extracted with ethyl acetate (2 x 25ml) The extracts were combined, dried (M SO4) concentrated and the residue purified by preparative layer chromatography, eluting five times with 2.5% methanol in dichloromethane, to afford the title compound (14 2mg), δn (360MHz, CDCb) 1.83 (IH, dd, J 12 8, 8 8Hz, 4-H- , 1 95 (2H, m, 10-Ha, 10-Hb), 2.22 (IH, dd, J 12.8, 8 2Hz, 4-Hb), 2 48 (IH, dt, J 17 8. 6 1Hz. 9-Ha), 2 75 (IH, m, 9-Hb), 3.18 (IH, d, J 12 4Hz, 6-Ha), 3 27 (IH, d, J
12 4Hz, 6-Hb), 3 71 (IH, m, 3-H), 3 82 (IH, apparent t, J 8Hz, 2-Ha), 3 89 (3H, s, A1OCH3), 4 12 (IH, dd, J 8 7, 7 1Hz, 2-Hb), 4 57 (IH, d, J 14 8Hz, NCHAHBPh), 4 66 (IH, d, J 14 8Hz, NCHAHBPh), 6.95 (1Η, d, J 8 5Ηz, 3'-H), 7 18-7 36 (7H, m, ArH), 8 29 (IH, s, tnazole H), m/z (ES+) 487 ([M+H]+)

Claims

CLAIMS:
A compound of the formula (I):
Figure imgf000086_0001
(I) wherein
R represents Ci-ualkyl, C2-oalkenyl, C2-r>alkynyl, C3-7cycloalkyl, C;i 7cycloalkylCι.4alkyl, which groups are optionally substituted by a group selected from hydroxy, Cicalkoxy or NRaRb, where Ra and Rb each independently represent hydrogen or Cι.4alkyl; or R represents a Cι.4alkyl group substituted by the group Ar, and optionally further substituted by one or both of the groups R and R5;
R1 represents hydrogen, hydroxy, Ci-ealkyl, C.-ealkenyl, C∑-ealkynyl, C-i.7cycl0a.kyl, C.i-7cycloalkylCι-4alkyl, Ci-calkoxy, fluoroCi-ϋaikyl, fluoroCi ήalkoxy, hydroxyCι-4alkyi,
Figure imgf000086_0002
Ci-oalkoxyCualkoxy.
[luoroCu-.alkoxyCι-4alkyl, C'2-Galkenyloxy, C3-7cycloalkoxy, C 7cycloalkylCι.4alkoxy, phenoxy, benzyloxy, cyano, halogen, tπmethylsilyl, nitro, NRaRb, SRa, SORa, S02Ra, OSO2R1'. COR", CO2R", CONR»Rb, S02NRaRb, or OCi.-ialkylNR-R1-, where Ra and R each independently represent hydrogen, C1.4a.kyl or fluoroCι-4alkyl; R represents hydrogen, halogen, Ci-calkyl or Ci-nalkoxy; or when R- is adjacent to R1, they may be joined together such that there is formed a 5- or 6-membered saturated or unsaturated ring containing one or two atoms selected from nitrogen, oxygen and sulphur, which ring is optionally substituted by a grouj) selected from Ci-ialkyl, CF.-i, =0 or =S; Rό represents hydrogen, halogen, Cι-ι;alkyl, Cv.fialkenyl, C2-c-,alkynyl. fkioroCi.,;alkyl. Cu>alkoxy, fluoroCi-oalkoxy, C.3-7cycloalkyl, C.;.7cycloalkylCι .ιalkyl, hvdroxy, phenoxy, benzyloxy, fπmethylsilyi, nitro, cyano. SR '. SOR . S( )2R ', N IMi1'. COR". O-Al". CONR"Rl\ St bNR R1'. Ci - .alkylNR-R . NR'CO R1. or Ci-talkyl substituted by a Cι-»alkoxy, hydroxy, cyano or COaR3 group, where Rn and R are as previously defined and Rd is Ci-βalkyl, Ci-calkoxy, fluoroCi-όalkyl or phenyl; or R3 represents a 5- or 6-membered aromatic heterocychc group containing 1, 2, 3 or 4 heteroatoms, selected from nitrogen, oxygen and sulphur, which group is optionally substituted by one or two groups selected from Cι-r,alkyl, Ci-βalkoxy, C3-7C,ycloalkyl, C3-7cycloalkylG-4alkyl, trifluoromethyl, OCF3, NO2, CN, SR", SORa, SO2Ra, CORa, C02Rn, phenyl, -(CH2)rNRaRb, -(CH2)rNRaCURb, -(CH2)rCONR"Rb, or CH2C(0)Ra, where Ra and Rb are each independently hydrogen or Cι-4alkyl and r is zero, 1 or 2;
R4 and R5 each independently represent hydroxy, Cι.4alkyl, Ci- lkoxyCualkyl, hydroxyCι-4alkyl or Cι.4alkylNR°Rb where Ra and Rb are each independently hydrogen or C1.4a.kyl, or together R and Rs represent an oxo grouj) or when R4 and R5 are attached to the same carbon atom, they may be joined together to form a C3-5cycloalkyl ring;
Ar represents phenyl optionally substituted by one or two substituents selected from halogen, Ci-βalkyl, Ci-ealkoxy, CF3, OCF3, NO2, CN, SRa, SORa, SO2R'. CORa. C02Ra. (CH2)rCONRaRb, (CH2)rNR"Rb or (CH2)rNRaCORb, where Ra and Rb are independently hydrogen or
Figure imgf000087_0001
and r is zero. 1 or 2; or Ar represents a 5-membered or 6-membered heterocychc ring containing 1 , 2 or 3 nitrogen atoms optionally substituted by = or =8 and optionally substituted by a group of the formula ZNR7R8 where
Z is Ci-βalkylene or C3-βcycloalkyl;
R7 is hydrogen or Ci-ialkyl, C3-7cycloalkyI, C:,-7cycloalkylCι-4alkyl, or -4alkyl substituted by Cicalkoxy or hydroxyl;
RH is hydrogen or Cualkyl, C.3-7cycloalkyl, C.v:eycloalkylCι-4alkyl, or (lalkyl substituted by Cicalkoxy, hydroxyl or a 4. 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, 0 and S; or R7, R* and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms, optionally substituted by one or two groups selected from hydroxy or Cicalkoxy oj tιonally substituted by a Cicalkoxy or hydroxyl groiq). and optionally containing a double bond, which ring mav optionally contain an oxygen or sulphur ring atom, a group S(O) or 8(0)2 or a second nitrogen atom which will be part of a NH or NRL moiety whore R' i s Ci-ialkyl optionally substituted by hydroxy or Cι-ιalkoxy; or R7, R8 and the nitrogen atom to which they are attached form a non-aromatic azabicychc ring system of 6 to 12 ring atoms; or Z, R7 and the nitrogen atom to which they are attached form a heteroaliphatic ring to 4 to 7 ring atoms which mav optionally contain an oxygen ring atom;
R9 and R10 each independently represent hydrogen, halogen, C .^alkyi, CH2()Re, oxo, CU2Ra or C()NRaRb where Ra and Rb are as previously defined and R* represents hydrogen, Ci-salkyl or phenyl;
X represents -CH2, or -CH2CH2-;
Y represents -CI I=, -CH2-, -CH2CH= or -CH2CH2-. wit h the proviso that, the sum total of carbon atoms in X+Y is 2 or 3; and when Y is -CH= or -CH2CH=, the broken line represents a double bond; or a pharmaceutically acceptable salt thereof.
2. A compound as claimed in claim 1 wherein R: is hydrogen,
Ci 6alkyl, Ci.oalkoxy, fluoroCι-6alkoxy, Ca-7Cycloalkoxy, halogen or NR 'R1'.
3. A compound as claimed in claim 1 or claim 2 wherein R- is a hydrogen, fluorine or chlorine atom.
4. A compound as claimed in any one of claims 1 to 3 wherein J is halogen, Ci-iialkyl, fluoroCi-ualkyl, Ci-nalkoxy, fluoroCi βalkoxy, cyano ur a 5-membered aromatic heterocychc group as defined in claim 1 .
5. A compound as claimed in any one of claims 1 to 4 wherein R represents a C ' ι--ιalkyl group substituted by the group Ar, and optionally substituted by one or both of the groups R and R-'.
6. Λ compound as claimed in any one of claims 1 to 5 wherein 1 is
1 -ialkyl, or II 1 and R/' together represent an oxo grouj).
7. Λ comjiound as claimed in any one of claims 1 to 6 wherein Ar rejiresents a phenyl ring, optionally substituted by one or two halogen atoms or Cicalkoxy, or Ar represents a pyπdvl grouj).
8. Λ compound as claimed in any one of claims 1 to 7 wherein R1' and
Ruι are both hydrogen atoms.
9. A compound as claimed in any one of claims 1 to 8 wherein X is
-ChV, dnd Y is -Cl l2- or -CH=.
10. A compound as claimed in claim 1 of the formula (lb) or a jiharmaceutically acceptable salt thereof:
Figure imgf000089_0001
wherein R1, R- R3 and R' are as defined in in claim 1 , the broken line is an optional double bond, and R1- and Rκ are each independently hydrogen, halogen or Ci-nalkoxy.
1 1. A compound as claimed in claim 1 of the formula (Ic) or a jdiarmaccu cally acceptable salt thereof:
Figure imgf000090_0001
(lc) wherein R1. R- and R3 are defined in claim 1 , the broken line is an optional double bond, and R12 and R i are each independently hydrogen, halogen or Ci- .alkoxy.
12. A compound as claimed in claim 1 wherein R represents Ci-βalkyl, C3-7cycloalkyl or C3-7CycloalkylCι-4alkyl; or R represents a Cι-4alkyl group substituted by the group Ar, and optionally further substituted by one or both of the groups R4 and Rfl;
R1 represents Ci calkoxy, fluoroCi. calkoxy,
Figure imgf000090_0002
C.' .;alkenyloxy, C.;.7cycloalkoxy or C:f 7CycloalkylC] ..ιalkoxy; R1' represents hydrogen;
R3 represents hydrogen, Ci-βalkoxy, fluoroCi-ualkoxy. phenoxy, benzyloxy, cyano, or NR-H R'1, where R" and Rb each indejiendently represent hydrogen, Cι-ιalkyl or fluoroCnalkyl and R'1 is Ci-ealkyl, Cicalkoxy, fluoroCι-ι;alkyl or phenyl; or R;! rejiresents a 5-membered aromatic heterocychc group containing 2, 3 or 4 nitrogen atoms, which group is optionally substituted by a group selected from Cι „alkyl or trifluoromethyl;
R 1 and R5 each independently represent hydroxy, C , calkyl. or together R4 and R:" represent an oxo groiqi; Λr represents phenyl optionally substituted by one or two subst.u uent s selected from halogen. Cw, lkyl, Cι-r.alkoxy or CF-.; or Ar represents a 5-membered or 6-membered heterocychc ring containing 1 , 2 or 3 nitrogen atoms optionally substituted by a grouj) of the formula ZNR7RΛ;
R7 is hydrogen or Ci-ialkyl; R8 is hydrogen or Cmalkyl;
R' and Rlϋ each rejiresent hydrogen; X represents -CH2; Y represents -CI I=, or -CH2-; Z is Ci -salkylene; and when Y is -CH= the broken line represents a double bond; or a pharmaceutically acceptable salt thereof.
13. A compound selected from:
7-benzyl-3-(2-methoxy])henyl)- l-oxa-7-azaspiro[4,5]dec-3-ene; 7 -benzyl-3-(2-methoxy-5-(5-tnfluoromethy 1- 1 H-tetrazol- 1 -yl)phenyl)- 1 -oxa- 7- uzaspιro[4,5]dee-3-eno;
7-benzyl-3-(2-methoxy-5-(lH-tetrazol- l -yOphenyl)- l-oxa-7-azaspιro[4,5]dec-3-ene;
7-benzyl-3-(2-methoxy-5-(4-pyndyl)phenyl)- l-oxa-7-azaspιro(4,5]dec-3-ene;
7-benzyl-3-(2-methoxy-5-cyanophenyl)- l -oxa-7-azaspιro[4,5]dec-3-ene; 7-beιιzyl-3-(2-methoxy-5-trifluoromethoxyphcnyl)- l-oxa-7-azaspιro[4,5|dec-3-ene;
7-benzyl-3-(2-methoxy-5-(:?-frιfluoromethyl-4H- l,2,4-tπazol-4-yl)phenyl)- l -oxa-7- azaspιro|4,5]-(lec-3-ene;
7-benzyl-,3-(2-methoxy-5-(2-triΩuoromethyl-lH-ιmιdazol- l -yl)phenyl)- l -oxa-7- azaspιro[4,5]-dec-3-ene; 7-benzyl-3-(2-methoxy-5-benzyloxyphenyl)- l-oxa-7-azaspιro[4,5]dec-3-ene;
7-benzoyl-3-(2-methoxy-5-(5- trifluoromethyl- lH-fetrazol- 1 -yOphenyl)- 1 -oxa-7- azaspιro[4, 5]dec-3-ene;
7-(3.4-dιehlornbcnzyl)-3-(2-methoxy-5-(5-trifluoromethy I- 1 H-tetrazol- 1 -yDphenyl)-
1 -oxa-7-azaspιro|4,5)dec-3-ene; 7-(4-j)yrιdyl)-3-(2-methoxy-5-(5-trifluoromethyl- l H-tetrazol- 1 -yOphenyl)- l -oxa-7- azaspιro|4,5)(l(H,-3-en(>;
7-( 3-pyrιdyl)-;ι-(2-mefhoxy-5-(5-frιfluorυmefhyl- l H-tetrazol- 1 -yOphenyl)- 1 -oxa-7- a-/.as|)iro|4.5)dec-3-ene; 7-(2-])yπdyl)-3-(2-methoxy-5-(5-trιfluoromethyl-l H-tetrazol- l-yl)phenyl)-l -oxa-7- azaspιro[4,5]dec-3-ene;
7-(2-methoxybenzyl)-3-(2-methoxy-5-(5-trifluoromethyl-lH-tetrazol-l-yl)phenyl)- l-oxa-7-azasj)iro(4,5|dec-3-ene; 7-(l-phenylethyl)-3-(2-methoxy-5-(5-trιfluoromethyl- II I-tetrazol-1 -yl)phenyi)- 1- oxa-7-spιro[4,5]dec-3-ene;
7-(2-phenylethyl)-3-(2-methoxy-5-(5-trifluoromethyl-lH-tetrazol-l -yOphenyl)- 1 - oxa-7-azaspiro[4,5]dec-3-ene;
7-cyclohexylmethyl-3-(2-methoxy-5-(5-trιfluoromethyI-lH-tetrazol-l-yl)phenyl)-l- υxa-7-azaspιro[4,5]dec-3-ene;
7-(5-dιmethylamιnomethyl-lH-l,2,3-trιazol-4-yl)methyl-3-(2-methoxy-5-(5- trifluoromethyl- 1 H-tetrazol- 1 -yOphenyl)- 1 -oxa-7-azaspιro[4,5]dec-3-ene;
(±)-(3R*,5R*)-7-benzyl-3-(2-methoxy-5-(5-trifluoromethyl-lH-tetrazol-l- yOphenyl)- 1 -oxa-7-azaspiro[4,5]decane; (±)-(3S*,5R*)-7-benzyl-3-(2-methoxy-5-(5-trιfluoromethyl-lH-tetrazol-l- yl)phenyl)-l-oxa-7-azaspiro[4,5]decane;
(±)-(3R*,5R*)-7-benzoyl-3-(2-methoxy-5-(5-t fluoromethyl-lH-tetrazol-l- yl)phenyl)-l-oxa-7-azaspiro[4,5]decane;
(±)-(3R*,5R*)-7-(2-phenylethyl)-3-(2-methoxy-5-(5-tnfluoromethyl-l H-tetrazol- 1- yl)phenyl)- 1 -oxa-7-azaspiro[4,5]decane;
7-benzyl-3-(2-methoxy-5-(5-methyl- IH- 1 , 2, 4- tπazol- 1 -yOphenyl)- 1 -υxa-7- azaspιrol4,5)-dec-3-ene;
7-benzyl-3-(2-methoxy-5-(5-trifluoromethyl- IH- 1,2,4-tπazol- 1 -yl)phenyl)- 1 -oxa-7- azaspιro|4,5]-dec-3-ene; 7-benzyl-3-(2-methoxy-5-(N-methyItrifluoroacetamιdo)-l-oxa-7-azaspιro[4,5)dec-
3-ene;
7-benzyl-3-(2-ιsopropoxy-5-(2-tπfluoromethyl-lH-ιmιdazol-l -yOphenyl)- l-oxa-7- azaspιro[4.5]dec-3-ene;
7-benzyl-3-(2-methoxy-5-(5-trifluoromethyl- 1 H-tetrazol- 1 -yOmethylphenyl)- 1 -oxa- 7-azasj)iro|4.5]dec-3-ene;
(ι)-(3R*,5R*)-7-benzyl-3-(2-methoxy-5-(2-trιfluoromethyl-lH-ιmιdazol-l- vl)j)henyl)-l-υxa-7-azasι>iro[4,5|decane; i )-(3R*,5RM lR*/8*)-:,)-(2-mefhoxy-5-(2-frιfluoromethyl-lH-ιmιdazol-l- yl)phenyl)-7-(l-phenyl)ethyl-l-oxa-7-azasi)iro(4,5]decane; (r)-(3R* 5R*)-3-(2-methoxy-5-(2-tnfluoromethyl-lH-ιmιdazol-] -yl)phenyl)-7-(2- j)henyl)ethyl- 1 -oxa-7-azaspιro[4,51decane;
(±)-(3R*.5R*)-3-(2-methoxy-5-(2-trifluoromethyl-lH-ιmιdazol- l-yl)phenyl)-7- phenvlacetyl- 1 -oxa-7-azaspιro[4,5]decane;
(±)-(3R*,5R*)-7-(2-oxo-2-phenyl)ethyl-3-(2-methoxy-5-(2-trιfluoromethyl-lH- ιmulazol- 1 -yOphenyl)- l-oxa-7-azaspιro[4,5]decane; (±)-(3R*,5R*, l2S*/R*)-7-(2-hydroxy-2-phenyl)ethyl-3-(2-methoxy-5-(2- trιfluoromethyl- lH-ιmιdazol-1 -yl)phenyl)- l-oxa-7-azaspιro[4,51decane; or a pharmaceutically acceptable salt thereof.
14 A compound as claimed in claim 1 wherein R1 is at the 2' -position, R3 is at the 5'-posιfιon and R9 and R10 are at the 8- and 9-posιtιons.
15. A compound as claimed in any preceding claim for use in therapy.
16. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 14 in association with a pharmaceutically acceptable carrier or excipient.
17. A method for the treatment or prevention of physiological disorders associated with an excess of tachykinins, which method comprises administration to a patient in need thereof of a tachykinin reducing amount of a comjiound according to claim 1.
18. A method according to claim 17 for the treatment or prevention of pain or inflammation.
19. A method according to claim 17 for the treatment or prevention of migraine
20. A method according to claim 17 for the treatment or prevention of emesis.
21. A method according to claim 17 for the treatment or j)reventιon of jiostherpetic neuralgia.
22. The use of a compound as claimed in any one of claims 1 to 14 for the manufacture of a medicament for the treatment or jirovention of a physiological disorder associated with an excess of tachykinins.
23. The use of a compound as claimed in any one of claims 1 to 14 for the manufacture of a medicament for the treatment or prevention of pain or inflammation.
24. The use of a compound as claimed in any one of claims 1 to 14 for the manufacture of a medicament for the treatment or jirevention of migraine.
25. The use of a compound as claimed in any one of claims 1 to 14 for the manufacture of a medicament for the treatment or prevention of emesis.
26. The use of a compound as claimed in any one of claims 1 to 14 for t he manufacture of a medicament for the treatment or prevention of postherpetic neuralgia.
27 A jirocess for the jireparation of a compound as claimed in Claim 1 which comprises:
(A. l), where X is -CH2- and Y is -CI I2 or -CH2CH2-. reducing a compound of formula (I IA)
Figure imgf000095_0001
(HA)
w herein Y' is
Figure imgf000095_0002
or
(A.2), where X is -CII - and Y is -CH2CII2-, reducing a compound of formula (IIBϊ
Figure imgf000095_0003
(IIB)
wherein Y' is -CH2- or -CH2CH2-; or
(B), where X is -CII2- and Y is -CH= or
Figure imgf000095_0004
and the broken line is a double bond, reacting of a compound of formula (III)
Figure imgf000095_0005
(III)
wheπMii Y' i-- -CI 1= or -CI I2CI 1= and each Wr- is a Ci lalkyl group, wilb a com|)ound of formula (IV)
Figure imgf000096_0001
(IV) wherein R50 is a leaving group; or
(C) reacting a compound of formula (V)
Figure imgf000096_0002
(V) with a compound of formula (VI):
LG-R' (VI)
where R is a group of the formula R as defined in claim 1 or a precursor therefor and I I is a leaving group; and, if Rz is a precursor group, converting it to a grouj) R. or
(D) interconversion of a compound of formula (1) to give another comj)ound of formula (1): or (E), where R3 is a tetrazol- 1-yl group, reacting an intermediate of formula
(VI I
Figure imgf000097_0001
I
R
(VII)
with ammonium chloride and sodium azide at elevated temjierature; or
(F) a coupling reaction between a compound of formula (VIII) and (IX)
Figure imgf000097_0002
I
R
(VIII) (IX)
wherein one of R10 and R41 is B(OH)2 or 8n(alkyl)3 or a derivative thereof, and the other is a leaving group; or (G) cychsing a comjjound of formula (X)
Figure imgf000098_0001
(X) wherein Y" is -CH2- or -CH2CH2-, by an acid catalysed intramolecular cvclisation reaction or bv a dehydration reaction; or
(H) reacting comjκ nd of formula (XX)
Figure imgf000098_0002
R
(XX)
with a coirqiound of formula (IV), under the conditions of a reductive Heck reaction; or
(d), where R1 is Cicalkoxy, fluoroCi-ealkoxy, C2-βalkenoxy, C3-7cycloalkoxy, C TcycloalkyK'i ialkoxy or benzyloxy, reacting a compound of formula (XXVI)
Figure imgf000099_0001
(XXVI)
with an appropriate alkyl-. ttuoroalkyl-, alkenyl-, cycloalkyi-. cycloalkylalkyl- or aralkyl-halide. m the presence of a base; or
(K), where Y is -CH= or -CH2CH=, dehydrating of a compound of formula (XXVII)
Figure imgf000099_0002
(XXVI 1)
using an acid such as trifluoroacetic acid; or (L) reacting a compound of formula (XXVI I I)
Figure imgf000100_0001
(XXVII I)
with lithium naphthalenide;
each process being followed, where necessary, by the removal of any protecting group where present; and when the compound of formula (I) is obtained as a mixture of enantiomers or diastereoisomers, optionally resolving the mixture to obtain the desired enantiomer: and or, if desired, converting the resulting compound of formula (I) or a salt thereof, into a pharmaceutically acceptable salt thereof
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AU722660B2 (en) 2000-08-10
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