EP1140880A1 - Homopiperazine derivatives as selective emopamil inhibitors - Google Patents

Homopiperazine derivatives as selective emopamil inhibitors

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Publication number
EP1140880A1
EP1140880A1 EP99962380A EP99962380A EP1140880A1 EP 1140880 A1 EP1140880 A1 EP 1140880A1 EP 99962380 A EP99962380 A EP 99962380A EP 99962380 A EP99962380 A EP 99962380A EP 1140880 A1 EP1140880 A1 EP 1140880A1
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Prior art keywords
alkyl
substituted
formula
unsubstituted
homopiperazine
Prior art date
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EP99962380A
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German (de)
French (fr)
Inventor
Thomas Richard Simpson
Sally Ann Walsh
Edward John Warawa
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AstraZeneca AB
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AstraZeneca AB
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
    • C07D295/03—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to acyclic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/06—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals
    • C07D295/073—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals with the ring nitrogen atoms and the substituents separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to chemical compounds, in particular homopiperazines, 5 to processes for their preparation and to chemical intermediates useful in such processes.
  • the present invention further relates to homopiperazines, to pharmaceutical compositions containing them and to their use in methods of therapeutic treatment of animals including man, in particular in the treatment of neurological disorders. Background
  • Neurological disorders include stroke, head trauma, transient cerebral ischaemic attack, and chronic neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, diabetic neuropathy, amyotrophic lateral sclerosis, multiple sclerosis and AIDS-related dementia.
  • Emopamil has classically been thought of as a neuroprotective agent whose efficacy is
  • VSCC 15 most likely derived from actions at either voltage-sensitive calcium channels (VSCC) or
  • [ H] -Emopamil binding defines a unique high affinity site that is not related to VSCC, is found in the brain, but is most prevalent in the liver (Moebius et al, Mol. Pharmacol. 43: 139-148, 1993). Moebius et al. have termed this the "anti-ischaemic" binding site on the basis of high affinity displacement by several chemically disparate neuroprotective agents.
  • liver
  • the [ 3 H]-emopamil binding site is localised to the endoplasmic reticulum.
  • Neuroprotective compounds are known, for example emopamil and ifenprodil, that exhibit high affinity for the [ H]-emopamil binding site. However these are not selective inhibitors and exhibit activity either at neuronal VSCC, the polyamine site of the NMDA receptor (N-Methyl-D-aspartate) and/or the sigma-1 binding site. It is thought that compounds
  • the present invention provides compounds of formula I:
  • R 1 is hydrogen, substituted or unsubstituted C ⁇ _ 8 alkyl, substituted or unsubstituted C . 8 alkenyl or substituted or unsubstituted C 2 _ 8 alkynyl; wherein said C ⁇ _ 8 alkyl, C 2 . 8 alkenyl and C 2 . 8 alkynyl, when substituted, are substituted with one or more substituents independently selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C ⁇ - alkoxy, C
  • G is substituted or unsubstituted aryl, substituted or unsubstituted carbon linked heteroaryl, substituted or unsubstituted carbon-linked heterocycle or substituted or unsubstituted C 3 - ⁇ 2 cycloalkyl
  • p is an integer selected from the range 0 to 6
  • X is a linking group selected from -C(O)-, -O-, -OC(O)-, -S-, -S(O)-, -S(O) 2 -, -S(O) 2 ⁇ R 4 -, -NR 4 S(O) 2 -, -NR 4 -, -C(O)O-, -C(O)NR 4 -, -NR 4 C(O)-, -OC(O)NR 4 -, -C(O)NR SO 2 -, -NR 4 C(O)O-, -C(S)NR 4 - or -NR 4 C(S)-,
  • any aryl, heteroaryl, heterocycle or C . ⁇ 2 cycloalkyl may be unsubstituted or substituted on a ring carbon with one or more groups selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C ⁇ . 6 alkyl, C 2 _ 6 alkenyl, C 2 . 6 alkynyl, C ⁇ . 6 alkoxy, C ⁇ . 6 alkanoyl, C ⁇ .
  • A is a ring selected from phenyl and naphthyl
  • R" at each occurrence is independently selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino. carboxy, carbamoyl, mercapto, sulphamoyl, C ⁇ - 6 alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C
  • W (CH 2 ) p -B- LB wherein W is halo, nitro, hydroxy, C ⁇ - alkoxy, cyano, amino, trifluoromethyl, trifluoromethoxy, carboxy, carbamoyl, mercapto, sulphamoyl, mesyl, N-C ⁇ _ 6 alkylamino, N,N-(C ⁇ _ 6 alkyl) amino, C ⁇ - 6 alkoxycarbonyl, N-C ⁇ . alkylcarbamoyl or
  • N,N-(C ! _ 6 alkyl) 2 carbamoyl p is an integer selected from the range 1 to 6, and B is a bond, oxy, imino, N-(C ⁇ _ 6 alkyl)imino or -C(O) ⁇ H-, with the proviso that p is 2 or more unless B is a bond, -C(O)NH-, or
  • R 2 is a group of formula IC:
  • D is substituted or unsubstituted phenyl and E is selected from a bond, C ⁇ _ 6 alkylene, C ⁇ . 6 alkyleneoxy, oxy, imino, N-(C ⁇ _ 6 alkyl)imino, C]_ 6 alkyleneimino, N-(C ⁇ . 6 alkyl)-C,_ 6 alkyleneimino, -C(O) ⁇ H-, -SO 2 NH-, -NHSO 2 -, sulphonylC ⁇ . 6 alkylene, carbonylC ⁇ classroom 6 alkyleneoxycarbonyl-C ⁇ - 6 alkylene and C 2 .
  • m is an integer selected from the range 0 to 5 where at each occurrence R 2 is independently selected from any foregoing moiety; or a pharmaceutically-acceptable salt or and in v/vo-hydrolysable ester, amide or carbamate thereof; with the following provisos: when A is phenyl: a) if A and R 2 in combination is 4-mesyl then R 1 is not 2-methoxycarbonylethyl; b) if A and R 2 in combination is 4-chloro then R 1 is not 2-methoxycarbonylethyl, 3-mercaptopropyl, 3-chloropropyl or 3-aminopropyl; c) if m is 0 then R 1 is not 3-chloropropyl, 2-aminoe
  • alkyl includes both straight and branched chain alkyl groups but references to individual alkyl groups such as “propyl” are specific for the straight chain version only.
  • alkenyl alkynyl
  • phenylC ⁇ _ alkyl includes 2-phenylethyl, 2-phenylpropyl and 3-phenylpropyl.
  • halo means fluoro, chloro, bromo and iodo.
  • aryl means an unsaturated carbon ring. Particularly aryl means phenyl, naphthyl or biphenyl. More particularly aryl means phenyl.
  • heteroaryl or “heteroaryl ring” means, unless otherwise further specified, a monocyclic-, bicyclic- or tricyclic- 5-14 membered ring that is unsaturated or partially unsaturated, with up to five ring heteroatoms selected from nitrogen, oxygen and sulphur wherein a -CH 2 - group can optionally be replaced by a -C(O)-, and a ring nitrogen atom may be optionally oxidised to form the N-oxide.
  • heteroaryls examples include thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, pyridyl, pyridyl-N-oxide, oxopyridyl, oxoquinolyl, pyrimidinyl, pyrazinyl, oxopyrazinyl, pyridazinyl, indolinyl, benzofuranyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolinyl, quinazolinyl, xanthenyl, quinoxalinyl, indazolyl, benzofuranyl and cinnolinolyl.
  • heterocyclyl or “heterocyclic ring” means, unless otherwise further specified, a mono- or bicyclic- 5-14 membered ring, that is totally saturated, with up to five ring heteroatoms selected from nitrogen, oxygen and sulphur wherein a -CH 2 - group can optionally be replaced by a -C(O)-.
  • heterocyclyls include morpholinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, homopiperidinyl, homopiperazinyl and quinuclidinyl.
  • examples of C ⁇ _ 8 alkyl include C]. alkyl, Ci-salkyl, C ⁇ _ 4 alkyl, methyl, ethyl, isopropyl and t-butyl; examples of C ⁇ - 6 alkoxycarbonyl include C ⁇ _ 4 alkoxycarbonyl, methoxycarbonyl, ethoxycarbonyl and n- and t-butoxycarbonyl; examples of C]_ 6 alkoxy include C ⁇ - 4 alkoxy, methoxy, ethoxy and propoxy; examples of
  • C ⁇ . 6 alkanoylamino include formamido, acetamido and propionylamino; examples of C ⁇ _ 6 alkylS(O) a where a is 0-2 include methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl and ethylsulphonyl; examples of C ⁇ _ 6 alkanoyl include propionyl and acetyl; examples of N-C ⁇ . alkylamino include N-methylamino and N-ethylamino; examples of N,N-(C
  • examples of C . 8 alkenyl include C 2 - 6 alkenyl, vinyl, allyl and 1-propenyl; examples of C 2 . 8 alkynyl include C 2 _ alkynyl, ethynyl, 1-propynyl and 2-propynyl; examples of N-(C ⁇ _ 6 alkyl)sulphamoyl include N-methylsulphamoyl and N-ethylsulphamoyl; examples of N,N-(C ⁇ _ 6 alkyl) 2 sulphamoyl include N,N-dimethylsulphamoyl and N-methyl-N-ethylsulphamoyl; examples of N-(C ⁇ _ 6 alkyl)carbamoyl include N-methylcarbamoyl and N-ethylcarbamoyl; examples of N,N-(C ⁇ _6alkyl) 2 carbamoyl include
  • examples of C ⁇ _ 6 alkylene include -CH 2 CH 2 - and -CH CH(CH 3 )CH 2 -;
  • examples of C ⁇ _ 6 alkyleneoxy include C ⁇ . 4 alkyleneoxy, -CH 2 CH 2 O- and -CH 2 CH(CH 3 )CH 2 O-;
  • examples of ⁇ -(C ⁇ _ 6 alkyl)imino include -N(Me)- and -N('Pr)-;
  • examples of C ⁇ _ 6 alkyleneimino include -CH 2 CH 2 NH- and -CH 2 CH(CH 3 )CH 2 NH-; examples of N-(C 1 . 6 alkyl)-C ⁇ .
  • 6 alkyleneimino include -CH 2 CH 2 N(Me)- and -CH 2 CH(CH 3 )CH 2 N( i Pr)-; examples of sulphonylCj. 6 alkylene include sulphonylC,. 4 alkylene, -SO 2 CH 2 CH 2 - and -SO 2 CH 2 CH(CH 3 )CH 2 -; examples of carbonylC ⁇ - 6 alkyleneoxycarbonyl-C ⁇ .
  • alkylene examples include -C(O)CH 2 CH 2 OC(O)CH 2 - and -C(O)CH 2 CH(CH 3 )CH 2 OC(O)CH 2 CH 2 -;
  • examples of C 2 _ 6 alkanoylimino include -CH 2 CH 2 C(O)NH- and -CH 2 CH(CH 3 )CH 2 C(O)NH-.
  • R 1 is other than hydrogen.
  • R 1 is C ⁇ _ 8 alkyl substituted with one or more halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C ⁇ _ 6 alkoxy, C ⁇ .
  • alkyl 2 sulphamoyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted heteroaryl, substituted or unsubstituted C 3 . ⁇ cycloalkyl, or a group of formula IA:
  • G is substituted or unsubstituted aryl, substituted or unsubstituted carbon linked heteroaryl, substituted or unsubstituted carbon-linked heterocycle or substituted or unsubstituted C 3 _ ⁇ 2 cycloalkyl
  • p is 0 to 6
  • X is a linking group and is selected from -C(O)-, -O-, -OC(O)-, -S-, -S(O)-, -S(O) 2 -, -S(O) 2 NR 4 -, -NR 4 S(O) 2 -, -NR 4 -, -C(O)O-, -C(O)NR 4 -, -NR 4 C(O)-, -OC(O)NR 4 -, -C(O)NR 4 SO 2 -, -NR 4 C(O)O-, -C(S)NR 4 - or -NR 4 C(S)- wherein R 4
  • any aryl, heteroaryl, heterocycle or C 3 _ ⁇ cycloalkyl may be unsubstituted or substituted on a ring carbon with one or more groups selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C ⁇ _ 6 alkyl, C 2 _ 6 alkenyl, C _ alkynyl, C ⁇ _ alkoxy, C ⁇ . 6 alkanoyl, C ⁇ _ 6 alkanoyloxy, N-(C ⁇ _ 6 alkyl)amino, N,N-(C ⁇ .
  • alkynyl C].6alkanoyl, C ⁇ - 6 alkylsulphonyl or phenylC ⁇ _ 6 alkyl and with the proviso that when R 1 is substituted C]. 8 alkyl, substituted C 2 . 8 alkenyl or substituted C 2 _ 8 alkynyl the carbon atom adjacent to the homopiperazine ring is not directly substituted by any heteroatom other than fluoro.
  • R is hydrogen or C ⁇ _ 8 alkyl optionally substituted with fluoro or aryl.
  • R is hydrogen or C
  • R 1 is hydrogen, methyl, n-propyl, 3-methylbutyl, isopropyl, benzyl,
  • R 1 is methyl, n-propyl, 3-methylbutyl, isopropyl, benzyl, 3-fluoropropyl or 3-phenylpropyl.
  • R 1 is methyl.
  • Ring A is phenyl.
  • Ring A is naphthyl
  • R " is halo, nitro, trifluoromethyl, trifluoromethoxy, C ⁇ . 6 alkyl, ⁇ alkoxy, C]. 6 alkoxycarbonyl, or a group of the formula IC as disclosed above, wherein D is phenyl and E is a bond, C ⁇ _ alkyleneoxy or sulphonylC ⁇ _ alkylene.
  • R 2 is fluoro, chloro, bromo, iodo, nitro, trifluoromethyl, trifluoromethoxy, methyl, methoxy, methoxycarbonyl or a group of the formula IC as depicted above, wherein D is phenyl and E is a bond, methyleneoxy or sulphonylmethylene.
  • R 2 is fluoro, chloro, bromo, iodo, nitro, trifluoromethyl, trifluoromethoxy, methyl, methoxy, methoxycarbonyl or a group of the formula IC as depicted above, wherein D is phenyl and E is a bond or methyleneoxy.
  • m is an integer selected from the range 0 to 3. In a particular aspect of the invention m is an integer selected from the range 0 to 2.
  • Ring A and (R " ) m are as follows: such combinations are phenyl, naphth-1-yl, biphen-2-yl, 2-bromophenyl, 2-nitrophenyl, 2-trifluoromethylphenyl, 2-(phenylsulphonylmethyl)phenyl, 3-fluorophenyl, 3-chlorophenyl, 3-iodophenyl, 3-nitrophenyl, 3-trifluoromethylphenyl, 3-methoxyphenyl, 3-methoxycarbonylphenyl, 4-fluorophenyl, 4-bromophenyl, 4-nitrophenyl.
  • Ring A and (R 2 ) m are 4-benzyloxyphenyl, 2,4-ditrifluoromethylphenyl or 3-iodophenyl.
  • R 1 is hydrogen or C ⁇ . 8 alkyl optionally substituted with fluoro or aryl;
  • Ring A is phenyl or naphthyl
  • R 2 is halo, nitro, trifluoromethyl, trifluoromethoxy, C ⁇ - 6 alkyl, C ⁇ . 6 alkoxy, C ⁇ _ 6 alkoxycarbonyl, or a group of the formula IC as disclosed herein, wherein D is phenyl and E is a bond, C ⁇ _ alkyleneoxy or sulphonylC ⁇ _ 6 alkylene; and m is an integer selected from the range 0 to 3; or a pharmaceutically-acceptable salt or and in v/vo-hydrolysable ester, amide or carbamate thereof; with the provisos that when A is phenyl: a) if A and R 2 in combination is 3-chloro or 4-chloro then R 1 is not 3-chloropropyl; b) if m is 0 then R 1 is not 3-chloropropyl, methyl, ethyl, isopropyl or isobutyl; and c) when R 1 is a substituted
  • R 1 is hydrogen, C ⁇ _ 8 alkyl optionally substituted with fluoro or phenyl; Ring A is phenyl or naphthyl;
  • R" is fluoro, chloro, bromo, iodo, nitro, trifluoromethyl, trifluoromethoxy, methyl, methoxy, methoxycarbonyl or a group of the formula IC as depicted above, wherein D is phenyl and E is a bond, methyleneoxy or sulphonylmethylene; and m is an integer selected from the range 0 to 3; or a pharmaceutically-acceptable salt or and in v/vohydrolysable ester, amide or carbamate thereof; with the proviso that when A is phenyl and a) m is 0 then R 1 is not methyl, ethyl, isopropyl or isobutyl b) R 1 is a substituted straight chain C ⁇ . 4 alkyl group, the distal carbon atom, that is, the carbon atom of said C ⁇ . 4 alkyl group furthest from the homopiperazine ring, is not substituted with two phenyl
  • R 1 is hydrogen, methyl, n-propyl, 3-methylbutyl, isopropyl, benzyl, 3-fluoropropyl or 3-phenylpropyl;
  • R 1 is methyl, n-propyl, 3-methylbutyl, isopropyl, benzyl, 3-fluoropropyl or 3-phenylpropyl;
  • R 1 is methyl, n-propyl, 3-methylbutyl, isopropyl, benzyl, 3-fluoropropyl or 3-phenylpropyl;
  • Ring A and R 2 in combination form 4-benzyloxyphenyl, 2,4-ditrifluoromethylphenyl or 3-iodophenyl; or a pharmaceutically-acceptable salt or and in vivo-hydrolysable ester, amide or carbamate thereof.
  • Particular compounds of the invention are those of Examples and include: l-methyl-4-(4-benzyloxybenzyl)homopiperazine; l-methyl-4-(2,4-bis(trifluoromethyl)benzyl)homopiperazine; l-propyl-4-(4-benzyloxybenzyl)homopiperazine; l-benzyl-4-(4-benzyloxybenzyl)homopiperazine; l-pentyl-4-(4-benzyloxybenzyl)homopiperazine; l-methyl-4-(3,5-bis(trifluoromethyl)benzyl)homopiperazine;
  • Suitable pharmaceutically-acceptable salts include acid-addition salts such as methanesulphonate, fumarate, hydrochloride, hydrobromide, citrate, maleate, phosphate and sulphate.
  • suitable salts are base salts such as an alkali metal salt, for example sodium, an alkaline earth metal salt, for example calcium or magnesium, an organic amine salt, for example triethylamine, morpholine, N-methylpiperidine, N-ethylpiperidine, procaine, dibenzylamine and NN-dibenzylethylamine, or amino acids, for example lysine.
  • a compound of the invention may have more than one cation or anion depending on the number of charged functions and the valency of the cations or anions.
  • a preferred pharmaceutically-acceptable salt is a sodium salt.
  • v vo-hydrolysable esters, amides and carbamates are compounds that hydrolyse in the human body to produce the parent compound. Such esters, amides and carbamates can be identified by administering, for example intravenously to a test animal, the compound under test and subsequently examining the test animal's body fluids. Suitable in v/vo-hydrolysable amides and carbamates include ⁇ -carbomethoxy and ⁇ -acetyl.
  • An in v/vo-hydrolysable ester of a compound of the formula I containing carboxy or hydroxy group is, for example, a pharmaceutically-acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol.
  • Suitable pharmaceutically-acceptable esters for carboxy include C ⁇ _ 6 alkoxymefhyl esters, for example methoxymethyl; C ⁇ -6alkanoyloxymethyl esters, for example pivaloyloxymethyl; phthalidyl esters; C 3 . 8 cycloalkoxy-carbonyloxyC ⁇ _ 6 alkyl esters, for example 1-cyclohexylcarbonyloxyethyl; 1 ,3-dioxolen-2-onylmethyl esters, for example 5-methyl-l,3-dioxolen-2-onylmethyl; and C ⁇ . 6 alkoxycarbonyloxyethyl esters, for example 1-methoxycarbonyloxyethyl.
  • Such esters may be formed at any carboxy group in a compound of this invention.
  • An in v/vo-hydrolysable ester of a compound of the formula I having a hydroxy group includes inorganic esters such as phosphate esters and ⁇ -acyloxyalkyl ethers and related compounds which, as a result of the in vivo hydrolysis of the ester, yield the parent hydroxy group.
  • inorganic esters such as phosphate esters and ⁇ -acyloxyalkyl ethers and related compounds which, as a result of the in vivo hydrolysis of the ester, yield the parent hydroxy group.
  • ⁇ -acyloxyalkyl ethers include acetoxymethoxy and 2, 2-dimethylpropionyloxy methoxy.
  • a selection of in v vo-hydroly sable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl.
  • Another aspect of the present invention provides a process for preparing a compound of formula I or a pharmaceutically-acceptable salt or an in v vo-hydrolysable ester, amide or carbamate thereof which process, wherein R , R " , Ring A and m are, unless otherwise specified, as defined for formula I comprises: a) reacting a compound of the formula II:
  • L is a suitable displaceable group, with a compound of the formula III: m
  • R 1 of a compound of formula I when R 1 of a compound of formula I is hydrogen R a is suitable amino protecting group such as those defined below; or when R 1 of a compound of formula I is not hydrogen R a is R'; or b) for preparing a compound of formula I wherein R 1 is not hydrogen, reacting a compound of formula IV:
  • R b is hydrogen or substituted or unsubstituted C ⁇ . alkyl, substituted or unsubstituted C 2 _ alkenyl or substituted or unsubstituted C 2 . 7 alkynyl and R c is hydrogen or hydroxy; and thereafter if necessary: i) converting a compound of the formula I into another compound of the formula I; ii) removing any protecting groups; or iii) forming a pharmaceutically-acceptable salt or in v/vo-hydrolysable ester, amide or carbamate.
  • the L is a displaceable group, and suitable values for L are, for example, a halogeno or sulphonyloxy group, such groups are chloro, bromo, methanesulphonyloxy or toluene-4-sulphonyloxy group.
  • reaction conditions for reactions a) and b) are as follows.
  • Compounds of formula II and III and compounds of formula IV and V are reacted together under standard alkylation conditions.
  • an organic solvent for example an anhydrous aprotic solvent such as dimethylformamide, dimethylacetamide or tetrahydrofuran, optionally in the presence of a catalyst, such as an iodide salt for example potassium iodide, and at a temperature in the range of 0-100 °C, preferably 40-80 °C.
  • a catalyst such as an iodide salt for example potassium iodide
  • reaction conditions for reactions c) and d) are as follows. Amines may be reacted with aldehydes under standard reductive amination conditions. For example in the presence of a reducing agent such as hydrogen and a hydrogenation catalyst, for example palladium on carbon, or zinc and hydrochloric acid, or sodium cyanoborohydride, or sodium triacetoxyborohydride, or sodium borohydride, iron pentacarbonyl and alcoholic potassium hydroxide, or borane and pyridine or formic acid. The reaction is preferable carried out in the presence of a suitable solvent such as an alcohol, for example methanol or ethanol, and at a temperature in the range of 0-50 °C, preferably at or near room temperature.
  • a suitable solvent such as an alcohol, for example methanol or ethanol
  • aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid, the introduction of an acyl group using, for example, an acyl halide and Lewis acid, such as aluminium trichloride, under Friedel Crafts conditions; the introduction of an alkyl group using an alkyl halide and Lewis acid, such as aluminium trichloride, under Friedel Crafts conditions; and the introduction of a halogeno group.
  • modifications include the reduction of a nitro group to an amino group by for example, catalytic hydrogenation with a nickel catalyst or treatment with iron in the presence of hydrochloric acid with heating; oxidation of alkylthio to alkylsulphinyl or alkylsulphonyl.
  • a suitable protecting group for an amino or alkylamino group is, for example, an acyl group; for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl.
  • the deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • an acyl group such as a t-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate).
  • a suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.
  • a suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl.
  • the deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • a suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • a base such as sodium hydroxide
  • a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • the protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art.
  • a compound of the formula I or a pharmaceutically-acceptable salt or in v vo-hydrolysable ester, amide or carbamate thereof for the therapeutic treatment (including prophylactic treatment) of mammals including humans, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
  • the pharmaceutical compositions of compounds of this invention may be administered in standard manner for the disease condition that it is desired to treat, for example by oral, topical, parenteral, buccal, nasal, vaginal or rectal administration or by inhalation.
  • the compounds of this invention may be formulated by means known in the art into the form of, for example, tablets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, finely divided powders or aerosols for inhalation, and for parenteral use such as intravenous, intramuscular or infusion, sterile aqueous or oily solutions or suspensions or sterile emulsions.
  • a preferred route of administration is intravenously in sterile isotonic solution.
  • composition of this invention may also contain, or be simultaneously or sequentially co-administered with, one or more pharmacological agents of value in treating one or more disease conditions referred to hereinabove.
  • compositions of this invention will normally be administered to humans so that, for example, a daily dose of 0.05 to 75 mg/kg body weight (and preferably of 0.1 to 30 mg/kg body weight) is received.
  • This daily dose may be given in divided doses as necessary, the precise amount of the compound received and the route of administration depending on the weight, age and sex of the patient being treated and on the particular disease condition being treated according to principles known in the art.
  • unit dosage forms will contain about 1 mg to 500 mg of a compound of this invention.
  • composition which comprises a compound of the formula I:
  • R 1 is hydrogen, substituted or unsubstituted Cj. 8 alkyl, substituted or unsubstituted C 2 . 8 alkenyl or substituted or unsubstituted C 2 . 8 alkynyl; wherein said C ⁇ _ 8 alkyl, C 2 . 8 alkenyl and C 2 . 8 alkynyl are unsubstituted or substituted with one or more substituents independently selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C ⁇ _ 6 alkoxy, C
  • G is substituted or unsubstituted aryl, substituted or unsubstituted carbon linked heteroaryl, substituted or unsubstituted carbon-linked heterocycle or substituted or unsubstituted C 3 .
  • p is an integer selected from the range 0 to 6 and
  • X is a linking group selected from -C(O)-, -O-, -OC(O)-, -S-, -S(O)-, -S(O) 2 -, -S(O) 2 ⁇ R 4 -, -NR 4 S(O) 2 -, -NR 4 -, -C(O)O-, -C(O)NR 4 -, -NR 4 C(O)-, -OC(O)NR 4 -, -C(O)NR 4 SO 2 -, -NR 4 C(O)O-, -C(S)NR 4 - or -NR 4 C(S)-, wherein
  • alkyl)sulphamoyl, N,N-(C ⁇ _6alkyl) 2 sulphamoyl or phenylC ⁇ _ 6 alkyl and a heterocycle or heteroaryl containing an - ⁇ H- group may be substituted or unsubstituted on a ring nitrogen with C ⁇ _ alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C ⁇ _ alkanoyl, - ⁇ alkylsulphonyl or phenylC ⁇ . alkyl;
  • A is a ring selected from phenyl and naphthyl;
  • R 2 at each occurrence is independently selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C ⁇ . 6 alkyl, C 2 . 6 alkenyl, C 2 _ 6 alkynyl, C ⁇ _ 6 alkoxy, C ⁇ . 6 alkanoyl, C ⁇ alkanoyloxy, N-(C ⁇ - 6 alkyl)amino, N,N-(C ⁇ _ 6 alkyl) 2 amino, C ⁇ .6alkanoylamino, N-(C ⁇ .
  • W (CH 2 ) p -B- LB wherein W is halo, nitro, hydroxy, C
  • N,N-(C ⁇ . 6 alkyl) 2 carbamoyl p is an integer selected from the range 1 to 6, and B is a bond, oxy, imino, N-(C ⁇ - 6 alkyl)imino or -C(O) ⁇ H-, with the proviso that p is 2 or more unless B is a bond, -C(O)NH-, or
  • R 2 is a group of formula IC:
  • D is unsubstituted or substituted phenyl and E is selected from a bond, C
  • m is an integer selected from the range 0 to 5 where at each occurrence R 2 is independently selected from any foregoing moiety; or a pharmaceutically-acceptable salt or and in v/vo-hydrolysable ester, amide or carbamate thereof; with the following provisos: when A is phenyl: a) if A and R 2 in combination is 4-chlorophenyl then R !
  • R 1 is not 3-mercaptopropyl; b) if A and R 2 in combination is 3,4,5-trimethoxyphenyl then R 1 is not cyanomethyl or 2-aminoethyl; and c) when R 1 is a substituted straight chain C ⁇ _ alkyl group, the distal carbon atom, that is the carbon atom of this C ⁇ .
  • a further feature of the present invention is a compound of formula I' and pharmaceutically-acceptable salts or an in v/vo-hydrolysable ester, amide or carbamate thereof, for use as a medicament.
  • such a compound of formula F is a compound of formula (I"):
  • R 1 is hydrogen, substituted or unsubstituted C ⁇ - 8 alkyl, substituted or unsubstituted C 2 - 8 alkenyl or substituted or unsubstituted C 2 - 8 alkynyl; wherein said C ⁇ _ 8 alkyl, C . 8 alkenyl and C 2 _ 8 alkynyl are unsubstituted or substituted with one or more substituents independently selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C ⁇ . 6 alkoxy, C ⁇ _ alkanoyl, C ⁇ - alkoxycarbonyl, C ⁇ .
  • alkanoyloxy N-(C ⁇ - 6 alkyl)amino, N,N-(C ⁇ . 6 alkyl) 2 amino, C ⁇ . 6 alkanoylamino, N-(C
  • G is substituted or unsubstituted aryl, substituted or unsubstituted carbon linked heteroaryl, substituted or unsubstituted carbon-linked heterocycle or substituted or unsubstituted C 3 .
  • any aryl, heteroaryl, heterocycle or C _ ⁇ cycloalkyl may be unsubstituted or substituted on a ring carbon with one or more groups selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C ⁇ - 6 alkyl, C 2 _ 6 alkenyl, C 2 . 6 alkynyl, C ⁇ _ 6 alkoxy, C ⁇ _ 6 alkanoyl, C ⁇ _ alkanoyloxy, N-(C ⁇ .
  • A is a ring selected from phenyl and naphthyl;
  • R 2 at each occurrence is independently selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C ⁇ _ alkyl, C 2 . alkenyl, C 2 . 6 alkynyl, C ⁇ _ 6 alkoxy, C ⁇ . 6 alkanoyl, C ⁇ _ alkanoyloxy, N-(C ⁇ . 6 alkyl)amino, N,N-(C ⁇ _ 6 alkyl) 2 amino, C ⁇ . 6 alkanoylamino, N-(C ⁇ .
  • W (CH 2 ) p -B- LB wherein W is halo, nitro, hydroxy, C ⁇ - 6 alkoxy, cyano, amino, trifluoromethyl, trifluoromethoxy, carboxy, carbamoyl, mercapto, sulphamoyl, mesyl, N-C ⁇ . 6 alkylamino, N,N-(C ⁇ - 6 alkyl) 2 amino, C ⁇ .
  • alkoxycarbonyl N-C ⁇ _ 6 alkylcarbamoyl or N,N-(Ci- 6 alkyl) 2 carbamoyl
  • p is an integer selected from the range 1 to 6
  • B is a bond, oxy, imino, N-(C ⁇ _ alkyl)imino or -C(O) ⁇ H-, with the proviso that p is 2 or more unless B is a bond, -C(O)NH-, or
  • R 2 is a group of formula IC:
  • D— E IC wherein D is substituted or unsubstituted phenyl and E is selected from a bond, C ⁇ _ 6 alkylene,
  • a method of inhibiting of the [ 3 H] -emopamil binding site in a warm-blooded animal, such as a human being, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula I" or a pharmaceutically-acceptable salt or an in v/vo-hydrolysable ester, amide or carbamate thereof, as defined hereinbefore.
  • Binding at the [ 3 H]-emopamil binding site was determined by a modification of the method described by Zech, C, Staudinger R., Miihlbacher, J. and Glossmann, H. Novel sites for phenylalkylamines: characterisation of a sodium-sensitive drug receptor with (-)- 3 H- emopamil. Eur. J. Pharm. 208: 119-130, 1991.
  • Guinea-pig liver membrane preparation
  • Assay buffer 10 mM Tris-HCl, 0.1 mM phenylmethylsulfonyl fluoride (PMSF), 0.2% bovine serum albumin (BSA), pH 7.4 at 4 °C.
  • Radioligand 0.96 nM (-)- H-emopamil (Amersham).
  • Guinea pig liver membranes 40mg/mL original wet weight.
  • H-D-888 binding to rat brain cortical membranes 3 H-D-888 binding was determined by a modification of Reynolds, I.J., Snowman,
  • the homogenate was spun at 1000 x g for 10 minutes at 4 °C in a SS-34 rotor. The supernatant was then spun at 29,000 x g for 20 minutes. The resulting pellet was resuspended in membrane buffer (5 mM Hepes, 0.2% BSA, pH 7.4) to a final concentration of 60 mg original wet weight/mL.
  • Assay Reaction Mixture Assay buffer: 50 mM Hepes, 0.2% BSA, pH 7.4
  • Radioligand l ⁇ M 3 H-D888 (Amersham)
  • Rat cortical membranes 6 mg/mL original wet weight
  • This mixture was incubated for 60 minutes at 25 °C.
  • the assay was terminated by filtering with a Brandel Cell Harvester over Whatman GF/C filters that had been soaked for at least 120 minutes in 0.3% polyethylenamine (PEI) and washed three times with 5 mL of wash buffer containing 20 mM Hepes, 20 mM MgCl 2 , pH 7.4. Specific binding was measured with 10 ⁇ M methoxy verapamil (D-600).
  • This assay was used to determine in vitro selectivity of compounds vs. L-type voltage sensitive calcium channels, i.e. high affinity for the ⁇ -D888 binding site would show a lack of selectivity.
  • the IC 50 of compounds of the invention at the ⁇ -D888 binding site was between 542 nM and 4098 nM.
  • the gerbils are brought to the surgical suite and dosed intraperitoneally with the test agent or vehicle, forty five minutes prior to surgery. Drugs are administered at a volume of 5 mL/kg (intraperitoneal). Vehicle is generally saline, with sodium phosphate added to adjust the pH, if needed. Forty-five minutes after dosing the gerbils are anaesthetised with halothane (3.3%) which is delivered along with oxygen (1.5 1/M) through a face mask. After the gerbils are anaesthetised, halothane is continued at a maintenance level of 1.5-2 % along with oxygen. The ventral surface of the neck is shaved and cleaned with alcohol.
  • Surgical procedures are carried out on a thermostat-controlled heating pad set to 37 °C.
  • An incision is made in the neck, the carotid arteries are dissected away from the surrounding tissue, and isolated with a 5 cm length of Silastic tubing.
  • both arteries have been isolated they are clamped with microaneurysm clips (Roboz Instruments).
  • the arteries are visually inspected to determine that the blood flow has been stopped. After 5 minutes the clips are gently removed from the arteries and blood flow begins again.
  • a sham control group is treated identically but is not subjected to carotid artery occlusion.
  • the incisions are closed with suture and the gerbils WO 00/39110 ,,, PCT/GB99/04330
  • Kieselgel silica (Art. 9385);
  • DMSO dimethylsulphoxide
  • THF is tetrahydrofuran
  • DCM is dichloromethane -2 ⁇ -
  • NMP is N-methylpyrrolidone.
  • Example 1 l-Methyl-4-(2,4-bis(trifluoromethyl)benzyl)homopiperazine
  • a solution of 1-methylhomopiperazine (4.05 mL; 3.7 g, 32.6 mmol) in THF (250 mL).
  • Triethylamine (4.54 mL, 3.3 g, 32.6 mmol) and then 3,5-bistrifluoromethylbenzyl bromide (5.97 mL, 10.0 g, 32.6 mmol) were added.
  • the solution was immersed in a 60 °C oil bath for 16 hours during which time a precipitate formed.
  • Example 40 l-(3-(4-chlorophenoxy)-2-hvdroxypropyl)-4-(4-benzyloxybenzyl)homopiperazine
  • a 4-dram vial was charged with l-(4-benzyloxybenzyl)homopiperazine (250 mg, 0.84 mmol) and 4-chlorophenyl 2,3-epoxypropyl ether (0.20 mL, 310 mg, 1.68 mmol).
  • a loose cover was placed over the vial and the vial was irradiated with microwaves for 1.50 minutes at hi power.
  • the resulting light yellow product was purified by column chromatography using 5% methanol in methylene chloride to obtain the title compound as a light orange oil (370 mg).
  • Example 50 l-methyl-4-(2,5-bistrifluoromethylbenzyl)homopiperazine A solution of 1-methyl-homopiperazine (456 mg, 4.0 mmol), 2,5-difluorobenzyl bromide (1.23 g, 4.0 mmol) and triethylamine (400 mg, 4.0 mmol) in 40 mL THF was prepared and stirred at ambient temperature for two days. The resulting mixture was filtered. The filtrate was concentrated, dissolved in diethyl ether, washed with water and then concentrated. The resulting oil was purified by column chromatography using 5% methanol in methylene chloride to provided the title compound (1.0 g).
  • Example 54 l-(2-phenylethyl)-4-(4-benzyloxybenzyl)homopiperazine
  • a solution of l-(4-benzyloxybenzyl)homopiperazine (500 mg, 1.7 mmol), 2- bromoethylbenzene (620 mg, 3.4 mmol) and triethylamine (340 mg, 3.4 mmol) in 40 mL THF was prepared and stirred at 60 °C for 16 hours. Additional 2-bromoethylbenzene (620 mg, 3.4 mmol) and triethylamine (340 mg, 3.4 mmol) were then added to the solution and stirring at 60 °C was continued for another 16 hours.
  • Example 65 l-Methyl-4-(2,4-bis(trifluoromethyl)benzyl)homopiperazine dihydrochloride
  • a solution of Example 1 (7.0 g) in ethanol (25 mL) was treated with saturated ethanolic HC1. Diethyl ether was added while stirring until precipitation began. The solution was placed in a 0 °C refrigerator for 16 hours during which time a precipitate formed. The mixture was filtered and the resulting white solid was dried in vacuo at 48 °C for 16 hours to give the title compound (8.1 g).
  • Example 66 l-Methyl-4-(4-benzyloxybenzyl)homopiperazine dimaleate salt
  • a solution of Example 2 ( 11.1 g) in ethanol (35 mL) was prepared in a 250 mL erlenmeyer flask.
  • a solution of maleic acid (9 g) in ethanol (50 mL) was added and a precipitate began to form.
  • Diethyl ether (30 mL) was then added and the mixture was stirred.
  • the mixture was placed in a 0 °C refrigerator for 16 hours during which time a precipitate continued to form.
  • the mixture was filtered and the resulting white solid was dried in vacuo at 48 °C for 16 hours to give the title compound (15.86 g).
  • Example 40 Following conventional procedures well known in the pharmaceutical art the following exemplary pharmaceutical dosage forms containing compounds of formula I, I' or I" can be prepared: (a) Tablet mg/tablet
  • HPMC Hydroxypropylmethylcellulose
  • a compound of Formula I, I' or I" is dissolved in an isotonic sterile solution at a concentration of 5 mg/mL.

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Abstract

Homopiperazines of formula (I), wherein R1 is hydrogen, C¿1-8?alkyl, C2-8alkenyl or C2-8alkynyl substituted or unsubstituted with a variety of groups as defined herein; A is a ring selected from phenyl and naphthyl; R?2¿ at each occurrence is independently selected from a variety of groups as defined herein; m is an integer selected from the range 0 to 5 where at each occurrence R2 is independently selected; together with processes for their manufacture and compositions containing them. Compounds of formula (I) are pharmacologically useful in the treatment of neurological disorders.

Description

HOMOPIPERAZINE DERIVATIVES AS SELECTIVE EMOPAMIL INHIBITORS
Field of The Invention
The present invention relates to chemical compounds, in particular homopiperazines, 5 to processes for their preparation and to chemical intermediates useful in such processes. The present invention further relates to homopiperazines, to pharmaceutical compositions containing them and to their use in methods of therapeutic treatment of animals including man, in particular in the treatment of neurological disorders. Background
10 Neurological disorders, to which the present invention relates, include stroke, head trauma, transient cerebral ischaemic attack, and chronic neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, diabetic neuropathy, amyotrophic lateral sclerosis, multiple sclerosis and AIDS-related dementia.
Emopamil has classically been thought of as a neuroprotective agent whose efficacy is
15 most likely derived from actions at either voltage-sensitive calcium channels (VSCC) or
5-HT2 receptors. An apparent paradox to this logic is that verapamil, although chemically and pharmacologically very similar to emopamil, is not neuroprotective. While the lack of neuroprotective efficacy by verapamil was initially explained by lack of CNS penetration, recent studies suggest other factors may be involved (Keith et al., Br. J. Pharmacol. 1 13:
20 379-384, 1994).
[ H] -Emopamil binding defines a unique high affinity site that is not related to VSCC, is found in the brain, but is most prevalent in the liver (Moebius et al, Mol. Pharmacol. 43: 139-148, 1993). Moebius et al. have termed this the "anti-ischaemic" binding site on the basis of high affinity displacement by several chemically disparate neuroprotective agents. In liver,
25 the [3H]-emopamil binding site is localised to the endoplasmic reticulum.
Neuroprotective compounds are known, for example emopamil and ifenprodil, that exhibit high affinity for the [ H]-emopamil binding site. However these are not selective inhibitors and exhibit activity either at neuronal VSCC, the polyamine site of the NMDA receptor (N-Methyl-D-aspartate) and/or the sigma-1 binding site. It is thought that compounds
30 that interact with either the VSCC or the NMDA receptor, are responsible for the side effects usually seen with emopamil, such as hypotension, or those seen with ifenprodil, such as behavioural manifestations. Summarv of The Invention
We have now found a class of compounds that show selective binding at the [3H] -emopamil binding site.
The present invention provides compounds of formula I:
wherein:
R1 is hydrogen, substituted or unsubstituted Cι_8alkyl, substituted or unsubstituted C .8alkenyl or substituted or unsubstituted C2_8alkynyl; wherein said Cι_8alkyl, C2.8alkenyl and C2.8alkynyl, when substituted, are substituted with one or more substituents independently selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Cι- alkoxy, C|_6alkanoyl, Cι-6alkoxycarbonyl, Cι.6alkanoyloxy, N-(Cι.βalkyl)amino, NN-(Cι_6alkyl)2amino, C|_6alkanoylamino, N-(Cι.6alkyl)carbamoyl, N,N-(Cι-6alkyl)2carbamoyl, Cι_6alkoxyCι- alkoxy, Cι_6alkylS(O)a wherein a is 0 to 2, N-(Cι.6alkyl)sulphamoyl or N,N-(Cι.6alkyl)2sulphamoyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-ι2cycloalkyl, and a group of formula IA:
G- CCH^X-
IA wherein:
G is substituted or unsubstituted aryl, substituted or unsubstituted carbon linked heteroaryl, substituted or unsubstituted carbon-linked heterocycle or substituted or unsubstituted C3-ι2cycloalkyl, p is an integer selected from the range 0 to 6 and X is a linking group selected from -C(O)-, -O-, -OC(O)-, -S-, -S(O)-, -S(O)2-, -S(O)2ΝR4-, -NR4S(O)2-, -NR4-, -C(O)O-, -C(O)NR4-, -NR4C(O)-, -OC(O)NR4-, -C(O)NR SO2-, -NR4C(O)O-, -C(S)NR4- or -NR4C(S)-, wherein R4 is selected from hydrogen and C,.4alkyl; wherein any aryl, heteroaryl, heterocycle or C .ι2cycloalkyl may be unsubstituted or substituted on a ring carbon with one or more groups selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Cι.6alkyl, C2_6alkenyl, C2.6alkynyl, Cι.6alkoxy, Cι.6alkanoyl, Cι. alkanoyloxy, N-(Cι_6alkyl)amino, N,N-(Cι_6alkyl)2amιno, N,N-(Cι.6alkyl)2carbamoyl, Cι-6alkylSOa where a is an integer selected from the range 0 to 2, Cι_6alkoxycarbonyl, N-(Cι.6alkyl)sulphamoyl, NN-(Cι_6alkyl) sulphamoyl or phenylCι_ alkyl and a heterocycle or heteroaryl containing an -ΝH- group may be unsubstituted or substituted on a ring nitrogen with Cι_ alkyl, C2_6alkenyl, C2-6alkynyl, Ci-όalkanoyl, Cι_6alkylsulphonyl or phenylCι_6alkyl;
A is a ring selected from phenyl and naphthyl;
R" at each occurrence is independently selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino. carboxy, carbamoyl, mercapto, sulphamoyl, Cι-6alkyl, C2.6alkenyl, C2.6alkynyl, C|-6alkoxy, Cι_6alkanoyl, Cι_6alkanoyloxy, N-(Ci_6alkyl)amino, N,N-(C|.6alkyl)2amino, C,_6alkanoylamino, N-(Cι_6alkyl)carbamoyl, N,N-(Cι_6alkyl)2carbamoyl, Cι.6alkylSOa where a is an integer selected from the range 0 to 2, Cι.6alkoxycarbonyl, Λ-(Cι.6alkyl)sulphamoyl, NN-(C|.6alkyl)2sulphamoyl, and a group of the formula:
W- (CH2)p-B- LB wherein W is halo, nitro, hydroxy, Cι- alkoxy, cyano, amino, trifluoromethyl, trifluoromethoxy, carboxy, carbamoyl, mercapto, sulphamoyl, mesyl, N-Cι_6alkylamino, N,N-(Cι_6alkyl) amino, Cι-6alkoxycarbonyl, N-Cι. alkylcarbamoyl or
N,N-(C!_6alkyl)2carbamoyl, p is an integer selected from the range 1 to 6, and B is a bond, oxy, imino, N-(Cι_6alkyl)imino or -C(O)ΝH-, with the proviso that p is 2 or more unless B is a bond, -C(O)NH-, or
R2 is a group of formula IC:
D— E
IC wherein D is substituted or unsubstituted phenyl and E is selected from a bond, Cι_6alkylene, Cι.6alkyleneoxy, oxy, imino, N-(Cι_6alkyl)imino, C]_6alkyleneimino, N-(Cι.6alkyl)-C,_6alkyleneimino, -C(O)ΝH-, -SO2NH-, -NHSO2-, sulphonylCι.6alkylene, carbonylCι„6alkyleneoxycarbonyl-Cι-6alkylene and C2.6alkanoylimino, wherein said phenyl when substituted is substituted with one or more groups selected from halo, nitro, hydroxy, Cι_6alkoxy, cyano, amino, trifluoromethyl, trifluoromethoxy, carboxy, carbamoyl, mercapto, sulphamoyl, mesyl, N-Cι.6alkylamino, N,N-(C]„6alkyl)2amino, N-Cι_6alkylcarbamoyl or N,N-(Cι„6alkyl)2carbamoyl; m is an integer selected from the range 0 to 5 where at each occurrence R2 is independently selected from any foregoing moiety; or a pharmaceutically-acceptable salt or and in v/vo-hydrolysable ester, amide or carbamate thereof; with the following provisos: when A is phenyl: a) if A and R2 in combination is 4-mesyl then R1 is not 2-methoxycarbonylethyl; b) if A and R2 in combination is 4-chloro then R1 is not 2-methoxycarbonylethyl, 3-mercaptopropyl, 3-chloropropyl or 3-aminopropyl; c) if m is 0 then R1 is not 3-chloropropyl, 2-aminoethyl, 3-aminopropyl,
2-hydroxyethyl, methyl, ethyl, isopropyl or isobutyl; d) if A and R" in combination is 3-chloro then R is not 4-acetyl-4-ethoxycarbonylbutyl or 3-chloropropyl; e) if A and R~ in combination is 3,4,5-trimethoxy then R1 is not cyanomethyl or 2-aminoethyl; and f) when R1 is a substituted straight chain C|. alkyl group, the distal carbon atom, that is, the carbon atom of said C|.4alkyl group furthest from the homopiperazine ring, is not substituted with, i) two aryl rings, ii) two heteroaryl rings, or, iii) a heteroaryl and a phenyl ring; and with the further proviso that when R1 is substituted Cι_8alkyl, substituted C2.8alkenyl or substituted C2.8alkynyl the carbon atom adjacent to the homopiperazine ring is not directly substituted by any heteroatom other than fluoro. Detailed description of The Invention
As used herein the term "alkyl" includes both straight and branched chain alkyl groups but references to individual alkyl groups such as "propyl" are specific for the straight chain version only. A similar convention applies to "alkenyl", "alkynyl" and other radicals, for example "phenylCι_ alkyl" includes 2-phenylethyl, 2-phenylpropyl and 3-phenylpropyl. As used herein the term "halo" means fluoro, chloro, bromo and iodo. As used herein the term "aryl" means an unsaturated carbon ring. Particularly aryl means phenyl, naphthyl or biphenyl. More particularly aryl means phenyl.
As used herein the term "heteroaryl" or "heteroaryl ring" means, unless otherwise further specified, a monocyclic-, bicyclic- or tricyclic- 5-14 membered ring that is unsaturated or partially unsaturated, with up to five ring heteroatoms selected from nitrogen, oxygen and sulphur wherein a -CH2- group can optionally be replaced by a -C(O)-, and a ring nitrogen atom may be optionally oxidised to form the N-oxide. Examples of such heteroaryls include thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, pyridyl, pyridyl-N-oxide, oxopyridyl, oxoquinolyl, pyrimidinyl, pyrazinyl, oxopyrazinyl, pyridazinyl, indolinyl, benzofuranyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolinyl, quinazolinyl, xanthenyl, quinoxalinyl, indazolyl, benzofuranyl and cinnolinolyl.
As used herein the term "heterocyclyl" or "heterocyclic ring" means, unless otherwise further specified, a mono- or bicyclic- 5-14 membered ring, that is totally saturated, with up to five ring heteroatoms selected from nitrogen, oxygen and sulphur wherein a -CH2- group can optionally be replaced by a -C(O)-. Examples of such heterocyclyls include morpholinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, homopiperidinyl, homopiperazinyl and quinuclidinyl.
As used herein, where optional substituents are selected from "one or more" groups it is to be understood that this encompasses compounds where all substituents are chosen from one of the specified groups and compounds where substituents are chosen from more than one of the specified groups.
In the present invention, examples of Cι_8alkyl include C]. alkyl, Ci-salkyl, Cι_4alkyl, methyl, ethyl, isopropyl and t-butyl; examples of Cι-6alkoxycarbonyl include Cι_4alkoxycarbonyl, methoxycarbonyl, ethoxycarbonyl and n- and t-butoxycarbonyl; examples of C]_6alkoxy include Cι-4alkoxy, methoxy, ethoxy and propoxy; examples of
Cι.6alkanoylamino include formamido, acetamido and propionylamino; examples of Cι_6alkylS(O)a where a is 0-2 include methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl and ethylsulphonyl; examples of Cι_6alkanoyl include propionyl and acetyl; examples of N-Cι. alkylamino include N-methylamino and N-ethylamino; examples of N,N-(C|. alkyl)2amino include N,N-dimethylamino, N,N-diethylamino and
N-ethyl-N-methylamino; examples of C .8alkenyl include C2-6alkenyl, vinyl, allyl and 1-propenyl; examples of C2.8alkynyl include C2_ alkynyl, ethynyl, 1-propynyl and 2-propynyl; examples of N-(Cι_6alkyl)sulphamoyl include N-methylsulphamoyl and N-ethylsulphamoyl; examples of N,N-(Cι_6alkyl)2sulphamoyl include N,N-dimethylsulphamoyl and N-methyl-N-ethylsulphamoyl; examples of N-(Cι_6alkyl)carbamoyl include N-methylcarbamoyl and N-ethylcarbamoyl; examples of N,N-(Cι_6alkyl)2carbamoyl include N,N-dimethylcarbamoyl and N-methyl-N-ethylcarbamoyl; examples of Cι_ alkanoyloxy include propionyloxy, acetyloxy and formyloxy; examples of Cι_ alkoxyCι_6alkoxy include methoxymethoxy, methoxyethoxy and ethoxymethoxy; examples of Cj-βalkylsulphonyl include mesyl and ethylsulphonyl; examples of C3_ι2cycloalkyl include cyclopropyl and cyclohexyl.
In the linking groups B and E that fall within the definition of R", examples of Cι_6alkylene include -CH2CH2- and -CH CH(CH3)CH2-; examples of Cι_6alkyleneoxy include Cι.4alkyleneoxy, -CH2CH2O- and -CH2CH(CH3)CH2O-; examples of Ν-(Cι_6alkyl)imino include -N(Me)- and -N('Pr)-; examples of Cι_6alkyleneimino include -CH2CH2NH- and -CH2CH(CH3)CH2NH-; examples of N-(C1.6alkyl)-Cι.6alkyleneimino include -CH2CH2N(Me)- and -CH2CH(CH3)CH2N(iPr)-; examples of sulphonylCj.6alkylene include sulphonylC,.4alkylene, -SO2CH2CH2- and -SO2CH2CH(CH3)CH2-; examples of carbonylCι-6alkyleneoxycarbonyl-Cι. alkylene include -C(O)CH2CH2OC(O)CH2- and -C(O)CH2CH(CH3)CH2OC(O)CH2CH2-; examples of C2_6alkanoylimino include -CH2CH2C(O)NH- and -CH2CH(CH3)CH2C(O)NH-.
In a particular aspect of the invention R1 is other than hydrogen. Particularly, R1 is Cι_8alkyl substituted with one or more halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Cι_6alkoxy, Cι.6alkanoyl, Cι_6alkoxycarbonyl, Cι-6alkanoyloxy, N-(Cι_ alkyl)amino, N,N-(Cι-6alkyl)2amino, Ci-βalkanoylamino, N-(Cι_ alkyl)carbamoyl, N,N-(Cι_6alkyl) carbamoyl, Cι_6alkoxyCι.6alkoxy, Cι_ alkylS(O)a wherein a is 0 to 2, N-(Cι_6alkyl)sulphamoyl or N,N-(Cι. alkyl)2sulphamoyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3.ι cycloalkyl, or a group of formula IA:
G- CCH^X-
IA wherein G is substituted or unsubstituted aryl, substituted or unsubstituted carbon linked heteroaryl, substituted or unsubstituted carbon-linked heterocycle or substituted or unsubstituted C3_ι2cycloalkyl, p is 0 to 6 and X is a linking group and is selected from -C(O)-, -O-, -OC(O)-, -S-, -S(O)-, -S(O)2-, -S(O)2NR4-, -NR4S(O)2-, -NR4-, -C(O)O-, -C(O)NR4-, -NR4C(O)-, -OC(O)NR4-, -C(O)NR4SO2-, -NR4C(O)O-, -C(S)NR4- or -NR4C(S)- wherein R4 is selected from hydrogen and C).4alkyl; wherein in any of the foregoing, any aryl, heteroaryl, heterocycle or C3_ι cycloalkyl may be unsubstituted or substituted on a ring carbon with one or more groups selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Cι_6alkyl, C2_6alkenyl, C _ alkynyl, Cι_ alkoxy, Cι.6alkanoyl, Cι_6alkanoyloxy, N-(Cι_6alkyl)amino, N,N-(Cι.6alkyl)2amino, Cι.6alkanoylamino, N-(Cι-6alkyl)carbamoyl, N,N-(Cι.6alkyl)2carbamoyl, Cι.6alkylS(O)a wherein a is 0 to 2, Cι.6alkoxycarbonyl, N-(Cι_6alkyl)sulphamoyl, N,N-(Cι_6alkyl)2sulphamoyl or and a heterocycle or heteroaryl containing an -ΝH- group may be unsubstituted or substituted with Cι_6alkyl, C2.6alkenyl, C2. alkynyl, C].6alkanoyl, Cι-6alkylsulphonyl or phenylCι_6alkyl and with the proviso that when R1 is substituted C].8alkyl, substituted C2.8alkenyl or substituted C2_8alkynyl the carbon atom adjacent to the homopiperazine ring is not directly substituted by any heteroatom other than fluoro.
In another aspect of the invention. R is hydrogen or Cι_8alkyl optionally substituted with fluoro or aryl.
In a particular aspect of the invention R is hydrogen or C|.8alkyl optionally substituted with fluoro or phenyl. Particularly R1 is hydrogen, methyl, n-propyl, 3-methylbutyl, isopropyl, benzyl,
3-fluoropropyl or 3-phenylpropyl.
More particularly R1 is methyl, n-propyl, 3-methylbutyl, isopropyl, benzyl, 3-fluoropropyl or 3-phenylpropyl.
Most particularly R1 is methyl. In one aspect of the invention, Ring A is phenyl.
In another aspect of the invention, Ring A is naphthyl.
In one aspect of the inventions R" is halo, nitro, trifluoromethyl, trifluoromethoxy, Cι.6alkyl, ^alkoxy, C].6alkoxycarbonyl, or a group of the formula IC as disclosed above, wherein D is phenyl and E is a bond, Cι_ alkyleneoxy or sulphonylCι_ alkylene. More particularly R2 is fluoro, chloro, bromo, iodo, nitro, trifluoromethyl, trifluoromethoxy, methyl, methoxy, methoxycarbonyl or a group of the formula IC as depicted above, wherein D is phenyl and E is a bond, methyleneoxy or sulphonylmethylene. -σ-
Particularly R2 is fluoro, chloro, bromo, iodo, nitro, trifluoromethyl, trifluoromethoxy, methyl, methoxy, methoxycarbonyl or a group of the formula IC as depicted above, wherein D is phenyl and E is a bond or methyleneoxy.
In one aspect of the invention m is an integer selected from the range 0 to 3. In a particular aspect of the invention m is an integer selected from the range 0 to 2.
Particular combinations of Ring A and (R")m are as follows: such combinations are phenyl, naphth-1-yl, biphen-2-yl, 2-bromophenyl, 2-nitrophenyl, 2-trifluoromethylphenyl, 2-(phenylsulphonylmethyl)phenyl, 3-fluorophenyl, 3-chlorophenyl, 3-iodophenyl, 3-nitrophenyl, 3-trifluoromethylphenyl, 3-methoxyphenyl, 3-methoxycarbonylphenyl, 4-fluorophenyl, 4-bromophenyl, 4-nitrophenyl. 4-methylphenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 4-methoxycarbonylphenyl, 4-benzyloxyphenyl, 2,4-difluorophenyl, 2,4-ditrifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl, 2-methoxy-5-nitrophenyl, 3,4-difluorophenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 3,5-ditrifluoromethylphenyl or 4,5-dimethoxy-2-nitrophenyl. More particular combinations of Ring A and (R")m are naphth-1-yl, biphen-2-yl,
3-fluorophenyl, 3-chlorophenyl, 3-iodophenyl, 3-nitrophenyl, 3-trifluoromethylphenyl, 3-methoxyphenyl, 3-methoxycarbonylphenyl, 4-bromophenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 4-methoxycarbonylphenyl, 4-benzyloxyphenyl, 2,4-ditrifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl, 2-methoxy-5-nitrophenyl, 3,4-difluorophenyl, 3,4-dimethylphenyl, 3,5-ditrifluoromethylphenyl or 4,5-dimethoxy-2-nitrophenyl.
Most particularly combinations of Ring A and (R2)m are 4-benzyloxyphenyl, 2,4-ditrifluoromethylphenyl or 3-iodophenyl.
Therefore, in a particular aspect of the invention, there is provided a compound of formula I as disclosed herein wherein:
R1 is hydrogen or Cι.8alkyl optionally substituted with fluoro or aryl;
Ring A is phenyl or naphthyl;
R2 is halo, nitro, trifluoromethyl, trifluoromethoxy, Cι-6alkyl, Cι.6alkoxy, Cι_6alkoxycarbonyl, or a group of the formula IC as disclosed herein, wherein D is phenyl and E is a bond, Cι_ alkyleneoxy or sulphonylCι_6alkylene; and m is an integer selected from the range 0 to 3; or a pharmaceutically-acceptable salt or and in v/vo-hydrolysable ester, amide or carbamate thereof; with the provisos that when A is phenyl: a) if A and R2 in combination is 3-chloro or 4-chloro then R1 is not 3-chloropropyl; b) if m is 0 then R1 is not 3-chloropropyl, methyl, ethyl, isopropyl or isobutyl; and c) when R1 is a substituted straight chain Cι.4alkyl group, the distal carbon atom, that is, the carbon atom of said Cι. alkyl group furthest from the homopiperazine ring, is not substituted with two aryl rings.
Therefore, in a more particular aspect of the invention, there is provided a compound of formula I as depicted above wherein:
R1 is hydrogen, Cι_8alkyl optionally substituted with fluoro or phenyl; Ring A is phenyl or naphthyl;
R" is fluoro, chloro, bromo, iodo, nitro, trifluoromethyl, trifluoromethoxy, methyl, methoxy, methoxycarbonyl or a group of the formula IC as depicted above, wherein D is phenyl and E is a bond, methyleneoxy or sulphonylmethylene; and m is an integer selected from the range 0 to 3; or a pharmaceutically-acceptable salt or and in v/vohydrolysable ester, amide or carbamate thereof; with the proviso that when A is phenyl and a) m is 0 then R1 is not methyl, ethyl, isopropyl or isobutyl b) R1 is a substituted straight chain Cι.4alkyl group, the distal carbon atom, that is, the carbon atom of said Cι.4alkyl group furthest from the homopiperazine ring, is not substituted with two phenyl rings.
Therefore, in a further particular aspect of the invention, there is provided a compound of formula I as depicted above wherein:
R1 is hydrogen, methyl, n-propyl, 3-methylbutyl, isopropyl, benzyl, 3-fluoropropyl or 3-phenylpropyl; and
Ring A and R2 in combination form phenyl, naphth-1-yl, biphen-2-yl, 2-bromophenyl, 2-nitrophenyl, 2-trifluoromethylphenyl, 2-(phenylsulphonylmethyl)phenyl, 3-fluorophenyl, 3-chlorophenyl, 3-iodophenyl, 3-nitrophenyl, 3-trifluoromethylphenyl, 3-methoxyphenyl, 3-methoxycarbonylphenyl, 4-fluorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 4-methoxycarbonylphenyl, 4-benzyloxyphenyl, 2,4-difluorophenyl, 2,4-ditrifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl, 2-methoxy-5-nitrophenyl, 3,4-difluorophenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 3,5-ditrifluoromethylphenyl or 4,5-dimethoxy-2-nitrophenyl; or a pharmaceutically-acceptable salt or and in v/vo-hydrolysable ester, amide or carbamate thereof; with the proviso that when Ring A and R" in combination are phenyl then R is not methyl, isopropyl or isobutyl.
Therefore, in another aspect of the invention, there is provided a compound of formula I as depicted above wherein:
R1 is methyl, n-propyl, 3-methylbutyl, isopropyl, benzyl, 3-fluoropropyl or 3-phenylpropyl; and
Ring A and R" in combination form naphth-1-yl, biphen-2-yl, 3-fluorophenyl, 3-chlorophenyl, 3-iodophenyl, 3-nitrophenyl, 3-trifluoromethylphenyl, 3-methoxyphenyl, 3-methoxycarbonylphenyl, 4-bromophenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 4-methoxycarbonylphenyl, 4-benzyloxyphenyl, 2,4-ditrifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl, 2-methoxy-5-nitrophenyl, 3,4-difluorophenyl, 3,4-dimethylphenyl, 3,5-ditrifluoromethylphenyl or 4,5-dimethoxy-2-nitrophenyl; or a pharmaceutically-acceptable salt or and in v vo-hydrolysable ester, amide or carbamate thereof. Therefore, in another particular aspect of the invention, there is provided a compound of formula I as depicted above wherein:
R1 is methyl, n-propyl, 3-methylbutyl, isopropyl, benzyl, 3-fluoropropyl or 3-phenylpropyl; and
Ring A and R2 in combination form 4-benzyloxyphenyl, 2,4-ditrifluoromethylphenyl or 3-iodophenyl; or a pharmaceutically-acceptable salt or and in vivo-hydrolysable ester, amide or carbamate thereof.
Particular compounds of the invention are those of Examples and include: l-methyl-4-(4-benzyloxybenzyl)homopiperazine; l-methyl-4-(2,4-bis(trifluoromethyl)benzyl)homopiperazine; l-propyl-4-(4-benzyloxybenzyl)homopiperazine; l-benzyl-4-(4-benzyloxybenzyl)homopiperazine; l-pentyl-4-(4-benzyloxybenzyl)homopiperazine; l-methyl-4-(3,5-bis(trifluoromethyl)benzyl)homopiperazine;
1 -(2-pheny lethyl)-4-(4-benzy loxybenzyl)homopiperazine ; l-(3,5-difluorobenzyl)-4-(4-benzyloxybenzyl)homopiperazine; l-(3,4,4-trifluoro-but-3-enyl)-4-(4-benzyloxybenzyl)homopiperazine;
1 -butyl-4-(4-benzyloxybenzy l)homopiperazine ; l-isopropyl-4-(4-benzyloxybenzyl)homopiperazine; l-(2-methylpropyl)-4-(4-benzyloxybenzyl)homopiperazine; l-ethyl-4-(4-benzyloxybenzyl)homopiperazine; l-methyl-4-(4-tert-butylbenzyl)homopiperazine, and l-(2-hydroxypropyl)-4-(4-benzyloxybenzyl)homopiperazine.
Suitable pharmaceutically-acceptable salts include acid-addition salts such as methanesulphonate, fumarate, hydrochloride, hydrobromide, citrate, maleate, phosphate and sulphate. In another aspect suitable salts are base salts such as an alkali metal salt, for example sodium, an alkaline earth metal salt, for example calcium or magnesium, an organic amine salt, for example triethylamine, morpholine, N-methylpiperidine, N-ethylpiperidine, procaine, dibenzylamine and NN-dibenzylethylamine, or amino acids, for example lysine. A compound of the invention may have more than one cation or anion depending on the number of charged functions and the valency of the cations or anions. A preferred pharmaceutically-acceptable salt is a sodium salt.
Compounds of formula I may possess a chiral centre. It is to be understood that the invention encompasses all optical isomers and diasteroisomers of compounds of formula I that act at the [3H]-emopamil binding site. Further, all tautomeric forms of compounds of formula I are compounds of the present invention. It is also to be understood that certain compounds of the formula I can exist in unsolvated as well as solvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms.
In v vo-hydrolysable esters, amides and carbamates are compounds that hydrolyse in the human body to produce the parent compound. Such esters, amides and carbamates can be identified by administering, for example intravenously to a test animal, the compound under test and subsequently examining the test animal's body fluids. Suitable in v/vo-hydrolysable amides and carbamates include Ν-carbomethoxy and Ν-acetyl. An in v/vo-hydrolysable ester of a compound of the formula I containing carboxy or hydroxy group is, for example, a pharmaceutically-acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol.
Suitable pharmaceutically-acceptable esters for carboxy include Cι_6alkoxymefhyl esters, for example methoxymethyl; Cι-6alkanoyloxymethyl esters, for example pivaloyloxymethyl; phthalidyl esters; C3.8cycloalkoxy-carbonyloxyCι_6alkyl esters, for example 1-cyclohexylcarbonyloxyethyl; 1 ,3-dioxolen-2-onylmethyl esters, for example 5-methyl-l,3-dioxolen-2-onylmethyl; and Cι.6alkoxycarbonyloxyethyl esters, for example 1-methoxycarbonyloxyethyl. Such esters may be formed at any carboxy group in a compound of this invention.
An in v/vo-hydrolysable ester of a compound of the formula I having a hydroxy group includes inorganic esters such as phosphate esters and α-acyloxyalkyl ethers and related compounds which, as a result of the in vivo hydrolysis of the ester, yield the parent hydroxy group. Examples of α-acyloxyalkyl ethers include acetoxymethoxy and 2, 2-dimethylpropionyloxy methoxy. A selection of in v vo-hydroly sable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl. Another aspect of the present invention provides a process for preparing a compound of formula I or a pharmaceutically-acceptable salt or an in v vo-hydrolysable ester, amide or carbamate thereof which process, wherein R , R", Ring A and m are, unless otherwise specified, as defined for formula I comprises: a) reacting a compound of the formula II:
wherein
L is a suitable displaceable group, with a compound of the formula III: m
wherein, when R1 of a compound of formula I is hydrogen Ra is suitable amino protecting group such as those defined below; or when R1 of a compound of formula I is not hydrogen Ra is R'; or b) for preparing a compound of formula I wherein R1 is not hydrogen, reacting a compound of formula IV:
IV with a compound of formula V:
R'-L V wherein L is a suitable displaceable group and R1 is not hydrogen; or c) reacting a compound of the formula VI:
VI with a compound of the formula III; or d) for preparing compounds of formula I wherein R1 is not hydrogen and there is a -CH2- or CH3- moiety attached to the nitrogen of the homopiperazine ring, reacting a compound of formula IV with a compound for formula VII:
VII wherein Rb is hydrogen or substituted or unsubstituted Cι. alkyl, substituted or unsubstituted C2_ alkenyl or substituted or unsubstituted C2.7alkynyl and Rc is hydrogen or hydroxy; and thereafter if necessary: i) converting a compound of the formula I into another compound of the formula I; ii) removing any protecting groups; or iii) forming a pharmaceutically-acceptable salt or in v/vo-hydrolysable ester, amide or carbamate. As used herein, the L is a displaceable group, and suitable values for L are, for example, a halogeno or sulphonyloxy group, such groups are chloro, bromo, methanesulphonyloxy or toluene-4-sulphonyloxy group.
Specific reaction conditions for reactions a) and b) are as follows. Compounds of formula II and III and compounds of formula IV and V are reacted together under standard alkylation conditions. For example in an organic solvent, for example an anhydrous aprotic solvent such as dimethylformamide, dimethylacetamide or tetrahydrofuran, optionally in the presence of a catalyst, such as an iodide salt for example potassium iodide, and at a temperature in the range of 0-100 °C, preferably 40-80 °C. Compounds of formula II, III and V are commercially available compounds, are disclosed in the literature, or are prepared by standard processes known in the art.
Compounds of formula IV may be prepared according to the following scheme:
IVA IVB IVC wherein Pg is a suitable amino protecting group such as those described hereinbelow that can be removed by standard deprotection conditions such as those also described hereinbelow. Specific reaction conditions for reactions c) and d) are as follows. Amines may be reacted with aldehydes under standard reductive amination conditions. For example in the presence of a reducing agent such as hydrogen and a hydrogenation catalyst, for example palladium on carbon, or zinc and hydrochloric acid, or sodium cyanoborohydride, or sodium triacetoxyborohydride, or sodium borohydride, iron pentacarbonyl and alcoholic potassium hydroxide, or borane and pyridine or formic acid. The reaction is preferable carried out in the presence of a suitable solvent such as an alcohol, for example methanol or ethanol, and at a temperature in the range of 0-50 °C, preferably at or near room temperature.
Compounds of formula VI and VII are commercially available compounds, or they are known in the literature, or they are prepared by standard processes known in the art.
It will be appreciated that certain of the various ring substituents in the compounds of the present invention may be introduced by standard aromatic substitution reactions or generated by conventional functional group modifications either prior to or immediately following the processes mentioned above, and as such are included in the process aspect of the invention. Such reactions and modifications include, for example, introduction of a substituent by means of an aromatic substitution reaction, reduction of substituents, alkylation of substituents and oxidation of substituents. The reagents and reaction conditions for such procedures are well known in the chemical art. Particular examples of aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid, the introduction of an acyl group using, for example, an acyl halide and Lewis acid, such as aluminium trichloride, under Friedel Crafts conditions; the introduction of an alkyl group using an alkyl halide and Lewis acid, such as aluminium trichloride, under Friedel Crafts conditions; and the introduction of a halogeno group. Particular examples of modifications include the reduction of a nitro group to an amino group by for example, catalytic hydrogenation with a nickel catalyst or treatment with iron in the presence of hydrochloric acid with heating; oxidation of alkylthio to alkylsulphinyl or alkylsulphonyl.
It will also be appreciated that in some of the reactions mentioned herein it may be necessary or desirable to protect any sensitive groups in the compounds. The instances where protection is necessary or desirable and suitable methods for protection are known to those skilled in the art. Conventional protecting groups may be used in accordance with standard practice (for illustration see T.W. Greene, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991). Thus, if reactants include groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein.
A suitable protecting group for an amino or alkylamino group is, for example, an acyl group; for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a t-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.
A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
The protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art. In order to use a compound of the formula I or a pharmaceutically-acceptable salt or in v vo-hydrolysable ester, amide or carbamate thereof for the therapeutic treatment (including prophylactic treatment) of mammals including humans, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition. The pharmaceutical compositions of compounds of this invention may be administered in standard manner for the disease condition that it is desired to treat, for example by oral, topical, parenteral, buccal, nasal, vaginal or rectal administration or by inhalation. For these purposes the compounds of this invention may be formulated by means known in the art into the form of, for example, tablets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, finely divided powders or aerosols for inhalation, and for parenteral use such as intravenous, intramuscular or infusion, sterile aqueous or oily solutions or suspensions or sterile emulsions. A preferred route of administration is intravenously in sterile isotonic solution.
In addition to the compounds of the present invention the pharmaceutical composition of this invention may also contain, or be simultaneously or sequentially co-administered with, one or more pharmacological agents of value in treating one or more disease conditions referred to hereinabove.
The pharmaceutical compositions of this invention will normally be administered to humans so that, for example, a daily dose of 0.05 to 75 mg/kg body weight (and preferably of 0.1 to 30 mg/kg body weight) is received. This daily dose may be given in divided doses as necessary, the precise amount of the compound received and the route of administration depending on the weight, age and sex of the patient being treated and on the particular disease condition being treated according to principles known in the art.
Typically unit dosage forms will contain about 1 mg to 500 mg of a compound of this invention.
According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the formula I:
-lo- r wherein:
R1 is hydrogen, substituted or unsubstituted Cj.8alkyl, substituted or unsubstituted C2.8alkenyl or substituted or unsubstituted C2.8alkynyl; wherein said Cι_8alkyl, C2.8alkenyl and C2.8alkynyl are unsubstituted or substituted with one or more substituents independently selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Cι_6alkoxy, C|.6alkanoyl, Cι_6alkoxycarbonyl, N-(Cι_6alkyl)amino, N,N-(Cι_6alkyl)2amino, C]_6alkanoylamino, N-(Cι_6alkyl)carbamoyl, N,N-(Cι-6alkyl)2carbamoyl, Cι.6alkoxyC).6alkoxy, Cι-6alkylS(O)a wherein a is 0 to 2, N-(Cι_6alkyl)sulphamoyl or N,N-(Cι.6alkyl)2sulphamoyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3_|2cycloalkyl, and a group of formula IA:
G- CCH^X-
IA wherein:
G is substituted or unsubstituted aryl, substituted or unsubstituted carbon linked heteroaryl, substituted or unsubstituted carbon-linked heterocycle or substituted or unsubstituted C3.ι2cycloalkyl, p is an integer selected from the range 0 to 6 and X is a linking group selected from -C(O)-, -O-, -OC(O)-, -S-, -S(O)-, -S(O)2-, -S(O)2ΝR4-, -NR4S(O)2-, -NR4-, -C(O)O-, -C(O)NR4-, -NR4C(O)-, -OC(O)NR4-, -C(O)NR4SO2-, -NR4C(O)O-, -C(S)NR4- or -NR4C(S)-, wherein R4 is selected from hydrogen and C alkyl; wherein any aryl, heteroaryl, heterocycle or C3_ι2cycloalkyl may be substituted or unsubstituted on a ring carbon with one or more groups selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Cι-6alkyl, C2.6alkenyl, C2.6alkynyl, Cι_6alkoxy, Cι_ alkanoyl, Cι.6alkanoyloxy, N-(Cι.6alkyl)amino, N,N-(Ci-6alkyl)2amino, Cι_6alkanoylamino, N-(Cι.6alkyl)carbamoyl, N,N-(Ci_6alkyl)2carbamoyl, Cι-6alkylSOa where a is an integer selected from the range 0 to 2, Cι.6alkoxycarbonyl, N-(Cj. alkyl)sulphamoyl, N,N-(Cι_6alkyl)2sulphamoyl or phenylCι_6alkyl and a heterocycle or heteroaryl containing an -ΝH- group may be substituted or unsubstituted on a ring nitrogen with Cι_ alkyl, C2.6alkenyl, C2.6alkynyl, Cι_ alkanoyl, -βalkylsulphonyl or phenylCι. alkyl; A is a ring selected from phenyl and naphthyl;
R2 at each occurrence is independently selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Cι.6alkyl, C2.6alkenyl, C2_6alkynyl, Cι_6alkoxy, Cι.6alkanoyl, C^alkanoyloxy, N-(Cι-6alkyl)amino, N,N-(Cι_6alkyl)2amino, Cι.6alkanoylamino, N-(Cι.6alkyl)carbamoyl, N,N-(Cι_6alkyl)2carbamoyl, Cι-6alkylSOa where a is an integer selected from the range 0 to 2, Cι_ alkoxycarbonyl, N-(Cι-6alkyl)sulphamoyl, N,N-(Cι_6alkyl)2sulphamoyl, and a group of the formula:
W- (CH2)p-B- LB wherein W is halo, nitro, hydroxy, C|_6alkoxy, cyano, amino, trifluoromethyl, trifluoromethoxy, carboxy, carbamoyl, mercapto. sulphamoyl, mesyl, N-Cι.6alkylamino, N,N-(Cι.6alkyl)2amino, Cι_6alkoxycarbonyl, N-C|_6alkylcarbamoyl or
N,N-(Cι.6alkyl)2carbamoyl, p is an integer selected from the range 1 to 6, and B is a bond, oxy, imino, N-(Cι-6alkyl)imino or -C(O)ΝH-, with the proviso that p is 2 or more unless B is a bond, -C(O)NH-, or
R2 is a group of formula IC:
D— E
IC wherein D is unsubstituted or substituted phenyl and E is selected from a bond, C|.6alkylene, Cι_6alkyleneoxy, oxy, imino, N-(Cι_6alkyl)imino, Cι_6alkyleneimino, N-(C!.6alkyl)-Cι.6alkyleneimino, -C(O)ΝH-, -SO2NH-, -NHSO2-, sulphonylCι.6alkylene, carbonylCι.6alkyleneoxycarbonyl-Cι.6alkylene and C2_6alkanoylimino, wherein said phenyl when substituted is substituted with one or more groups selected from halo, nitro, hydroxy, Cι. alkoxy, cyano, amino, trifluoromethyl, trifluoromethoxy, carboxy, carbamoyl, mercapto, sulphamoyl, mesyl, N-Cι.6alkylamino, N,N-(Cι_6alkyl)2amino, Cι_6alkoxycarbonyl, N-Cι.6alkylcarbamoyl or N,N-(Cι.6alkyl)2carbamoyl; m is an integer selected from the range 0 to 5 where at each occurrence R2 is independently selected from any foregoing moiety; or a pharmaceutically-acceptable salt or and in v/vo-hydrolysable ester, amide or carbamate thereof; with the following provisos: when A is phenyl: a) if A and R2 in combination is 4-chlorophenyl then R! is not 3-mercaptopropyl; b) if A and R2 in combination is 3,4,5-trimethoxyphenyl then R1 is not cyanomethyl or 2-aminoethyl; and c) when R1 is a substituted straight chain Cι_ alkyl group, the distal carbon atom, that is the carbon atom of this Cι.4alkyl group furthest from the homopiperazine ring, is not substituted with i) two aryl rings, ii) two heteroaryl rings or iii) a heteroaryl and a phenyl ring; and with the further proviso that when Rl is substituted C|_8alkyl, substituted C -8alkenyl or substituted C2-8alkynyl the carbon atom adjacent to the homopiperazine ring is not directly substituted by any heteroatom other than fluoro.
According to a further aspect of the present invention there is provided a compound of the formula I' or a pharmaceutically-acceptable salt or an in v/vo-hydrolysable ester, amide or carbamate thereof, as defined hereinbefore for use in a method of treatment of the human or animal body by therapy. A further feature of the present invention is a compound of formula I' and pharmaceutically-acceptable salts or an in v/vo-hydrolysable ester, amide or carbamate thereof, for use as a medicament.
Conveniently, such a compound of formula F is a compound of formula (I"):
I" wherein:
R1 is hydrogen, substituted or unsubstituted Cι-8alkyl, substituted or unsubstituted C2-8alkenyl or substituted or unsubstituted C2-8alkynyl; wherein said Cι_8alkyl, C .8alkenyl and C2_8alkynyl are unsubstituted or substituted with one or more substituents independently selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Cι.6alkoxy, Cι_ alkanoyl, Cι- alkoxycarbonyl, Cι. alkanoyloxy, N-(Cι-6alkyl)amino, N,N-(Cι.6alkyl)2amino, Cι.6alkanoylamino, N-(C|.6alkyl)carbamoyl, N,N-(Cι.6alkyl)2carbamoyl, Cι-6alkoxyCι_6alkoxy, C|_ alkylS(O)a wherein a is 0 to 2, N-(C].6alkyl)sulphamoyl or N,N-(Cι_6alkyl)2sulphamoyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted heteroaryl, substituted or unsubstituted C .ι2cycloalkyl, and a group of formula IA:
G- CCH^X-
IA wherein:
G is substituted or unsubstituted aryl, substituted or unsubstituted carbon linked heteroaryl, substituted or unsubstituted carbon-linked heterocycle or substituted or unsubstituted C3.|2cycloalkyl, p is an integer selected from the range 0 to 6 and X is a linking group selected from -C(O)-, -O-, -OC(O)-, -S-, -S(O)-, -S(O)2-, -S(O)2ΝR4-, -NR4S(O)2-, -NR4-, -C(O)O-, -C(O)NR4-, -NR4C(O)-, -OC(O)NR4-, -C(O)NR4SO2-, -NR4C(O)O-, -C(S)NR4- or -NR4C(S)-, wherein R4 is selected from hydrogen and C,.4alkyl; wherein any aryl, heteroaryl, heterocycle or C _ι cycloalkyl may be unsubstituted or substituted on a ring carbon with one or more groups selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Cι-6alkyl, C2_6alkenyl, C2.6alkynyl, Cι_6alkoxy, Cι_6alkanoyl, Cι_ alkanoyloxy, N-(Cι.6alkyl)amino, N,N-(Cι_6alkyI) amino, Cι.6alkanoylamino, N-(Cι_6alkyl)carbamoyl, NN-(Cι.6alkyl)2carbamoyl, Cι_6alkylSOa where a is an integer selected from the range 0 to 2, Cι-6alkoxycarbonyl, N-(Cι_6alkyl)sulphamoyl, NN-(Cι_6alkyl)2sulphamoyl or phenylCι_6alkyl and a heterocycle or heteroaryl containing an -ΝH- group may be unsubstituted or substituted on a ring nitrogen with Cι.6alkyl, C2. alkenyl, C2.6alkynyl, Cι„ alkanoyl, Cι.6alkylsulphonyl or phenylCι.6alkyl;
A is a ring selected from phenyl and naphthyl; R2 at each occurrence is independently selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Cι_ alkyl, C2. alkenyl, C2.6alkynyl, Cι_6alkoxy, Cι.6alkanoyl, Cι_ alkanoyloxy, N-(Cι.6alkyl)amino, N,N-(Cι_6alkyl)2amino, Cι.6alkanoylamino, N-(Cι.6alkyl)carbamoyl, N,N-(Cι.6alkyl)2carbamoyl, Cι.6alkylSOa where a is an integer selected from the range 0 to 2, Cι-6alkoxycarbonyl, N-(Cι.6alkyl)sulphamoyl, N,N-(Cι_6alkyl)2sulphamoyl, and a group of the formula:
W- (CH2)p-B- LB wherein W is halo, nitro, hydroxy, Cι-6alkoxy, cyano, amino, trifluoromethyl, trifluoromethoxy, carboxy, carbamoyl, mercapto, sulphamoyl, mesyl, N-Cι.6alkylamino, N,N-(Cι-6alkyl)2amino, Cι. alkoxycarbonyl, N-Cι_6alkylcarbamoyl or N,N-(Ci-6alkyl)2carbamoyl, p is an integer selected from the range 1 to 6, and B is a bond, oxy, imino, N-(Cι_ alkyl)imino or -C(O)ΝH-, with the proviso that p is 2 or more unless B is a bond, -C(O)NH-, or
R2 is a group of formula IC:
D— E IC wherein D is substituted or unsubstituted phenyl and E is selected from a bond, Cι_6alkylene,
Cι.6alkyleneoxy, oxy, imino, N-(C|_6alkyl)imino, Cι.6alkyleneimino,
N-(C,.6alkyl)-Cι.6alkyleneimino, -C(O)ΝH-, -SO2NH-, -NHSO2-, sulphonylC ^alkylene, carbonylCι-6alkyleneoxycarbonyl-Cι_6alkylene and C2.6alkanoylimino, wherein said phenyl when substituted is substituted with one or more groups selected from halo, nitro, hydroxy,
Cι-6alkoxy, cyano, amino, trifluoromethyl, trifluoromethoxy, carboxy, carbamoyl, mercapto, sulphamoyl, mesyl, N-Ci-ealkylamino, N,N-(Cι.6alkyl)2amino, Ci .^alkoxycarbonyl,
N-C).6alkylcarbamoyl or NN-(Cι_6alkyl) carbamoyl; m is an integer selected from the range 0 to 5 where at each occurrence R2 is independently selected from any foregoing moiety; or a pharmaceutically-acceptable salt or and in v/vo-hydrolysable ester, amide or carbamate thereof; with the following proviso: when R1 is substituted Cι-8alkyl, substituted C2.8alkenyl or substituted C2.8alkynyl the carbon atom adjacent to the homopiperazine ring is not directly substituted by any heteroatom other than fluoro; for use as a medicament to inhibit the [3H] -emopamil binding site in a warm-blooded animal such as a human being.
Thus according to a further aspect of the invention there is provided the use of a compound of the formula I", or a pharmaceutically-acceptable salt or an in v vo-hydrolysable ester, amide or carbamate thereof, in the manufacture of a medicament for use in the inhibition of the [ H] -emopamil binding site in a warm-blooded animal such as a human being.
According to a further feature of the invention there is provided a method of inhibiting of the [3H] -emopamil binding site in a warm-blooded animal, such as a human being, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula I" or a pharmaceutically-acceptable salt or an in v/vo-hydrolysable ester, amide or carbamate thereof, as defined hereinbefore.
The following Biological Test Methods, Data and Examples serve to illustrate the present invention. The following Biological Test Methods, Results and Examples serve to illustrate the present invention. Biological Test Methods
3H-Emopamil binding to guinea pig liver membranes
Binding at the [3H]-emopamil binding site was determined by a modification of the method described by Zech, C, Staudinger R., Miihlbacher, J. and Glossmann, H. Novel sites for phenylalkylamines: characterisation of a sodium-sensitive drug receptor with (-)-3H- emopamil. Eur. J. Pharm. 208: 119-130, 1991.
Guinea-pig liver membrane preparation:
Male guinea pigs were sacrificed by CO asphyxiation with dry ice. The livers were quickly excised and weighed and rinsed in membrane preparation buffer containing 10 mM Hepes, 1 mM Tris base-EDTA, 250 mM sucrose, pH 7.4. The livers were then minced, homogenised in 10 times volume with a motor driven Teflon-glass homogeniser with three strokes on ice. The homogenate was centrifuged at 1000 x g in a SS34 rotor for 5 minutes at 4 °C. The supernatant was filtered through 4 layers of gauze and then centrifuged at 8000 x g for 10 minutes at 4 °C. This resulting supernatant was centrifuged at 40,000 x g for 15 minutes at 4 °C. The resulting pellet was resuspended in assay buffer and centrifuged again at 40,000 x g for 15 minutes at 4 °C. This pellet was resuspended in assay buffer (2.5 fold with respect to original wet weight) and homogenised with one stroke with the Teflon-glass homogeniser. Aliquots of 1 mL were stored at -70 °C. Assay Reaction Mixture:
Assay buffer: 10 mM Tris-HCl, 0.1 mM phenylmethylsulfonyl fluoride (PMSF), 0.2% bovine serum albumin (BSA), pH 7.4 at 4 °C. Radioligand: 0.96 nM (-)- H-emopamil (Amersham).
Guinea pig liver membranes: 40mg/mL original wet weight.
Compounds: 1-300 nM.
Total volume: 500 μL. This mixture was incubated for 60 minutes at 37 °C. The incubation was terminated by filtering with a Brandel Cell Harvester over Whatman GF/C filters that had been soaked for at least 120 minutes in 0.3% polyethylenimine (PEI) and washed three times with 5 mL of wash buffer containing 10 mM Tris-HCl, 10 mM MgCl2, 0.2% BSA, pH 7.4 at 25 °C. Specific binding was defined with 10 μM emopamil. In general compounds of the present invention bound to the [3H] -emopamil binding site with an IC50 below 200 nM in this test.
Results:
The following results were obtained in the H-Emopamil binding to guinea pig liver membranes test:
H-D-888 binding to rat brain cortical membranes 3H-D-888 binding was determined by a modification of Reynolds, I.J., Snowman,
A.M. and Synder, S.H. (-)-[3H] Desmethoxyverapamil labels multiple calcium channel modular receptors in brain and skeletal muscle membranes: differentiation by temperature and dihydropyridines. J. Pharmacol. Exp. Ther. 237: no.3, 731-738, 1986. Rat brain cortical membrane preparation Male Sprague-Dawley Rats were sacrificed by decapitation and the brains were quickly excised. The cerebellum and brain stem were removed and discarded; and the rest of the brain was rinsed in 320 mM sucrose. The brain was then homogenised in a 10-fold volume of 320 mM sucrose with a motor driven Teflon-glass homogeniser using 10 strokes on ice. The homogenate was spun at 1000 x g for 10 minutes at 4 °C in a SS-34 rotor. The supernatant was then spun at 29,000 x g for 20 minutes. The resulting pellet was resuspended in membrane buffer (5 mM Hepes, 0.2% BSA, pH 7.4) to a final concentration of 60 mg original wet weight/mL.
Assay Reaction Mixture: Assay buffer: 50 mM Hepes, 0.2% BSA, pH 7.4
Radioligand: lηM 3H-D888 (Amersham)
Rat cortical membranes: 6 mg/mL original wet weight
Compounds: 0.3-100 μM Total volume: 1000 μL
This mixture was incubated for 60 minutes at 25 °C. The assay was terminated by filtering with a Brandel Cell Harvester over Whatman GF/C filters that had been soaked for at least 120 minutes in 0.3% polyethylenamine (PEI) and washed three times with 5 mL of wash buffer containing 20 mM Hepes, 20 mM MgCl2, pH 7.4. Specific binding was measured with 10 μM methoxy verapamil (D-600). This assay was used to determine in vitro selectivity of compounds vs. L-type voltage sensitive calcium channels, i.e. high affinity for the Η-D888 binding site would show a lack of selectivity. The IC50 of compounds of the invention at the Η-D888 binding site was between 542 nM and 4098 nM.
Gerbil Global Model of Cerebral Ischaemia Male Mongolian gerbils (Charles River) weighing 60-70 grams are used in these experiments. They are housed in individual cages with food (Purina Rodent Chow) and water available ad libitum. The animal room is maintained at 23 ± 2 °C, and is on an automatic 12 hour light cycle.
The gerbils are brought to the surgical suite and dosed intraperitoneally with the test agent or vehicle, forty five minutes prior to surgery. Drugs are administered at a volume of 5 mL/kg (intraperitoneal). Vehicle is generally saline, with sodium phosphate added to adjust the pH, if needed. Forty-five minutes after dosing the gerbils are anaesthetised with halothane (3.3%) which is delivered along with oxygen (1.5 1/M) through a face mask. After the gerbils are anaesthetised, halothane is continued at a maintenance level of 1.5-2 % along with oxygen. The ventral surface of the neck is shaved and cleaned with alcohol. Surgical procedures are carried out on a thermostat-controlled heating pad set to 37 °C. An incision is made in the neck, the carotid arteries are dissected away from the surrounding tissue, and isolated with a 5 cm length of Silastic tubing. When both arteries have been isolated they are clamped with microaneurysm clips (Roboz Instruments). The arteries are visually inspected to determine that the blood flow has been stopped. After 5 minutes the clips are gently removed from the arteries and blood flow begins again. A sham control group is treated identically but is not subjected to carotid artery occlusion. The incisions are closed with suture and the gerbils WO 00/39110 ,,, PCT/GB99/04330
removed from the anaesthesia masks and placed on another heating pad to recover from the anaesthesia. When they have regained the righting reflex and are beginning to walk around, they are again dosed with the test compound and returned to their home cages. This occurs approximately five minutes after the end of surgery. 5 Twenty-four hours post ischaemia gerbils are tested for spontaneous locomotor activity, using a Photobeam Activity System from San Diego Instruments. They are individually placed in Plexiglas chambers measuring 27.5 cm x 27.5 cm x 15 cm deep. The chambers are surrounded by photocells, and every time a beam is broken one count is recorded. Each gerbil is tested for two hours, and cumulative counts are recorded at 30, 60,
10 90, and 120 minutes. Mean counts are recorded for each group and drug groups are compared to control with an ANOVA and Bonferroni post test. After each gerbil is tested it is returned to its home cage. At this time gerbils are also observed for any changes from normal behaviour.
For the next two days no specific testing is performed, but the gerbils are observed two
15 to three times per day for any unusual behaviours or obvious neurological symptoms (i.e. ataxia, convulsions, stereotypic behaviour). Four days post ischaemia the gerbils are sacrificed by decapitation and their brains removed and preserved in 10% buffered formalin. Brains were removed, fixed and stained with hematoxylin and eosin. Under a light microscope, hippocampal fields were observed and graded for damage to the CA1 subfield: 0 to 4 scale, 0 with 0 representing no damage and 4 representing extensive damage. Transient focal ischaemia in rats
The method was performed substantially as described by Lin, T-N., He, Y.Y., Wu, G., Khan, M. And Hsu, C.Y. Effect of brain edema on infarct volume in a focal model cerebral ischaemia model in rats. Stroke 24: 117-121, 1993. This model is generally considered to be
25 relevant to the clinical situation. Male Long-Evans rats 250-350 g were used. Surgery to establish a focal ischaemia was conducted under anaesthesia induced with 100 mg/kg ketamine and 5 mg/kg i.m. xylazine. Rectal temperature was monitored and maintained at 37.0 + 0.5 °C. The right middle cerebral artery (MCA) was exposed using microsurgical techniques. The MCA trunk was ligated immediately above the rhinal fissure with 10-0
30 suture. Complete interruption of blood flow was confirmed under an operating microscope. Both common carotid arteries were then occluded using nontraumatic aneurysm clips. After a predetermined duration of ischaemia (45 min), blood flow was restored in all three arteries. Twenty-four hours post occlusion, rats were killed under ketamine anesthesia by intracardiac perfusion with 200 mL of 0.9% NaCl. The brain was removed and processed with 2% triphenyltetrazolium chloride to identify and quantitate the infarcted brain region. Compounds were administered by intravenous infusion for 4 hours. Examples: The Examples which follow are intended to illustrate but not limit the invention. In the Examples, unless otherwise stated:-
(i) concentrations were carried out by rotary evaporation in vacuo; (ii) operations were carried out at ambient temperature, that is in the range 18-26 °C and under a nitrogen atmosphere; (iii) column chromatography (by the flash procedure) was performed on Merck
Kieselgel silica (Art. 9385);
(iv) yields are given for illustration only and are not necessarily the maximum attainable;
(v) the structure of the end-products of the formula I were generally confirmed by NMR and mass spectral techniques [proton magnetic resonance spectra were determined in DMSO-d6 unless otherwise stated using a Varian Gemini 2000 spectrometer operating at a field strength of 300 MHz; chemical shifts are reported in parts per million downfield from tetramethylsilane as an internal standard (6 scale) and peak multiplicities are shown thus: s, singlet; bs, broad singlet; d, doublet; AB or dd, doublet of doublets; t, triplet, dt, double of triplets, m, multiplet; bm, broad multiplet; fast-atom bombardment (FAB) mass spectral data were obtained using a Platform spectrometer (supplied by Micromass) run in electrospray and, where appropriate, either positive ion data or negative ion data were collected, in this application, (M+H)+ is quoted;
(vi) intermediates were not generally fully characterised and purity was in general assessed mass spectral (MS) or NMR analysis; and
(vii) in which the following abbreviations (also used hereinabove) may be used :- DMF is N,N-dimethylformamide
DMSO is dimethylsulphoxide
CDC13 is deuterated chloroform m/s is mass spectroscopy
THF is tetrahydrofuran
DCM is dichloromethane -2σ-
NMP is N-methylpyrrolidone.
Example 1; l-Methyl-4-(2,4-bis(trifluoromethyl)benzyl)homopiperazine A 1 litre 3-necked flask equipped with a condenser was charged with a solution of 1-methylhomopiperazine (4.05 mL; 3.7 g, 32.6 mmol) in THF (250 mL). Triethylamine (4.54 mL, 3.3 g, 32.6 mmol) and then 3,5-bistrifluoromethylbenzyl bromide (5.97 mL, 10.0 g, 32.6 mmol) were added. The solution was immersed in a 60 °C oil bath for 16 hours during which time a precipitate formed. The resulting mixture was filtered and the filtrate was concentrated to give an orange oil. This crude product was purified by column chromatography ethyl acetate:hexane:methanol (4:5:1) to obtain the title compound as a yellow oil (7.0 g). Η NMR δ 8.08 (d, 1H), 7.86 (s, 1H), 7.79 (d, 1H). 3.85 (s, 2H), 2.80 - 2.61 (m, 8H), 2.38 (s, 3H), 1.89 - 1.81 (m, 2H); m/s: M+H+ 341.
Example 2: l-Methyl-4-(4-benzyloxybenzyl)homopiperazine
A 1 litre 3-necked flask equipped with a condenser was charged with a solution of 1-methylhomopiperazine (10.89 mL; 10 g. 88 mmol) in THF (600 mL). Triethylamine (12.24 mL, 8.8 g, 88 mmol) and then 4-benxyloxybenzyl chloride (20.5 g, 88 mmol) were added. The flask was immersed in a 60 °C oil bath for 16 hours during which time a precipitate formed. The resulting mixture was filtered and the filtrate was concentrated to give an orange oil. This crude product was purified by column chromatography using dichloromethane:methanol (90:10) as the solvent to obtain the title compound as a yellow oil (11.1 g). Η NMR δ 1.92 (m, 2H), 2.46 (s, 3H), 2.70-2.93 (m, 8H), 3.48 (s, 2H), 5.05 (s, 2H), 6.93 (d, 2H), 7.25 (d, 2H), 7.31-7.45 (m, 5H); m s: M+H+ 311.
Examples 3-30;
Using an analogous procedure to that described in Example 1 and 2, the appropriate benzyl bromide (or benzyl chloride) was reacted with the appropriate homopiperazine to give the compounds described in the following table.
1 This reaction was carried out at 60 °C for 2 hours and then at room temperature for 16 hours.
2 This reaction was carried out at room temperature for 2 days.
3 This reaction was carried out at 60 °C for 3 hours and then at room temperature for 16 hours.
Example 31: l-(Isopropyl)-4-(4-benzyloxybenzyl)homopiperazine
A solution of l-(4-benzyloxybenzyl)homopiperazine (400 mg, 1.35 mmol) in THF (20 mL) was placed in a 50 mL flask equipped with a condenser. Triethylamine (1.87 mL, 13.5 mmol) and then 2-bromopropane (1.66 g, 13.5 mmol) were added. The flask was immersed in a 60 °C oil bath for 2 days. Additional Triethylamine (0.374 mL, 2.7 mmol) and 2-bromopropane (1.66 g, 13.5 mmol) were added. The mixture was heated for an additional 2 days. The resulting mixture was filtered. The filtrate was poured into diethyl ether (50 mL) and washed with water and saturated sodium chloride. The diethyl ether layer was dried over anhydrous magnesium sulphate, filtered, and concentrated to give a crude product. This crude product was purified by column chromatography using dichloromethane:methanol (95:5) as the solvent to obtain the title compound as a yellow oil (240 mg). Η NMR: 1.00 (d, 6H), 1.76 (m, 2H), 2.62 - 2.74 (m, 8H), 2.88 (m, 1H), 3.57 (s, 2H), 5.05 (s, 2H), 6.92 (d, 2H), 7.25 (d, 2H), 7.30 - 7.46 (m, 5H); m/s: M+H+ 339.
Example 32: l-(3-Phenylpropyl)-4-(4-benzyloxybenzyl)homopiperazine
A solution of l-(4-benzyloxybenzyl)homopiperazine (500 mg, 1.7 mmol) in THF (40 mL) was placed in a 100 mL flask equipped with a condenser. Triethylamine (0.24 mL, 1.7 mmol) and l-bromo-3-phenylpropane (338 mg, 1.7 mmol) were added. The flask was immersed in a 60 °C oil bath for 16 hours. Additional Triethylamine (0.24 mL, 1.7 mmol) and 2-bromopropane (338 mg, 1.7 mmol) were added. The mixture was heated for an additional 24 hours. The resulting mixture was filtered. The filtrate was poured into diethyl ether (50 mL) and washed with water and saturated sodium chloride. The diethyl ether layer was dried over anhydrous magnesium sulphate, filtered, and concentrated to give a crude product. This crude product was purified by column chromatography using dichloromethane:methanol
(95:5) as the solvent to obtain the title compound as a yellow oil (510 mg). Η NMR: 1.87 (m, 4H), 2.55 - 2.83 (m, 12H), 3.59 (s, 2H), 5.05 (s, 2H), 6.92 (d, 2H), 7.16 - 7.45 (m, 12H); m s: M+H+ 415.
Examples 33-36:
Using an analogous procedure to that described in Example 32, the appropriate benzyl bromide (or benzyl chloride) was reacted with the appropriate homopiperazine to give the compounds described in the following table.
1 The reaction was carried out at for 2 days with 1 equivalent of base and the appropriate bromo compound.
Example 37: l-(4-Benzyloxybenzyl)homopiperazine
A solution of homopiperazine (43.0 g, 431 mmol) in DMAC (200 mL) was placed in a 1 litre flask. Potassium iodide (4.4 g, 27 mmol) was added. A solution of 4-benxyloxybenzyl chloride (25.0 g, 108 mmol) in DMAC (50 mL) was added and a precipitate began to form. The mixture was stirred at room temperature for 2 hours. The mixture was filtered. The filtrate was concentrated by distilling away the DMAC. The resulting residue was poured into diethyl ether and washed with water, aqueous sodium bicarbonate, and saturated aqueous sodium chloride. The diethyl ether layer was concentrated to give 1 1.4 g crude product. This crude product was purified in portions as needed. A 1.0 g portion of the crude product was purified by column chromatography using a gradient from 0 to 5% methanol in diethyl etheπhexane (1:1) to obtain the title compound as a yellow oil (0.48 g). Η NMR δ 1.66 (bs, 1H), 1.74 (m, 2H), 2.65 (m, 4H), 2.88 - 2.98 (m, 4H), 3.60 (s, 2H), 5.05 (s, 2H), 6.93 (d, 2H), 7.25 (d, 2H), 7.30 - 7.46 (m, 5H); m/s: M+H+ 297.
Example 38: l-(2-hydroxypropyl)-4-(4-benzyloxybenzyl)homopiperazine
A solution of l-(4-benzyloxybenzyl)homopiperazine (300 mg, 1.0 mmol) in t-butanol (5 mL) and toluene (5 mL) was placed in a flask equipped with a condenser. Propylene oxide (0.176 mL, 2.5 mmol) was added and then the flask was immersed in a 30 °C oil bath for 16 hours. Additional propylene oxide (0.176 mL, 2.5 mmol) was added and the mixture was heated for an additional 24 hours. The resulting mixture was concentrated. The resulting residue was purified by column chromatography using dichloromethane:methanol (95:5) as the solvent to obtain the title compound (220 mg). Η NMR δ (CDC13) 1.11 (d, 3H), 1.79 (m, 2H), 2.20 (dd, IH), 2.55-2.90 (m, 9H), 3.57 (s, 2H), 3.72 (m, IH), 5.05 (s, 2H), 6.92 (d, 2H), 7.24 (d, 2H), 7.32-7.43 (m, 5H); m/s: M+H+ 355.
Example 39: l-(2-hvdroxybutyl)-4-(4-benzyloxybenzyl)homopiperazine
A solution of l-(4-benzyloxybenzyl)homopiperazine (300 mg, 1.0 mmol) in t-butanol (5 mL) and toluene (5 mL) was placed in a flask equipped with a condenser. 1,2-epoxybutane (0.215 mL, 2.5 mmol) was added and then the flask was immersed in a 30 °C oil bath for 16 hours. Additional 1,2-epoxybutane (0.215 mL, 2.5 mmol) was added and the mixture was heated for an additional 24 hours. The resulting mixture was concentrated. The resulting residue was purified by column chromatography using dichloromethane:methanol (95:5) as the solvent to obtain the title compound (170 mg). Η NMR δ 0.97 (t, 3H), 1.36-1.64 (m, 3H), 1.80 (m, 2H), 2.23 (dd, IH), 2.58-2.91 (m, 9H), 3.47-3.57 (m, 3H), 5.05 (s, 2H), 6.92 (d, 2H), 7.24 (d, 2H), 7.32-7.45 (m, 5H); m/s: M+H+ 369.
Example 40: l-(3-(4-chlorophenoxy)-2-hvdroxypropyl)-4-(4-benzyloxybenzyl)homopiperazine A 4-dram vial was charged with l-(4-benzyloxybenzyl)homopiperazine (250 mg, 0.84 mmol) and 4-chlorophenyl 2,3-epoxypropyl ether (0.20 mL, 310 mg, 1.68 mmol). A loose cover was placed over the vial and the vial was irradiated with microwaves for 1.50 minutes at hi power. The resulting light yellow product was purified by column chromatography using 5% methanol in methylene chloride to obtain the title compound as a light orange oil (370 mg). Η NMR (CDC13) 1.81 (m, 2H), 2.52-2.94 (m, 1 IH), 3.58 (s, 2H), 3.90-4.02 (m, 3H), 5.05 (s, 2H), 6.84-6.94 (m, 4H), 7.20-7.25 (m, 4H), 7.31-7.45 (m, 5H); m/s: M+H+ 481, 483.
Examples 41 - 49:
Using an analogous procedure to that described in Example 40, the appropriate substituted epoxide was reacted with l-(4-benzyloxybenzyl)homopiperazine to give the compounds described in the following table.
Example 50: l-methyl-4-(2,5-bistrifluoromethylbenzyl)homopiperazine A solution of 1-methyl-homopiperazine (456 mg, 4.0 mmol), 2,5-difluorobenzyl bromide (1.23 g, 4.0 mmol) and triethylamine (400 mg, 4.0 mmol) in 40 mL THF was prepared and stirred at ambient temperature for two days. The resulting mixture was filtered. The filtrate was concentrated, dissolved in diethyl ether, washed with water and then concentrated. The resulting oil was purified by column chromatography using 5% methanol in methylene chloride to provided the title compound (1.0 g). Η NMR δ (CDC13) 1.90 (m, 2H), 2.43 (s, 3H), 2.68-2.78 (bm, 8H), 3.85 (s, 2H), 7.58 (d, IH), 7.75 (d, IH), 8.19 (s, IH); m/s: M+H+ 341.
Examples 51 - 52:
Using an analogous procedure to that described in Example 50, the appropriate benzyl bromide was reacted with 1-methyl-homopiperazine to give the compounds described in the following table.
Example 53: l-ethyl-4-(4-benzyloxybenzyl)homopiperazine
A solution of l-(4-benzyloxybenzyl)-homopiperazine (500 mg, 1.7 mmol), bromoethane (370 mg, 3.4 mmol) and triethylamine (340 mg, 3.4 mmol) in 40 mL THF was prepared and stirred at 60 °C for 16 hours. The resulting mixture was filtered and concentrated. The concentrate was dissolved in diethyl ether, washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated to give an orange-brown oil. This product was purified by column chromatography using 5% methanol in methylene chloride to provided the title compound as a light brown oil (480 mg). Η NMR δ (CDC13) 1.07 (t, 3H), 1.81 (m, 2H), 2.56 (q, 2H), 2.68-2.75 (bm, 8H), 3.57 (s, 2H), 5.05 (s, 2H), 6.92 (d, 2H), 7.21 (d, 2H), 7.30-7.46 (bm, 5H); m/s: M+H+ 325.
Example 54: l-(2-phenylethyl)-4-(4-benzyloxybenzyl)homopiperazine A solution of l-(4-benzyloxybenzyl)homopiperazine (500 mg, 1.7 mmol), 2- bromoethylbenzene (620 mg, 3.4 mmol) and triethylamine (340 mg, 3.4 mmol) in 40 mL THF was prepared and stirred at 60 °C for 16 hours. Additional 2-bromoethylbenzene (620 mg, 3.4 mmol) and triethylamine (340 mg, 3.4 mmol) were then added to the solution and stirring at 60 °C was continued for another 16 hours. The resulting mixture was filtered and concentrated. The concentrate was dissolved in diethyl ether, washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated to give an orange-brown oil. This product was purified by column chromatography using 5% methanol in methylene chloride to provided the title compound as a light brown oil (680 mg). Η NMR δ (CDC13) 1.85 (m, 2H), 2.70-2.87 (m, 8H), 3.16 (t, 2H), 3.57 (t, 2H), 3.59 (s, 2H), 5.05 (s, 2H), 6.93 (d, 2H), 7.19- 7.45 (m, 12H); m/s: M+H+ 401.
Examples 55 - XX
Using an analogous procedure to that described in Example 53 (Method A), or Example 54 (Method B), the appropriate benzyl bromide (or benzyl chloride) was reacted with l-(4-benzyloxybenzyl)homopiperazine to give the compounds described in the following table.
1 The reaction was carried out at for 2 days with 1 equivalent of base and the appropriate bromo compound.
Reference Example 1
Using an analogous procedure to that described in Example 1 and 2, benzyl chloride was reacted with 1-methylhomopiperazine to give the compound described in the following table.
The following examples are intended to illustrate, but not limit, methods of preparing salts of compounds of formula I.
Example 65: l-Methyl-4-(2,4-bis(trifluoromethyl)benzyl)homopiperazine dihydrochloride A solution of Example 1 (7.0 g) in ethanol (25 mL) was treated with saturated ethanolic HC1. Diethyl ether was added while stirring until precipitation began. The solution was placed in a 0 °C refrigerator for 16 hours during which time a precipitate formed. The mixture was filtered and the resulting white solid was dried in vacuo at 48 °C for 16 hours to give the title compound (8.1 g). Mp 200-202 °C; Η NMR (CD3OD) δ 2.31 (m, 2H), 2.98 (s, 3H), 3.55 (m, 8H), 4.53 (bs, 2H), 8.12 - 8.10 (m, 2H), 8.31 (d, IH); Anal; Calcd. for C15Hι8N2F6-2HCl-0.7H2O-0.2ethanol: C, 42.51 ; H, 5.24; N, 6.44. Found: C, 42.45; H, 5.17; N, 6.18. m/s: M+H+ 341.
Example 66: l-Methyl-4-(4-benzyloxybenzyl)homopiperazine dimaleate salt A solution of Example 2 ( 11.1 g) in ethanol (35 mL) was prepared in a 250 mL erlenmeyer flask. A solution of maleic acid (9 g) in ethanol (50 mL) was added and a precipitate began to form. Diethyl ether (30 mL) was then added and the mixture was stirred. The mixture was placed in a 0 °C refrigerator for 16 hours during which time a precipitate continued to form. The mixture was filtered and the resulting white solid was dried in vacuo at 48 °C for 16 hours to give the title compound (15.86 g). Mp 174-177 °C; Η NMR (DMSO-D6) δ 1.99 (m, 2H), 2.78 (s, 3H), 2.93 (m, 2H), 3.12 (m, 2H), 3.28 (m, 2H), 3.37 (m, 2H), 3.92 (m, 2H), 5.11 (s, 2H), 6.12 (s, 4H (CH=CH, maleic acid)), 7.03 (d, 2H), 7.39 (m, 7H); Anal; Calcd. for C2oH26N2O,-2C4H4O2 0.5H2O: C, 60.97; H, 6.40; N, 5.08. Found: C, 61.00; H, 6.25; N, 5.03. m/s: M+H+ 311.
Example 40: Following conventional procedures well known in the pharmaceutical art the following exemplary pharmaceutical dosage forms containing compounds of formula I, I' or I" can be prepared: (a) Tablet mg/tablet
Compound of Formula I, I' or I" 50.0
Mannitol, USP 223.75
Croscarmellose sodium 60
Maize starch 15.0
Hydroxypropylmethylcellulose (HPMC), USP 2.25
Magnesium stearate 3.0
(b) Capsule mg/capsule
Compound of Formula I, I' or I" 10.0
Mannitol, USP 488.5
Croscarmellose sodium 15.0
Magnesium stearate 1.5
(c) Injectable solution
For intravenous administration, a compound of Formula I, I' or I" is dissolved in an isotonic sterile solution at a concentration of 5 mg/mL.

Claims

Claims:
We claim:
1. Any compound of formula I:
wherein:
R1 is hydrogen, substituted or unsubstituted Cι_ alkyl, substituted or unsubstituted C2.8alkenyl or substituted or unsubstituted C2. alkynyl; wherein said Cj_8alkyl, C2_8alkenyl and C - alkynyl are unsubstituted or substituted with one or more substituents independently selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Cι_6alkoxy, Cι_6alkanoyl, Cι-6alkoxycarbonyl, Cι_6alkanoyloxy, N-(Cι_6alkyl)amino, NN-(Cι-6alkyl)2amino, Cι_ alkanoylamino, N-(Cι_ alkyl)carbamoyl,
NN-(Cι_6alkyl)2carbamoyl, Cι. alkoxyCι-6alkoxy, Cι_6alkylS(O)a wherein a is 0 to 2, N-(Cι.6alkyl)sulphamoyl or N,N-(Cι_ alkyl)2sulphamoyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3.ι2cycloalkyl, and a group of formula IA:
G- CCH^X- p
IA wherein:
G is substituted or unsubstituted aryl, substituted or unsubstituted carbon linked heteroaryl, substituted or unsubstituted carbon-linked heterocycle or substituted or unsubstituted C3.ι2cycloalkyl, p is an integer selected from the range 0 to 6 and X is a linking group selected from -C(O)-, -O-, -OC(O)-, -S-, -S(O)-, -S(O)2-, -S(O)2ΝR4-, -NR4S(O)2-, -NR4-, -C(O)O-, -C(O)NR4-, -NR4C(O)-, -OC(O)NR4-, -C(O)NR4SO2-, -NR4C(O)O-, -C(S)NR4- or -NR4C(S)-, wherein R4 is selected from hydrogen and C alkyl; wherein any aryl, heteroaryl, heterocycle or C3-ι cycloalkyl may be unsubstituted or substituted on a ring carbon with one or more groups independently selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C|.6alkyl, C2.6alkenyl, C2.6alkynyl, C|.6alkoxy, C).6alkanoyl, Cι.6alkanoyloxy, N-(Cι-6alkyl)amino, N,N-(Cι_6alkyl)2amino, Cι-6alkanoylamino, N-(Cι_6alkyl)carbamoyl, N,N-(Cι.6alkyl)2carbamoyl, Ci-6alkylSOa where a is an integer selected from the range 0 to 2, Cι_6alkoxycarbonyl, N-(C).6alkyl)sulphamoyl, NN-(Cι-6alkyl)2sulphamoyl or phenylCι.6alkyl and a heterocycle or heteroaryl containing an -ΝH- group may be unsubstituted or substituted on a ring nitrogen with Cι.6alkyl, C2.6alkenyl, C2.6alkynyl, Cι.6alkanoyl, Cι.6alkylsulphonyl or phenylCι-6alkyl;
A is a ring selected from phenyl and naphthyl;
R2 at each occurrence is independently selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Cι_6alkyl, C2.6alkenyl, C2.6alkynyl, Cι.6alkanoyl, N-(Cι_ alkyl)amino, NN-(Cι.6alkyl)2amino, Cι_6alkanoylamino, N-(Cι_6alkyl)carbamoyl, N,N-(Cι. alkyl)2carbamoyl, Cι_6alkylSOa where a is an integer selected from the range 0 to 2, Cι.6alkoxycarbonyl, N-(Cι- alkyl)sulphamoyl, N,N-(Cι_6alkyl)2sulphamoyl, and a group of the formula:
W- (CH,)p-B- LB wherein W is halo, nitro, hydroxy, C^alkoxy, cyano, amino, trifluoromethyl, trifluoromethoxy, carboxy, carbamoyl, mercapto, sulphamoyl, mesyl, N-Cι_6alkylamino, N,N-(Cι_6alkyl)2amino, Cι.6alkoxycarbonyl, N-Cι_6alkylcarbamoyl or
NN-(Ci_6alkyl)2carbamoyl, p is an integer selected from the range 1 to 6, and B is a bond, oxy, imino, N-(Cι_6alkyl)imino or -C(O)ΝH-, with the proviso that p is 2 or more unless B is a bond, -C(O)NH-, or
R2 is a group of formula IC:
D— fi-
IC wherein D is substituted or unsubstituted phenyl and E is selected from a bond, Cι.6alkylene, Cι-6alkyleneoxy, oxy, imino, N-(Cι. alkyl)imino, Cι. alkyleneimino, N-(Cι.6alkyl)-C,.6alkyleneimino, -C(O)ΝH-, -SO2NH-, -NHSO2-, sulphonylCι.6alkylene, carbonylCi-6alkyleneoxycarbonyl-Ci_6alkylene and C2.6alkanoylimino, wherein said phenyl when substituted is substituted with one or more groups selected from halo, nitro, hydroxy, Cι. alkoxy, cyano, amino, trifluoromethyl, trifluoromethoxy, carboxy, carbamoyl, mercapto, sulphamoyl, mesyl, N-Cι. alkylamino, N,N-(Cι- alkyl)2amino, Cι.6alkoxycarbonyl, N-Cι.6alkylcarbamoyl or N,N-(Cι„6alkyl) carbamoyl; m is an integer selected from the range 0 to 5 where at each occurrence R2 is independently selected from any foregoing moiety; or a pharmaceutically-acceptable salt or and in v/vo-hydrolysable ester, amide or carbamate thereof; with the following provisos: when A is phenyl: if A and R2 in combination is 4-mesyl then R1 is not 2-methoxycarbonylethyl; if A and R2 in combination is 4-chloro then R1 is not 2-methoxycarbonylethyl, 3-mercaptopropyl, 3-chloropropyl or 3-aminopropyl; if m is 0 then R1 is not 3-chloropropyl, 2-aminoethyl, 3-aminopropyl, 2-hydroxyethyl, methyl, ethyl, isopropyl or isobutyl; if A and R2 in combination is 3-chloro then R1 is not 4-acetyl-4-ethoxycarbonylbutyl or 3-chloropropyl; iiff AA aarnd R2 in combination is 3,4,5-trimethoxy then R1 is not cyanomethyl or 2-aminoethyl; when R1 is a substituted straight chain Cι_4alkyl group, the distal carbon atom is not substituted with, i) two aryl rings, ii) two heteroaryl rings, or, iii) a heteroaryl and a phenyl ring; and with the further proviso that if R1 is substituted Cι_8alkyl, substituted C2.8alkenyl or substituted C2. alkynyl the carbon atom adjacent to the homopiperazine ring is not directly substituted by any heteroatom other than fluoro.
2. A compound according to Claim 1, wherein:
R1 is hydrogen or Cι_8alkyl optionally substituted with fluoro or aryl; Ring A is phenyl or naphthyl;
R2 is halo, nitro, trifluoromethyl, trifluoromethoxy, C].6alkyl, Cι.6alkoxy, Cι-6alkoxycarbonyl, or a group of the formula IC D — E
IC wherein D is phenyl and E is selected from a bond, Cι_ alkyleneoxy or sulphonylC).6alkylene; and m is an integer selected from the range 0 to 3; or a pharmaceutically-acceptable salt or and in v/vo-hydrolysable ester, amide or carbamate thereof; with the provisos that if A is phenyl and: if A and R2 in combination is 3-chloro or 4-chloro then R1 is not 3-chloropropyl; if m is 0 then R1 is not 3-chloropropyl, methyl, ethyl, isopropyl or isobutyl; and when R1 is a substituted straight chain Cι_ alkyl group, the distal carbon atom is not substituted with two aryl rings.
3. A compound according to Claim 1, wherein: R1 is hydrogen, Cι_8alkyl optionally substituted with fluoro or phenyl;
Ring A is selected from phenyl and naphthyl;
R2 is selected from fluoro, chloro, bromo, iodo, nitro, trifluoromethyl, trifluoromethoxy, methyl, methoxy, methoxycarbonyl or a group of the formula IC
D— E IC wherein D is phenyl and E is selected from a bond, methyleneoxy and sulphonylmethylene; and m is an integer selected from the range 0 to 3; or a pharmaceutically-acceptable salt or and in v/vo-hydrolysable ester, amide or carbamate thereof; with the proviso that if A is phenyl and if m is 0 then R1 is not methyl, ethyl, isopropyl or isobutyl; if R1 is a substituted straight chain Cι_4alkyl group, the distal carbon atom is not substituted with two phenyl rings.
4. A compound according to Claim 1, wherein: R1 is selected from hydrogen, methyl, n-propyl, 3-methylbutyl, isopropyl, benzyl,
3-fluoropropyl and 3-phenylpropyl; and
Ring A and R2 in combination are selected from phenyl, naphth-1-yl, biphen-2-yl,
2-bromophenyl, 2-nitrophenyl, 2-trifluoromethylphenyl, 2-(phenylsulphonylmethyl)phenyl, 3-fluorophenyl, 3-chlorophenyl, 3-iodophenyl, 3-nitrophenyl, 3-trifluoromethylphenyl,
3-methoxyphenyl, 3-methoxycarbonylphenyl, 4-fluorophenyl, 4-bromophenyl, 4-nitrophenyl,
4-methylphenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl,
4-methoxycarbonylphenyl, 4-benzyloxyphenyl, 2,4-difluorophenyl,
2,4-ditrifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl, 2-methoxy-5-nitrophenyl, 3,4-difluorophenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 3,5-ditrifluoromethylphenyl and
4,5-dimethoxy-2-nitrophenyl; or a pharmaceutically-acceptable salt or and in v/vo-hydrolysable ester, amide or carbamate thereof; with the proviso that when Ring A and R~ in combination are phenyl then R is not methyl, isopropyl or isobutyl.
5. A compound according to Claim 1, wherein:
R1 is selected from methyl, n-propyl, 3-methylbutyl, isopropyl, benzyl, 3-fluoropropyl and 3-phenylpropyl; and Ring A and R2 in combination are selected from naphth-1-yl, biphen-2-yl,
3-fluorophenyl, 3-chlorophenyl, 3-iodophenyl, 3-nitrophenyl, 3-trifluoromethylphenyl, 3-methoxyphenyl, 3-methoxycarbonylphenyl, 4-bromophenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 4-methoxycarbonylphenyl, 4-benzyloxyphenyl, 2,4-ditrifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl, 2-methoxy-5-nitrophenyl, 3,4-difluorophenyl, 3,4-dimethylphenyl, 3,5-ditrifluoromethylphenyl or 4,5-dimethoxy-2-nitrophenyl; or a pharmaceutically-acceptable salt or and in v/vo-hydrolysable ester, amide or carbamate thereof.
6. A compound according to Claim 1, wherein:
R1 is selected from methyl, n-propyl, 3-methylbutyl, isopropyl, benzyl, 3-fluoropropyl and 3-phenylpropyl; and Ring A and R2 in combination form 4-benzyloxyphenyl, 2,4-ditrifluoromethylphenyl and 3-iodophenyl; or a pharmaceutically-acceptable salt or and in v/vo-hydrolysable ester, amide or carbamate thereof.
A compound according to Claim 1 , selected from: l-methyl-4-(4-benzyloxybenzyl)homopiperazine; l-methyl-4-(2,4-bis(trifluoromethyl)benzyl)homopiperazine; l-propyl-4-(4-benzyloxybenzyl)homopiperazine; l-benzyl-4-(4-benzyloxybenzyl)homopiperazine; l-pentyl-4-(4-benzyloxybenzyl)homopiperazine; l-methyl-4-(3,5-bis(trifluoromethyl)benzyl)homopiperazine; l-(2-phenylethyl)-4-(4-benzyloxybenzyl)homopiperazine;
1 -(3 ,5-difluorobenzyl)-4-(4-benzyloxybenzyl)homopiperazine; l-(3,4,4-trifluoro-but-3-enyl)-4-(4-benzyloxybenzyl)homopiperazine: l-butyl-4-(4-benzyloxybenzyl)homopiperazine; l-isopropyl-4-(4-benzyloxybenzyl)homopiperazine; l-(2-methylpropyl)-4-(4-benzyloxybenzyl)homopiperazine; l-ethyl-4-(4-benzyloxybenzyl)homopiperazine;
1 -methyl-4-(4-tert-butylbenzyl)homopiperazine, and l-(2-hydroxypropyl)-4-(4-benzyloxybenzyl)homopiperazine.
8. A pharmaceutical composition comprising as an active ingredient an effective amount of a compound according to any of Claims 1 to 6, together with a pharmaceutically-acceptable carrier.
9. Use of a pharmaceutical composition according to Claim 7, for the therapy or treatment of stroke, head trauma, transient cerebral ischaemic attack, Alzheimer's disease, Parkinson's disease, diabetic neuropathy, amyotrophic lateral sclerosis, multiple sclerosis or AIDS-related dementia.
10. A method for treating or preventing neurological diseases by inhibition of the [3H]-emopamil binding site, comprising administering to a mammal an effective amount of a compound according to any of Claims 1 to 6.
11. Use of a compound according to any of Claims 1 to 6, for preparation of a therapeutic agent or prophylactic agent for diseases treatable by inhibition of the [3H]-emopamil binding site.
12. A method for treating or preventing diseases treatable by inhibition of the
[ H] -emopamil binding site, comprising administering to a mammal an effective amount of a compound according to any of Claims 1 to 6.
13. A process for preparing a compound according to Claim 1 , or a pharmaceutically- acceptable salt, in v/vo-hydrolysable ester, amide or carbamate thereof, which process comprises either: a) reacting a compound of the formula II:
wherein
L is a suitable displaceable group, with a compound of the formula III:
m wherein, when R1 of a compound of formula I is hydrogen Ra is an amino protecting group; or when R1 of a compound of formula I is not hydrogen Ra is R1 ; or b) for preparing a compound of formula I wherein R1 is not hydrogen, reacting a compound of formula IV:
IV with a compound of formula V:
R'-L
V wherein L is a suitable displaceable group and R1 is not hydrogen; or c) reacting a compound of the formula VI:
VI with a compound of the formula III; or d) for preparing compounds of formula I wherein R1 is not hydrogen and there is a -CH2- or CH3- moiety attached to the nitrogen of the homopiperazine ring, reacting a compound of formula IV with a compound for formula VII:
VII wherein Rb is hydrogen or substituted or unsubstituted Cι-7alkyl, substituted or unsubstituted
C2-7alkenyl or substituted or unsubstituted C2.7alkynyl and Rc is hydrogen or hydroxy; and thereafter if necessary: i) converting a compound of the formula I into another compound of the formula I; ii) removing any protecting groups; or iii) forming a pharmaceutically-acceptable salt or in v/vo-hydrolysable ester, amide or carbamate.
EP99962380A 1998-12-24 1999-12-20 Homopiperazine derivatives as selective emopamil inhibitors Withdrawn EP1140880A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB9828435 1998-12-24
GBGB9828435.9A GB9828435D0 (en) 1998-12-24 1998-12-24 Chemical compounds
PCT/GB1999/004330 WO2000039110A1 (en) 1998-12-24 1999-12-20 Homopiperazine derivatives as selective emopamil inhibitors

Publications (1)

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EP1140880A1 true EP1140880A1 (en) 2001-10-10

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JP (1) JP2002533449A (en)
AU (1) AU1874600A (en)
GB (2) GB9828435D0 (en)
WO (1) WO2000039110A1 (en)

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US9834521B2 (en) * 2013-03-15 2017-12-05 Ariad Pharmaceuticals, Inc. Choline kinase inhibitors

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Publication number Priority date Publication date Assignee Title
NL278561A (en) * 1961-05-17
US3210336A (en) * 1963-06-20 1965-10-05 Union Carbide Corp Production of 1-substituted homopiperazines
WO1990013539A1 (en) * 1989-04-28 1990-11-15 Meiji Seika Kaisha, Ltd. New n-substituted piperazine derivatives and drug for improving functional disorder of brain
FR2687401B1 (en) * 1992-02-18 1994-05-20 Meram Laboratoires 1,4-DIALKYLPIPERAZINE DERIVATIVES, PROCESSES FOR OBTAINING SAME AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME.
DK78692D0 (en) * 1992-06-12 1992-06-12 Lundbeck & Co As H DIMER PIPERIDINE AND PIPERAZINE DERIVATIVES
GB9726736D0 (en) * 1997-12-18 1998-02-18 Zeneca Ltd Chemical compounds

Non-Patent Citations (1)

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Title
See references of WO0039110A1 *

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AU1874600A (en) 2000-07-31
GB9930013D0 (en) 2000-02-09
WO2000039110A1 (en) 2000-07-06
JP2002533449A (en) 2002-10-08

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