WO2000078736A1 - 1,4-diazacycloheptane derivatives as neuroprotective agents - Google Patents

1,4-diazacycloheptane derivatives as neuroprotective agents Download PDF

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Publication number
WO2000078736A1
WO2000078736A1 PCT/GB2000/002308 GB0002308W WO0078736A1 WO 2000078736 A1 WO2000078736 A1 WO 2000078736A1 GB 0002308 W GB0002308 W GB 0002308W WO 0078736 A1 WO0078736 A1 WO 0078736A1
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alkyl
hydroxy
optionally substituted
homopiperazine
tetrahydronaphth
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PCT/GB2000/002308
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French (fr)
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Thomas Richard Simpson
Margaret Joyce Schooler
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Astrazeneca Uk Limited
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Priority to EP00938921A priority Critical patent/EP1192141A1/en
Priority to AU54144/00A priority patent/AU5414400A/en
Priority to JP2001504902A priority patent/JP2003502411A/en
Publication of WO2000078736A1 publication Critical patent/WO2000078736A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/08—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 not condensed with other rings
    • 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
    • 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
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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

Definitions

  • the present invention relates to chemical compounds, in particular tetrahydronaphthylhomopiperazines, to processes for their preparation and to chemical intermediates useful in such processes.
  • the present invention further relates to tetrahydronaphthylhomopiperazines, 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.
  • Neurological disorders for which the present compounds are useful, 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.
  • the compounds useful in the present invention are believed to act by binding with the [ 3 H]-emopamil binding site.
  • Compounds with selective action at the [ 3 H]-emopamil binding site exhibit fewer associated side effects such as hypotension seen with emopamil or behavioural manifestations seen with ifenprodil. Background
  • Emopamil has classically been thought of as a neuroprotective agent whose efficacy is most likely derived from actions at either voltage-sensitive calcium channels (VSCC) or 5- HT 2 receptors.
  • VSCC voltage-sensitive calcium channels
  • 5- HT 2 receptors 5- HT 2 receptors.
  • 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. 113: 379- 384, 1994).
  • [ 3 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.
  • Neuroprotective compounds are known, for example emopamil and ifenprodil, that exhibit high affinity for the [ 3 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.
  • a new method for using compounds having selective action at the [ 3 H] -emopamil binding site and that are neuroprotective without acting directly at either VSCC or NMDA receptors is disclosed.
  • R 1 is halo, hydroxy, C ⁇ _ 6 alkyl, C ⁇ - 6 alkoxy, haloC ⁇ - 6 alkyl, cyano, nitro or C 2-6 alkenyl; p is 0, 1, 2, 3 or 4 wherein at each occurrence R 1 may be the same or different; R is C ⁇ - 6 alkyl; q is 0, 1 or 2 wherein at each occurrence R 2 may be the same or different; and R 3 is selcted from C ⁇ -8 alkyl, C 2-8 alkenyl or C 2-8 alkynyl, wherein said C ⁇ . 8 alkyl, C 2- 8 alkenyl or C 2 .
  • 8 alkynyl are optionally substituted with one or more groups selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C ⁇ -6 alkoxy, C ⁇ _ 6 alkanoyl, Ci- ⁇ alkoxycarbonyl, C ⁇ -6 alkanoyloxy, N-(C ⁇ . 6 alkyl)amino, N,N-(C 1- alkyl) 2 amino, C ⁇ -6 alkanoylamino, N-(C ⁇ -6 alkyl)carbamoyl, N,N-(C ⁇ .
  • B is aryl, heteroaryl, heterocyclyl or Cs. ⁇ cycloalkyl; r is 0, 1, 2, 3, 4, 5 or 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(0)0-, -C(S)NR 4 -, -NR 4 C(S)-, -NR 4 C(S)NR 5 -, NR C(O)NR 5 -, -NR 4 C(O)NR 5 SO 2 -,
  • aryl, heteroaryl heterocyclyl are optionally substituted on a ring carbon with one or more groups selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C ⁇ _
  • new pharmaceutical compositions containing compounds of formula (I), or in v/vo-hydrolysable esters, amides or carbamates thereof, together with a pharmaceutically-acceptable carrier such as an excipient, diluent or stabilizer or combinations thereof as further defined herein are disclosed.
  • 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 is disclosed.
  • novel compounds are disclosed which are compounds of formula (I) with a proviso wherein in such compounds: R 3 is not optionally substituted phenylC ⁇ - 8 alkyl or C 3 - 8 cycloalkylC ⁇ -8 alkyl, or if R is substituted C ⁇ -8 alkyl, substituted C 2-8 alkenyl or substituted C 2- alkynyl then the carbon atom adjacent to the homopiperazine ring is not directly substituted by any other than a fluoro heteroatom.
  • 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
  • haloC ⁇ -6 alkyl includes trifluoromethyl, 2-fluoroethyl, 2-bromopropyl and 3- chloropropyl.
  • halo refers to fluoro, chloro, bromo and iodo.
  • aryl refers to a phenyl, naphthyl or biphenyl.
  • heteroaryl refers to, unless otherwise further specified, a monocyclic-, bicyclic- or tricyclic- 5- to 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.
  • heteroaryl examples include thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, pyridyl, pyridyl-N-oxide, oxopyridyl, oxoquinolyl, pyrimidinyl, pyrazinyl, oxopyrazinyl, pyridazinyl, indolinyl, 1,3-benzdioxolanyl, benzofuranyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolinyl, quinazolinyl, xanthenyl, quinoxalinyl, indazolyl, benzofuranyl, phthalimidyl and cinnolinolyl.
  • heterocyclyl refers to, unless otherwise further specified, a mono- or bicyclic- 5- to 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,
  • examples of C ⁇ -8 alkyl include C ⁇ -6 alkyl, C ⁇ -4 alkyl, methyl, ethyl, isopropyl and t-butyl;
  • examples of C ⁇ -6 alkoxycarbonyl include C ⁇ - alkoxycarbonyl, methoxycarbonyl, ethoxycarbonyl and n- and t-butoxycarbonyl;
  • examples of include C ⁇ - alkoxy, methoxy, ethoxy and propoxy;
  • examples of C ⁇ - alkanoylamino include formamido, acetamido and propionylamino; examples of C ⁇ .
  • 6 alkylS(O) a where a is 0, 1 or 2 include C ⁇ -6 alkylsulphonyl, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl and ethylsulphonyl; examples of C i -6 alkanoyl include propionyl and acetyl; examples of N-C ⁇ -6 alkylamino include N-methylamino and N-ethylamino; examples of N,N-(C ⁇ .
  • C 6 alkyl) 2 amino include N,N-dimethylamino, N,N-diethylamino and N- ethyl-N-methylamino;
  • examples of C 3 _i 2 cycloalkyl include Cg. ⁇ cycloalkyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclododecyl and adamantyl;
  • examples of C 2 - 8 alkenyl include C 2 - 6 alkenyl, C 2 - 4 alkenyl, vinyl, allyl and 1-propenyl;
  • examples of C 2 - 8 alkynyl include C 2 - 6 alkynyl, C 2-4 alkynyl, ethynyl, 1-propynyl and 2-propynyl; examples of N-(C].
  • N-methylsulphamoyl and N-ethylsulphamoyl examples include N,N-(C ⁇ _ 6 alkyl) 2 sulphamoyl include N,N-dimethylsulphamoyl and N-methyl-N- ethylsulphamoyl; examples of N-(C i .
  • 6 alkyl)carbamoyl include N-methylcarbamoyl and N-ethylcarbamoyl; examples of N,N-(C ⁇ -6 alkyl) 2 carbamoyl include N,N-dimethylcarbamoyl and N-methyl-N- ethylcarbamoyl; examples of C ⁇ _ 6 alkanoyloxy include C ⁇ - alkanoyloxy, propionyloxy, acetyloxy and formyloxy, and examples of C i -6 alkoxyC i . 6 alkoxy include C i -4 alkoxyC i -4 alkoxy, methoxymethoxy, methoxyethoxy and ethoxypropoxy.
  • p is 0.
  • q is 0.
  • R 3 is substituted C ⁇ -8 alkyl, optionally substituted C 2 - 8 alkenyl or optionally substituted C 2 - 8 alkynyl; wherein said substituents are chosen from one or more groups selected from halo, cyano, hydroxy, carbamoyl, C ⁇ - alkoxy, C ⁇ -6 alkanoyl, C ⁇ -6 alkoxycarbonyl,
  • any aryl, heteroaryl and heterocyclyl may be optionally substituted on a ring carbon with one or more groups selected from halo, C ⁇ -6 alkyl or C ⁇ -6 alkoxy; with the proviso that R 3 cannot be optionally substituted phenylC ⁇ -8 alkyl and with the further proviso that when R 3 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 3 is substituted C ⁇ -6 alkyl, optionally substituted C2 -4 alkenyl or C 2- 4 alkynyl; wherein said substituents are chosen from one or two groups selected from halo, cyano, hydroxy, carbamoyl, C ⁇ - alkoxy, C ⁇ .
  • R 3 is carbamoylmethyl, isopropoxycarbonylmethyl, t- butoxycarbonylmethyl, t-butylcarbonylmethyl, benzoylmethyl, 4-methylbenzoylmethyl, 4- methoxybenzoylmethyl, 4-chlorobenzoylmethyl, 4-bromobenzoylmethyl, 4- phenylbenzoylmethyl, 2,4-dimethoxybenzoylmethyl, phenoxycarbonylmethyl, tetrahydropyran-2-ylmethyl, adamant-3-ylcarbonylmethyl, 2-fluoroethyl, 2-hydroxyethyl, 2- cyanoethyl, methoxyethyl, methoxyethoxyethyl, 2,2-dimethoxyethyl, 2,2-diethyloxyethyl, 2- acetoxyethyl, 2-methoxycarbonylethyl, 2-ethoxycarbonylethyl, 2-phenoxyethyl, 2-(4
  • R 3 is carbamoylmethyl, isopropoxycarbonylmethyl, t-butoxycarbonylmethyl, t-butylcarbonylmethyl, benzoylmethyl, 4-methylbenzoylmethyl, 4-methoxybenzoylmethyl, 4-chlorobenzoylmethyl, 4- bromobenzoylmethyl, 4-phenylbenzoylmethyl, 2,4-dimethoxybenzoylmethyl, phenoxycarbonylmethyl, tetrahydropyran-2-ylmethyl, adamant-3-ylcarbonylmethyl, 2- fluoroethyl, 2-hydroxyethyl, 2-cyanoethyl, methoxyethyl, methoxyethoxyethyl, 2,2- dimethoxyethyl, 2,2-diethyloxyethyl, 2-acetoxyethyl, 2-methoxycarbonylethyl, 2- ethoxycarbonylethyl, 2-phenoxyethyl,
  • R 3 is 2-fluoroethyl, methoxyethyl, methoxyethoxyethyl, 2,2- dimethoxyethyl, 2-methoxycarbonylethyl, 2-ethoxycarbonylethyl, 2-phenoxyethyl, 2-(l',3'- dioxolan-2'-yl)ethyl, 2-(l',3'-dioxan-2'-yl)ethyl, 3-fluoropropyl, 3-phenoxypropyl, 3- (tetrahydropyran-2'-yloxy)propyl, 4-cyanobutyl, 4-acetoxybutyl, 3-butenyl or 3,4,4-trifluoro-3- butenyl.
  • R 3 is 2-fluoroethyl, methoxyethyl, methoxyethoxyethyl, 2,2-dimethoxyethyl, 2-methoxycarbonylethyl, 2- ethoxycarbonylethyl, 2-phenoxyethyl, 2-(l',3'-dioxolan-2'-yl)ethyl, 2-(l',3'-dioxan-2'-yl)ethyl, 2,2,2-trifluoroethyl, 2-hydroxypropy 3-hydroxypropyl, 3-fluoropropyl, 3-phenoxypropyl, 3- (tetrahydropyran-2'-yloxy)propyl, 3-phenyl-3-oxopropyl, 3-(4-fluorophenyl)-3-oxopropyl, 3- (4-chlorophenyl)-3-oxopropyl, 3-(4-bromophenyl)-3-oxoxo
  • R 3 is 3-methyl-2-butenyl. Therefore in a preferred aspect of the invention, there is provided a compound of formula (I) wherein: p is 0; R 3 is substituted C] 8 alkyl, optionally substituted C 2 salkenyl or optionally substituted C 2-8 alkynyl, wherein said substituents are chosen from one or more groups selected from halo, cyano, hydroxy, carbamoyl, C ⁇ - 6 alkoxy, Ci 6 alkanoyl, C ⁇ -6 alkoxycarbonyl, Ci 6 alkanoyloxy, C ⁇ - 6 alkoxyC ⁇ -6 alkoxy, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl or a group of the formula (LA) as depicted above wherein B is optionally substituted aryl, optionally substituted heterocyclyl or C 3 ⁇ 2 cycloalkyl, r is 0, 1, 2, 3, 4, 5 or 6, and
  • R 3 is carbamoylmethyl, isopropoxycarbonylmethyl, t-butoxycarbonylmethyl, t- butylcarbonylmethyl, benzoylmethyl, 4-methylbenzoylmethyl, 4-methoxybenzoylmethyl, 4- chlorobenzoylmethyl, 4-bromobenzoylmethyl, 4-phenylbenzoylmethyl, 2,4- dimethoxybenzoylmethyl, phenoxycarbonylmethyl, tetrahydropyran-2-ylmethyl, adamant-3- ylcarbonylmethyl, 2-fluoroethyl, 2-hydroxyethyl, 2-cyanoethyl, methoxyethyl, methoxyethoxyethyl, 2,2-dimethoxyethyl, 2,2-d ⁇ ethyoxyethyl, 2-acetoxyethyl, 2- methoxycarbonylethyl, 2-ethoxycarbonylethyl, 2-phenoxyethyl, 2-(4'-ch
  • R 3 is carbamoylmethyl, isopropoxycarbonylmethyl, t-butoxycarbonylmethyl, t- butylcarbonylmethyl, benzoylmethyl, 4-methylbenzoylmethyl, 4-methoxybenzoylmethyl, 4- chlorobenzoylmethyl, 4-bromobenzoylmethyl, 4-phenylbenzoylmethyl, 2,4- dimethoxybenzoylmethyl, phenoxycarbonylmethyl, tetrahydropyran-2-ylmethyl, adamant-3- ylcarbonylmethyl, 2-fluoroethyl, 2-hydroxyethyl, 2-cyanoethyl, methoxyethyl, methoxyethoxyethyl, 2,2-dimethoxyethyl, 2,2-diethyloxyethyl, 2-acetoxyethyl, 2- methoxycarbonylethyl, 2-ethoxycarbonylethyl, 2-phenoxyethyl, 2-(4'-chlor
  • R 3 is 2-fluoroethyl, methoxyethyl, methoxyethoxyethyl, 2,2-dimethoxyethyl, 2- methoxycarbonylethyl, 2-ethoxycarbonylethyl, 2-phenoxyethyl, 2-(l',3'-dioxolan-2'-yl)ethyl, 2-(l',3'-dioxan-2'-yl)ethyl, 3-fluoropropyl, 3-phenoxypropyl, 3-(tetrahydropyran-2'- yloxy)propyl, 4-cyanobutyl, 4-acetoxybutyl, 3-butenyl or 3,4,4-trifluoro-3-butenyl; or a pharmaceutically-acceptable salt, or an in v/vo-hydrolysable ester, amide or carbamate thereof.
  • R 3 is R 3 is 2-fluoroethyl, methoxyethyl, methoxyethoxyethyl, 2,2-dimethoxyethyl, 2- methoxycarbonylethyl, 2-ethoxycarbonylethyl, 2-phenoxyethyl, 2-(l',3'-dioxolan-2'-yl)ethyl, 2-(l',3'-dioxan-2'-yl)ethyl, 2,2,2-trifluoroethyl, 2-hydroxypropy 3-hydroxypropyl, 3- fluoropropyl, 3-phenoxypropyl, 3-(tetrahydropyran-2'-yloxy)propyl, 3-phenyl-3-oxopropyl, 3- (4-fluorophenyl)-3-oxopropyl, 3-(4-chlorophenyl)-3-oxopropyl, 3-(4-bromophenyl)-3- oxopropyl,
  • Suitable pharmaceutically-acceptable salts include acid addition salts such as methanesulphonate, fumarate, hydrochloride, hydrobromide, citrate, maleate and salts formed with phosphoric and sulphuric acid.
  • 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-efhylpiperidine, procaine, dibenzylamine, N,N-dibenzylethylamine or amino acids for example lysine.
  • a preferred pharmaceutically-acceptable salt is a sodium salt.
  • the compounds of formula (I) possess at least one chiral centre. It is to be understood that the invention encompasses all optical isomers and diasteroisomers of compounds of formula (I) that inhibit the [ 3 H]-emopamil binding site.
  • the chiral centre is at the 1 -position of the 1,2,3,4-tetrahydronaphthalene ring system and it is prefe ⁇ ed that this centre has the S-stereochemistry under the Cahn-Prelog-Ingold sequence rules.
  • the invention further relates to all tautomeric forms of the compounds of formula
  • 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 N-carbomethoxy and N-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 alkoxymethyl esters for example methoxyme hyl, C ⁇ -6 alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, C 3-8 cycloalkoxy-carbonyloxyC ⁇ - alkyl esters for example 1-cyclohexylcarbonyloxyethyl; l,3-dioxolen-2-onylmethyl esters for example 5- methyl-l,3-dioxolen-2-onylmethyl; and C ⁇ -6 alkoxycarbonyloxyethyl esters for example 1- methoxycarbonyloxyethyl and may be formed at any carboxy group in the compounds of this invention.
  • An in v/vo-hydrolysable ester of a compound of the formula (I) containing 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 breakdown to give 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 breakdown to give the parent hydroxy group.
  • ⁇ -acyloxyalkyl ethers include acetoxymethoxy and 2,2- dimethylpropionyloxymethoxy.
  • a selection of in v/vo-hydrolysable 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 , R , p and q are, unless otherwise specified, as defined in formula (I)) comprises of: a) reacting a compound of the formula (II):
  • NTT wherein R a is C ⁇ -7 alkyl substituted with one or more of the substituents listed under R 3 above and Q 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.
  • L is a displaceable group, suitable values for L are for example, a halogeno or sulphonyloxy group, for example a chloro, bromo, methanesulphonyloxy or toluene-4- sulphonyloxy group.
  • reaction conditions for the reactions c) and d), above are as follows. Amines and ketones, aldehydes or carboxylic acids are reacted together 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.
  • 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.
  • 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.
  • 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 (including intravenous, intramuscular or infusion) sterile aqueous or oily solutions or suspensions or sterile emulsions.
  • a prefe ⁇ ed route of administration is intravenously in sterile isotonic solution.
  • composition of this invention may also contain, or be co-administered (simultaneously or sequentially) with, one or more pharmacological agents of value in treating one or more disease conditions refe ⁇ ed 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.
  • a pharmaceutical composition which comprises a compound of the formula (I) as defined hereinbefore or a pharmaceutically-acceptable salt or an in v/vo-hydrolysable ester, amide or carbamate thereof, in association with a pharmaceutically-acceptable excipient or carrier.
  • 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.
  • this is a compound of formula (I), or a pharmaceutically-acceptable salt or an in v/vo-hydrolysable ester, amide or carbamate thereof, for use as a medicament to inhibit the [ H] -emopamil binding site in a warm-blooded animal such as a human being.
  • 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 [ 3 H]-emopamil binding site in a warm-blooded animal such as a human being.
  • 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.
  • 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 (-)- 3 H-emopamil (Amersham).
  • Guinea pig liver membranes 40mg/mL original wet weight.
  • Compounds 1-300 nM. Total volume: 500 ⁇ l.
  • the assay tubes contained the following: 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 compounds: 0.3-100 ⁇ M
  • mice 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 pH, if needed. Forty-five minutes after dosing the gerbils are anaesthetised with halothane (3.3%o) which is delivered along with oxygen (1.5 L/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 su ⁇ ounding 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 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.
  • gerbils 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, 90, and 120 minutes. Mean counts are recorded for each group and drug groups are compared to control with an ANOVA and Bonfe ⁇ oni 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.
  • the MCA trunk was ligated immediately above the rhinal fissure with 10-0 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 anaesthesia by intracardiac perfusion with 200 mL of 0.9% ⁇ aCl. 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
  • microwave irradiation were performed using a kitchen grade 1000W microwave oven (Panasonic, the Genius Premier, model number NN-S567). (viii) in which the following abbreviations may be used :-
  • DMSO dimethylsulphoxide
  • CDCI 3 is deuterated chloroform m/s is mass spectroscopy
  • THF is tetrahydrofuran
  • NMP is N-methylpyrrolidone.
  • N- 1 -( 1,2,3 ,4-Tetrahydronaphth- 1 -yl)-N-4-(3-methyl-2-butenyl)homopiperazine A flask was charged with a solution of N-l-(l,2,3,4-tetrahydronaphthyl) homopiperazine (761 mg, 3.3 mmol) in THF (20 mL). Triethylamine (0.46 mL, 330 mg, 3.3 mmol) and l-bromo-3-methylbutene (0.38 mL, 490 mg, 3.3 mmol) were added. The solution was immersed in a 60 °C oil bath for 16 hours during which time a precipitate formed.
  • Examples 2-8 were prepared by reacting an appropriate substituted halo alkane with 1-(1, 2,3,4- tetrahydronaphthyl)homopiperazine.
  • Example 2
  • Example 7 N-l-(l,2,3,4-Tetrahvdronaphth-l-yl)-N-4-(3-oxo-3-(4-chloro-phenyl)-propyl)homopiperazine
  • the product was purified by chromatography performed using 1% methanol in diethyl ethe ⁇ hexane (1:1).
  • Example 3 A flask was charged with a solution of Example 3 (620 mg, 2.1 mmol) in diethyl ether (12 mL) and methanol (12 mL). A pellet of sodium borohydride (450 mg, 12 mmol) was added. After stirring for 40 minutes the reaction was quenched by the careful addition of water and then poured into water (100 mL). The resulting mixture was extracted with ether (2 x 100 mL) and the combined organic extracts were washed with brine (200 mL), dried over anhydrous magnesium sulphate, filtered and concentration to give an orange oil.
  • Example 10-14 were prepared by reducing an appropriate ketone.
  • Example 26 N-l-(l,2.3,4-Tetrahvdronaphth-l-yl)-N-4-(2-hydroxy-3-phenoxy-propyl)homopiperazine Using an analogous procedure to that described in Example 25, an appropriate substituted epoxide was reacted with N-l-(l,2,3,4-tetrahydronaphth-l-yl)homopiperazine to give the title compound.
  • R-(-)- ⁇ -(l,2,3,4-tetrahydronaphth-l-yl)homopiperazine was obtained as the second material to elute on subjecting racemic material (5.3 g), prepared as in Method A, to preparative Chiral Pak AD HPLC resolution using a hexane/ethanol mixture with modification with diethylamine.
  • the enantiomeric purity was determined on an analytical scale using hexane:ethanol:diethylamine (90:5:0.05, v:v) and detection at 220 nm.
  • N- 1 -( 1.2,3 ,4-Tetrahydronaphth- 1 -vP-N-4-(3-(t-butyldimethylsilyloxy)propyl) homopiperazine A flask was charged with a solution of N-l-(l,2,3,4-tetrahydronaphthyl) homopiperazine (1018 mg, 4.4 mmol) in THF (25 mL). Triethylamine (0.61 mL, 443 mg, 4.4 mmol) and l-bromo-3-(t-butyldimethylsilyloxy)propane (0.38 mL, 490 mg, 3.3 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 product was purified by column chromatography using a gradient from 0 to
  • HPMC Hydroxypropylmethylcellulose
  • a compound of formula (I) is dissolved in an isotonic sterile solution (5 mg/mL).

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Abstract

Methods for the use of compounds of formula (I) for treatment of neurological disorders, wherein p and q are as defined in the specification and R?1, R2 and R3¿ are various substituents, also as defined in the specification, such compounds and pharmaceutical compositions containing such compounds.

Description

1 , 4-DIAZACYCLOHEPTANE DERIVATIVES AS NEUROPROTECTIVE AGENTS
The present invention relates to chemical compounds, in particular tetrahydronaphthylhomopiperazines, to processes for their preparation and to chemical intermediates useful in such processes. The present invention further relates to tetrahydronaphthylhomopiperazines, 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.
Neurological disorders, for which the present compounds are useful, 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. The compounds useful in the present invention are believed to act by binding with the [3H]-emopamil binding site. Compounds with selective action at the [3H]-emopamil binding site exhibit fewer associated side effects such as hypotension seen with emopamil or behavioural manifestations seen with ifenprodil. Background
Emopamil has classically been thought of as a neuroprotective agent whose efficacy is 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. 113: 379- 384, 1994).
[3H] -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, 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 [3H]-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. Summarv of the Invention
In one aspect of the present invention a new method for using compounds having selective action at the [3H] -emopamil binding site and that are neuroprotective without acting directly at either VSCC or NMDA receptors is disclosed.
Compounds of the invention that have selective action at the [3H]-emopamil binding site are compounds of formula (I):
Figure imgf000003_0001
(I) wherein: R1 is halo, hydroxy, Cι_6alkyl, Cι-6alkoxy, haloCι-6alkyl, cyano, nitro or C2-6alkenyl; p is 0, 1, 2, 3 or 4 wherein at each occurrence R1 may be the same or different; R is Cι-6alkyl; q is 0, 1 or 2 wherein at each occurrence R2 may be the same or different; and R3 is selcted from Cι-8alkyl, C2-8alkenyl or C2-8alkynyl, wherein said Cι.8alkyl, C2- 8alkenyl or C2.8alkynyl are optionally substituted with one or more groups selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Cι-6alkoxy, Cι_6alkanoyl, Ci-όalkoxycarbonyl, Cι-6alkanoyloxy, N-(C\. 6alkyl)amino, N,N-(C1- alkyl)2amino, Cι-6alkanoylamino, N-(Cι-6alkyl)carbamoyl, N,N-(C\. 6alkyl) carbamoyl, Cι-6alkoxyCι-6alkoxy, Cι-6alkylS(O)a wherein a is 0, 1 or 2,
Figure imgf000003_0002
6alkyl) sulphamoyl, N,N-(Cι_6alkyl)2sulphamoyl, Cβ-πcycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl or a group of the formula:
B-(CH2)-X-
(IA) wherein B is aryl, heteroaryl, heterocyclyl or Cs.^cycloalkyl; r is 0, 1, 2, 3, 4, 5 or 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(0)0-, -C(S)NR4-, -NR4C(S)-, -NR4C(S)NR5-, NR C(O)NR5-, -NR4C(O)NR5SO2-, -
C(NOR4)- or -CH(OR4)-; wherein R4 and R5 are independently selected from hydrogen or C\.
4alkyl; and wherein said foregoing aryl, heteroaryl heterocyclyl are optionally 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-6alkanoyloxy, N-(C\.
6alkyl)amino, N,N-(Cι-6alkyl)2amino, Cι.6alkanoylamino, N-(Cι-6alkyl)carbamoyl, N,N-(C\.
6alkyl)2carbamoyl, Cι-6alkylS(O)a wherein a is 0, 1 or 2, Cι-6alkoxycarbonyl,
Figure imgf000004_0001
6alkyl)sulphamoyl, NN-(Cι- alkyl) sulphamoyl or phenylCι-6alkyl; and wherein any heterocyclyl or heteroaryl containing an -ΝH- moiety is optionally substituted on this ring nitrogen with one or more groups selected from Cι_6alkyl, C2-6alkenyl, C2-6alkynyl, . alkanoyl, Cι- alkylsulphonyl or phenylCι-6alkyl; or a pharmaceutically-acceptable salt, or an in v/vo-hydrolysable ester, amide or carbamate thereof. In another aspect of the present invention, new pharmaceutical compositions containing compounds of formula (I), or in v/vo-hydrolysable esters, amides or carbamates thereof, together with a pharmaceutically-acceptable carrier such as an excipient, diluent or stabilizer or combinations thereof as further defined herein are disclosed.
In a further aspect of the present invention, 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 is disclosed.
In yet a further aspect of the present invention, novel compounds are disclosed which are compounds of formula (I) with a proviso wherein in such compounds: R3 is not optionally substituted phenylCι-8alkyl or C3-8cycloalkylCι-8alkyl, or if R is substituted Cι-8alkyl, substituted C2-8alkenyl or substituted C2- alkynyl then the carbon atom adjacent to the homopiperazine ring is not directly substituted by any other than a fluoro heteroatom.
Detailed Description of the Invention In this specification 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 "haloCι-6alkyl" includes trifluoromethyl, 2-fluoroethyl, 2-bromopropyl and 3- chloropropyl. The term "halo" refers to fluoro, chloro, bromo and iodo. The term aryl refers to a phenyl, naphthyl or biphenyl.
The term "heteroaryl" refers to, unless otherwise further specified, a monocyclic-, bicyclic- or tricyclic- 5- to 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 "heteroaryl" include thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, pyridyl, pyridyl-N-oxide, oxopyridyl, oxoquinolyl, pyrimidinyl, pyrazinyl, oxopyrazinyl, pyridazinyl, indolinyl, 1,3-benzdioxolanyl, benzofuranyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolinyl, quinazolinyl, xanthenyl, quinoxalinyl, indazolyl, benzofuranyl, phthalimidyl and cinnolinolyl.
The term "heterocyclyl" refers to, unless otherwise further specified, a mono- or bicyclic- 5- to 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,
1,3-dioxolanyl, 1 ,4-dioxanyl, tetrahydropyranyl and quinuclidinyl.
Where optional substituents are chosen from "one or more" groups it is to be understood that this definition includes all substituents being chosen from one of the specified groups or the substituents being chosen from two or more of the specified groups.
In the present invention, examples of Cι-8alkyl include Cι-6alkyl, Cι-4alkyl, methyl, ethyl, isopropyl and t-butyl; examples of Cι-6alkoxycarbonyl include Cι- alkoxycarbonyl, methoxycarbonyl, ethoxycarbonyl and n- and t-butoxycarbonyl; examples of
Figure imgf000005_0001
include Cι- alkoxy, methoxy, ethoxy and propoxy; examples of Cι- alkanoylamino include formamido, acetamido and propionylamino; examples of Cι.6alkylS(O)a where a is 0, 1 or 2 include Cι-6alkylsulphonyl, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl and ethylsulphonyl; examples of C i -6alkanoyl include propionyl and acetyl; examples of N-Cι-6alkylamino include N-methylamino and N-ethylamino; examples of N,N-(Cι.6alkyl)2amino include N,N-dimethylamino, N,N-diethylamino and N- ethyl-N-methylamino; examples of C3_i2cycloalkyl include Cg.πcycloalkyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclododecyl and adamantyl; examples of C2-8alkenyl include C2-6alkenyl, C2-4alkenyl, vinyl, allyl and 1-propenyl; examples of C2-8alkynyl include C2-6alkynyl, C2-4alkynyl, ethynyl, 1-propynyl and 2-propynyl; examples of N-(C].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-(C i .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_6alkanoyloxy include Cι- alkanoyloxy, propionyloxy, acetyloxy and formyloxy, and examples of C i -6alkoxyC i .6alkoxy include C i -4alkoxyC i -4alkoxy, methoxymethoxy, methoxyethoxy and ethoxypropoxy. Preferably p is 0. Preferably q is 0.
Preferably R3 is substituted Cι-8alkyl, optionally substituted C2-8alkenyl or optionally substituted C2-8alkynyl; wherein said substituents are chosen from one or more groups selected from halo, cyano, hydroxy, carbamoyl, Cι- alkoxy, Cι-6alkanoyl, Cι-6alkoxycarbonyl,
Cι-6alkanoyloxy,
Figure imgf000006_0001
optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl or a group of the formula (LA) as depicted above wherein B is optionally substituted aryl, optionally substituted heterocyclyl or C3- ^cycloalkyl; r is 0, 1, 2, 3, 4, 5 or 6; and X is a linking group selected from -C(O)-, -O-, -
OC(O)-; and wherein any aryl, heteroaryl and heterocyclyl may be optionally substituted on a ring carbon with one or more groups selected from halo, Cι-6alkyl or Cι-6alkoxy; with the proviso that R3 cannot be optionally substituted phenylCι-8alkyl and with the further proviso that when R3 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. More preferably R3 is substituted Cι-6alkyl, optionally substituted C2-4alkenyl or C2- 4alkynyl; wherein said substituents are chosen from one or two groups selected from halo, cyano, hydroxy, carbamoyl, Cι- alkoxy, Cι.4alkanoyl, Cι- alkoxycarbonyl, Cι-4alkanoyloxy, Cι- alkoxyCι-4alkoxy, aryl, heterocyclyl, heteroaryl or a group of the formula (IA) as depicted above wherein B is optionally substituted aryl, heterocyclyl or C3_i2cycloalkyl; r is 0, 1, 2, 3 or 4; and X is a linking group selected from -C(O)-, -O-, -OC(O)-; and wherein any aryl, heteroaryl and heterocyclyl may be optionally substituted on a ring carbon with one or two groups selected from halo, Cj- alkyl or Cι- alkoxy; with the proviso that R3 cannot be optionally substituted
Figure imgf000007_0001
and with the further proviso that when R3 is substituted Cι-6alkyl, substituted C2- alkenyl or substituted C2- alkynyl the carbon atom adjacent to the homopiperazine ring is not directly substituted by any heteroatom other than fluoro.
Particularly R3 is carbamoylmethyl, isopropoxycarbonylmethyl, t- butoxycarbonylmethyl, t-butylcarbonylmethyl, benzoylmethyl, 4-methylbenzoylmethyl, 4- methoxybenzoylmethyl, 4-chlorobenzoylmethyl, 4-bromobenzoylmethyl, 4- phenylbenzoylmethyl, 2,4-dimethoxybenzoylmethyl, phenoxycarbonylmethyl, tetrahydropyran-2-ylmethyl, adamant-3-ylcarbonylmethyl, 2-fluoroethyl, 2-hydroxyethyl, 2- cyanoethyl, methoxyethyl, methoxyethoxyethyl, 2,2-dimethoxyethyl, 2,2-diethyloxyethyl, 2- acetoxyethyl, 2-methoxycarbonylethyl, 2-ethoxycarbonylethyl, 2-phenoxyethyl, 2-(4'- chlorophenoxy)ethyl, 2-(l',3'-dioxolan-2'-yl)ethyl, 2-(l',3'-dioxan-2'-yl)ethyl, 2-hydroxy-2- phenylethyl, 3-fluoropropyl, 3-cyanopropyl, 3-ethoxycarbonylpropyl, 3-phenoxypropyl, 3- benzyloxypropyl, 3-(tetrahydropyran-2'-yloxy)propyl, 3-(phthalimid-2'-yl)propyl, 2-hydroxy- 3-phenoxypropyl, 2-hydroxy-3-benzyloxypropyl, 2-methoxy-3-benzyloxypropyl, 2-hydroxy-3- isopropoxypropyl, 2-hydroxy-3-phenylpropyl, 4-fluorobutyl, 4-cyanobutyl, 4-acetoxybutyl, 4- ethoxycarbonylbutyl, 4-phenoxybutyl, 5-cyano-5-methylhexyl, 3-methoxycarbonylallyl, 3- phenylallyl, 3-butenyl, 3-methyl-2-butenyl, 3,4,4-trifluoro-3-butenyl or 2-propynyl. In another aspect of the invention particularly R3 is carbamoylmethyl, isopropoxycarbonylmethyl, t-butoxycarbonylmethyl, t-butylcarbonylmethyl, benzoylmethyl, 4-methylbenzoylmethyl, 4-methoxybenzoylmethyl, 4-chlorobenzoylmethyl, 4- bromobenzoylmethyl, 4-phenylbenzoylmethyl, 2,4-dimethoxybenzoylmethyl, phenoxycarbonylmethyl, tetrahydropyran-2-ylmethyl, adamant-3-ylcarbonylmethyl, 2- fluoroethyl, 2-hydroxyethyl, 2-cyanoethyl, methoxyethyl, methoxyethoxyethyl, 2,2- dimethoxyethyl, 2,2-diethyloxyethyl, 2-acetoxyethyl, 2-methoxycarbonylethyl, 2- ethoxycarbonylethyl, 2-phenoxyethyl, 2-(4'-chlorophenoxy)ethyl, 2-(l',3'-dioxolan-2'-yl)ethyl, 2-(l',3'-dioxan-2'-yl)ethyl, 2-hydroxy-2-phenylethyl, 2,2,2-trifluoroethyl, 2-hydroxypropyl, 3- fluoropropyl, 3-cyanopropyl, 3-hydroxypropyl, 3-ethoxycarbonylpropyl, 3-phenoxypropyl, 3- benzyloxypropyl, 3-(tetrahydropyran-2'-yloxy)propyl, 3-(phthalimid-2'-yl)propyl, 2-hydroxy- 3-phenoxypropyl, 2-hydroxy-3-benzyloxypropyl, 2-methoxy-3-benzyloxypropyl, 2-hydroxy-3- isopropoxypropyl, 2-hydroxy-3-phenylpropyl, 3-phenyl-3-oxopropyl, 3-(4-fluorophenyl)-3- oxopropyl, 3-(4-chlorophenyl)-3-oxopropyl, 3-(4-bromophenyl)-3-oxopropyl, 3-phenyl-3- hydroxypropyl, 3-(4-fluorophenyl)-3-hydroxypropyl, 3-(4-chlorophenyl)-3-hydroxypropyl, 3- (4-bromophenyl)-3-hydroxypropyl, 3-fur-2-ylmethoxy-2-hydroxypropyl, 3-hydroxy-3- methylbutyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-fluorobutyl, 4-cyanobutyl, 4-acetoxybutyl, 4- ethoxycarbonylbutyl, 4-phenoxybutyl, 3-oxobutyl, 4-bromo-3,3,4,4-tetrafluorobutyl, 3- oxopentyl, 3-hydroxypentyl, 5-cyano-5-methylhexyl, 3-methoxycarbonylallyl, 3-phenylallyl, 3-butenyl, 3-methyl-2-butenyl, 3,4,4-trifluoro-3-butenyl or 2-propynyl.
More particularly R3 is 2-fluoroethyl, methoxyethyl, methoxyethoxyethyl, 2,2- dimethoxyethyl, 2-methoxycarbonylethyl, 2-ethoxycarbonylethyl, 2-phenoxyethyl, 2-(l',3'- dioxolan-2'-yl)ethyl, 2-(l',3'-dioxan-2'-yl)ethyl, 3-fluoropropyl, 3-phenoxypropyl, 3- (tetrahydropyran-2'-yloxy)propyl, 4-cyanobutyl, 4-acetoxybutyl, 3-butenyl or 3,4,4-trifluoro-3- butenyl.
In another aspect of the invention more particularly R3 is 2-fluoroethyl, methoxyethyl, methoxyethoxyethyl, 2,2-dimethoxyethyl, 2-methoxycarbonylethyl, 2- ethoxycarbonylethyl, 2-phenoxyethyl, 2-(l',3'-dioxolan-2'-yl)ethyl, 2-(l',3'-dioxan-2'-yl)ethyl, 2,2,2-trifluoroethyl, 2-hydroxypropy 3-hydroxypropyl, 3-fluoropropyl, 3-phenoxypropyl, 3- (tetrahydropyran-2'-yloxy)propyl, 3-phenyl-3-oxopropyl, 3-(4-fluorophenyl)-3-oxopropyl, 3- (4-chlorophenyl)-3-oxopropyl, 3-(4-bromophenyl)-3-oxopropyl, 3-phenyl-3-hydroxypropyl, 3- (4-fluorophenyl)-3-hydroxypropyl, 3-(4-chlorophenyl)-3-hydroxypropyl, 3-(4-bromophenyl)- 3-hydroxypropyl, 3-fur-2-ylmethoxy-2-hydroxypropyl, 3 -hydroxy-3 -methylbutyl, 2- hydroxybutyl, 3-hydroxybutyl,4-cyanobutyl, 4-acetoxybutyl, 3-oxobutyl, 4-bromo-3, 3,4,4- tetrafluorobutyl, 3-oxopentyl, 3-hydroxypentyl, 3-butenyl or 3,4,4-trifluoro-3-butenyl.
In another aspect of the mvention particularly preferred R3 is 3-methyl-2-butenyl. Therefore in a preferred aspect of the invention, there is provided a compound of formula (I) wherein: p is 0; R3 is substituted C] 8alkyl, optionally substituted C2 salkenyl or optionally substituted C2-8alkynyl, wherein said substituents are chosen from one or more groups selected from halo, cyano, hydroxy, carbamoyl, Cι-6alkoxy, Ci 6alkanoyl, Cι-6alkoxycarbonyl, Ci 6alkanoyloxy, Cι-6alkoxyCι-6alkoxy, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl or a group of the formula (LA) as depicted above wherein B is optionally substituted aryl, optionally substituted heterocyclyl or C3 ι2cycloalkyl, r is 0, 1, 2, 3, 4, 5 or 6, and X is a linking group selected from -C(O)-, -O-, - OC(O)-, and wherein any aryl, heteroaryl and heterocyclyl may be optionally substituted on a πng carbon with one or more groups selected from halo,
Figure imgf000009_0001
or Cι-6alkoxy, or a pharmaceutically-acceptable salt, or an in vzvo-hydrolysable ester, amide or carbamate thereof, with the proviso that R3 is not optionally substituted phenylCι-8alkyl and with the further proviso that when R3 is substituted Cι_8alkyl, substituted C2-8alkenyl or substituted C2- 8alkynyl the carbon atom adjacent to the homopiperazine πng is not directly substituted by any heteroatom other than fluoro
In a more prefeπed aspect of the invention, there is provided a compound of formula (I) wherein p is 0,
R3 is carbamoylmethyl, isopropoxycarbonylmethyl, t-butoxycarbonylmethyl, t- butylcarbonylmethyl, benzoylmethyl, 4-methylbenzoylmethyl, 4-methoxybenzoylmethyl, 4- chlorobenzoylmethyl, 4-bromobenzoylmethyl, 4-phenylbenzoylmethyl, 2,4- dimethoxybenzoylmethyl, phenoxycarbonylmethyl, tetrahydropyran-2-ylmethyl, adamant-3- ylcarbonylmethyl, 2-fluoroethyl, 2-hydroxyethyl, 2-cyanoethyl, methoxyethyl, methoxyethoxyethyl, 2,2-dimethoxyethyl, 2,2-dιethyoxyethyl, 2-acetoxyethyl, 2- methoxycarbonylethyl, 2-ethoxycarbonylethyl, 2-phenoxyethyl, 2-(4'-chlorophenoxy)ethyl, 2- (l',3'-dιoxolan-2'-yl)ethyl, 2-(l',3'-dιoxan-2'-yl)ethyl, 2-hydroxy-2-phenylethyl, 3- fluoropropyl, 3-cyanopropyl, 3-ethoxycarbonylpropyl, 3-phenoxypropyl, 3-benzyloxypropyl, 3-(tetrahydropyran-2'-yloxy)propyl, 3-(phthahmιd-2'-yl)propyl, 2-hydroxy-3-phenoxypropyl, 2-hydroxy-3-benzyloxypropyl, 2-methoxy-3-benzyloxypropyl, 2-hydroxy-3-ιsopropoxypropyl, 2-hydroxy-3-phenylpropyl, 4-fluorobutyl, 4-cyanobutyl, 4-acetoxybutyl, 4- ethoxycarbonylbutyl, 4-phenoxybutyl, 5-cyano-5-methylhexyl, 3-methoxycarbonylallyl, 3- phenylallyl, 3-butenyl, 3-methyl-2-butenyl, 3,4,4-trifluoro-3-butenyl or 2-propynyl; or a pharmaceutically-acceptable salt, or an in v/vo-hydrolysable ester, amide or carbamate thereof. In another more prefeπed aspect of the invention, there is provided a compound of formula (I) wherein: p is 0; q is 0; and
R3 is carbamoylmethyl, isopropoxycarbonylmethyl, t-butoxycarbonylmethyl, t- butylcarbonylmethyl, benzoylmethyl, 4-methylbenzoylmethyl, 4-methoxybenzoylmethyl, 4- chlorobenzoylmethyl, 4-bromobenzoylmethyl, 4-phenylbenzoylmethyl, 2,4- dimethoxybenzoylmethyl, phenoxycarbonylmethyl, tetrahydropyran-2-ylmethyl, adamant-3- ylcarbonylmethyl, 2-fluoroethyl, 2-hydroxyethyl, 2-cyanoethyl, methoxyethyl, methoxyethoxyethyl, 2,2-dimethoxyethyl, 2,2-diethyloxyethyl, 2-acetoxyethyl, 2- methoxycarbonylethyl, 2-ethoxycarbonylethyl, 2-phenoxyethyl, 2-(4'-chlorophenoxy)ethyl, 2- (l',3'-dioxolan-2'-yl)ethyl, 2-(l',3'-dioxan-2'-yl)ethyl, 2-hydroxy-2-phenylethyl, 2,2,2- trifluoroethyl, 2-hydroxypropyl, 3-fluoropropyl, 3-cyanopropyl, 3-hydroxypropyl, 3- ethoxycarbonylpropyl, 3-phenoxypropyl, 3-benzyloxypropyl, 3-(tetrahydropyran-2'- yloxy)propyl, 3-(phthalimid-2'-yl)propyl, 2-hydroxy-3-phenoxypropyl, 2-hydroxy-3- benzyloxypropyl, 2-methoxy-3 -benzyloxypropyl, 2-hydroxy-3-isopropoxypropyl, 2-hydroxy- 3-phenylpropyl, 3-phenyl-3-oxopropyl, 3-(4-fluorophenyl)-3-oxopropyl, 3-(4-chlorophenyl)-3- oxopropyl, 3-(4-bromophenyl)-3-oxopropyl, 3-phenyl-3-hydroxypropyl, 3-(4-fluorophenyl)-3- hydroxypropyl, 3-(4-chlorophenyl)-3-hydroxypropyl, 3-(4-bromophenyl)-3-hydroxypropyl, 3- fur-2-ylmethoxy-2-hydroxypropyl, 3 -hydroxy-3 -methylbutyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-fluorobutyl, 4-cyanobutyl, 4-acetoxybutyl, 4-ethoxycarbonylbutyl, 4-phenoxybutyl, 3- oxobutyl, 4-bromo-3,3,4,4-tetrafluorobutyl, 3-oxopentyl, 3-hydroxypentyl, 5-cyano-5- methylhexyl, 3-methoxycarbonylallyl, 3-phenylallyl, 3-butenyl, 3-methyl-2-butenyl, 3,4,4- trifluoro-3-butenyl or 2-propynyl; or a pharmaceutically-acceptable salt, or an in v/vo-hydrolysable ester, amide or carbamate thereof.
In a particular aspect of the invention, there is provided a compound of formula (I) wherein: p is 0; q is 0; and
R3 is 2-fluoroethyl, methoxyethyl, methoxyethoxyethyl, 2,2-dimethoxyethyl, 2- methoxycarbonylethyl, 2-ethoxycarbonylethyl, 2-phenoxyethyl, 2-(l',3'-dioxolan-2'-yl)ethyl, 2-(l',3'-dioxan-2'-yl)ethyl, 3-fluoropropyl, 3-phenoxypropyl, 3-(tetrahydropyran-2'- yloxy)propyl, 4-cyanobutyl, 4-acetoxybutyl, 3-butenyl or 3,4,4-trifluoro-3-butenyl; or a pharmaceutically-acceptable salt, or an in v/vo-hydrolysable ester, amide or carbamate thereof.
In another particular aspect of the invention, there is provided a compound of formula (I) wherein: p is 0; q is 0; and
R3 is R3 is 2-fluoroethyl, methoxyethyl, methoxyethoxyethyl, 2,2-dimethoxyethyl, 2- methoxycarbonylethyl, 2-ethoxycarbonylethyl, 2-phenoxyethyl, 2-(l',3'-dioxolan-2'-yl)ethyl, 2-(l',3'-dioxan-2'-yl)ethyl, 2,2,2-trifluoroethyl, 2-hydroxypropy 3-hydroxypropyl, 3- fluoropropyl, 3-phenoxypropyl, 3-(tetrahydropyran-2'-yloxy)propyl, 3-phenyl-3-oxopropyl, 3- (4-fluorophenyl)-3-oxopropyl, 3-(4-chlorophenyl)-3-oxopropyl, 3-(4-bromophenyl)-3- oxopropyl, 3-phenyl-3-hydroxypropyl, 3-(4-fluorophenyl)-3-hydroxypropyl, 3-(4- chlorophenyl)-3 -hydroxypropyl, 3 -(4-bromophenyl)-3 -hydroxypropyl, 3-fur-2-ylmethoxy-2- hydroxypropyl, 3-hydroxy-3-methylbutyl, 2-hydroxybutyl, 3-hydroxybutyl,4-cyanobutyl, 4- acetoxybutyl, 3-oxobutyl, 4-bromo-3,3,4,4-tetrafluorobutyl, 3-oxopentyl, 3-hydroxypentyl, 3- butenyl or 3,4,4-trifluoro-3-butenyl; or a pharmaceutically-acceptable salt, or an in v/vo-hydrolysable ester, amide or carbamate thereof. Preferred compounds of the invention are those of Examples.
Suitable pharmaceutically-acceptable salts include acid addition salts such as methanesulphonate, fumarate, hydrochloride, hydrobromide, citrate, maleate and salts formed with phosphoric and sulphuric acid. 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-efhylpiperidine, procaine, dibenzylamine, N,N-dibenzylethylamine or amino acids for example lysine. There may be 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.
The compounds of formula (I) possess at least one chiral centre. It is to be understood that the invention encompasses all optical isomers and diasteroisomers of compounds of formula (I) that inhibit the [3H]-emopamil binding site. The chiral centre is at the 1 -position of the 1,2,3,4-tetrahydronaphthalene ring system and it is prefeπed that this centre has the S-stereochemistry under the Cahn-Prelog-Ingold sequence rules.
The invention further relates to all tautomeric forms of the compounds of formula
(I). It is also to be understood that certain compounds of the formula (I) can exist in solvated as well as unsolvated 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 N-carbomethoxy and N-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-6alkoxymethyl esters for example methoxyme hyl, Cι-6alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, C3-8cycloalkoxy-carbonyloxyCι- alkyl esters for example 1-cyclohexylcarbonyloxyethyl; l,3-dioxolen-2-onylmethyl esters for example 5- methyl-l,3-dioxolen-2-onylmethyl; and Cι-6alkoxycarbonyloxyethyl esters for example 1- methoxycarbonyloxyethyl and may be formed at any carboxy group in the compounds of this invention.
An in v/vo-hydrolysable ester of a compound of the formula (I) containing 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 breakdown to give the parent hydroxy group. Examples of α-acyloxyalkyl ethers include acetoxymethoxy and 2,2- dimethylpropionyloxymethoxy. A selection of in v/vo-hydrolysable 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 , R , p and q are, unless otherwise specified, as defined in formula (I)) comprises of: a) reacting a compound of the formula (II):
Figure imgf000013_0001
(H) wherein L is a suitable displaceable group, with a compound of the formula (LLL):
Figure imgf000013_0002
(HI) or b) for compounds of formula (I) wherein R is not hydrogen, reacting a compound of formula (IV):
Figure imgf000013_0003
(TV)
with a compound of formula (V): R3-L
(V) wherein L is a suitable displaceable group; or c) reacting a compound of the formula (VI):
Figure imgf000014_0001
(VI) with a compound of the formula (III); or d) for compounds of formula (I) wherein R" is substituted C2-8alkyl with no substitution on the carbon adjacent to the homopiperazine ring, reacting a compound of formula (TV) with a compound of formula (VII):
Figure imgf000014_0002
(NTT) wherein Ra is Cι-7alkyl substituted with one or more of the substituents listed under R3 above and Q 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. L is a displaceable group, suitable values for L are for example, a halogeno or sulphonyloxy group, for example a chloro, bromo, methanesulphonyloxy or toluene-4- sulphonyloxy group.
Specific reaction conditions for the reactions a) and b), above, 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, or they are known in the literature, or they are prepared by standard processes known in the art. Compounds of formula (TV) may be prepared according to the following scheme:
Figure imgf000015_0001
(IVB) Pg is an amino protecting group, suitable values for Pg as those as described hereinbelow. Compounds of formula (IV A) are commercially available compounds, or they are known in the literature, or they are prepared by standard processes known in the art.
Specific reaction conditions for the reactions c) and d), above, are as follows. Amines and ketones, aldehydes or carboxylic acids are reacted together 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 preferably 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/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 (including intravenous, intramuscular or infusion) sterile aqueous or oily solutions or suspensions or sterile emulsions. A prefeπed 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 co-administered (simultaneously or sequentially) with, one or more pharmacological agents of value in treating one or more disease conditions refeπed 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) as defined hereinbefore or a pharmaceutically-acceptable salt or an in v/vo-hydrolysable ester, amide or carbamate thereof, in association with a pharmaceutically-acceptable excipient or carrier. 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 this is a compound of formula (I), or a pharmaceutically-acceptable salt or an in v/vo-hydrolysable ester, amide or carbamate thereof, for use as a medicament to inhibit the [ H] -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 [3H]-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. Biological Test Methods
3H-Emopamil binding to guinea pig liver membranes
The method of (-)-3H-emopamil binding was a modification of Zech, C, Staudinger R., Mϋhlbacher, 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. The reaction mixture contained:
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 (-)-3H-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 with an IC50 below 300 nM in this test were of interest. Guinea-pig liver membrane preparation:
Male guinea pigs were sacrificed by CO2 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.
3H-D-888 binding to rat brain cortical membranes
The method of 3H-D-888 binding was 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.
The assay tubes contained the following: 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 MgC , pH 7.4. Specific binding was measured with
10 μM methoxyverapamil (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 3H-D888 binding site would show a lack of selectivity.
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. 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 pH, if needed. Forty-five minutes after dosing the gerbils are anaesthetised with halothane (3.3%o) which is delivered along with oxygen (1.5 L/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 suπounding 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 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.
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, 90, and 120 minutes. Mean counts are recorded for each group and drug groups are compared to control with an ANOVA and Bonfeπoni 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 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 sub field: 0 to 4 scale, with 0 representing no damage and 4 representing extensive damage. Transient Focal Ischaemia in Rats
The method was as described by Lin, T-N., He, Y.Y., Wu, G., Khan, M. And Hsu, CN. Effect of brain edema on infarct volume in a focal model cerebral ischaemia model in rats. Stroke 24:117-121, 1993, which model is considered to be relevant to the clinical situation. Male Long-Evans rats 250-350 g were used. Surgery leading to focal ischaemia was conducted under anaesthesia 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 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 anaesthesia by intracardiac perfusion with 200 mL of 0.9% ΝaCl. 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 invention is now illustrated but not limited by the following Examples in which unless otherwise stated :- (i) concentrations were carried out by rotary evaporation in vacua; (ii) operations were carried out at ambient temperature (room temperature), that is in the range 18-26 °C and under a nitrogen atmosphere otherwise stated;
(iii) column chromatography (by the flash procedure) was performed on ICΝ silica 32-
63, 60 A unless otherwise stated; (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 ΝMR and mass spectral techniques [proton magnetic resonance spectra were determined in CDC13 unless otherwise stated using a Brucker spectrometer operating at a field strength of 300 MHz; chemical shifts are reported in parts per million downfield from tetramethylsilane as an internal standard (δ 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; mass spectral data were obtained using a Platform spectrometer (supplied by Micromass) run using atmospheric pressure chemical ionisation (APCI) and, where appropriate, either positive ion data or negative ion data were collected]; (vi) intermediates were not generally fully characterised and purity was in general assessed mass spectral (MS) or NMR analysis; and
(vii) microwave irradiation were performed using a kitchen grade 1000W microwave oven (Panasonic, the Genius Premier, model number NN-S567). (viii) in which the following abbreviations may be used :-
DMF is N,N-dimethylformamide
DMSO is dimethylsulphoxide
CDCI3 is deuterated chloroform m/s is mass spectroscopy
THF is tetrahydrofuran
NMP is N-methylpyrrolidone.
Example 1
N- 1 -( 1,2,3 ,4-Tetrahydronaphth- 1 -yl)-N-4-(3-methyl-2-butenyl)homopiperazine A flask was charged with a solution of N-l-(l,2,3,4-tetrahydronaphthyl) homopiperazine (761 mg, 3.3 mmol) in THF (20 mL). Triethylamine (0.46 mL, 330 mg, 3.3 mmol) and l-bromo-3-methylbutene (0.38 mL, 490 mg, 3.3 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 product was purified by column chromatography using dichloromethane:methanol (95:5) to obtain the title compound as a yellow oil (520 mg). ΝMR: 1.57-1.71 (m, 2H), 1.71 (s, 3H), 1.82 (s, 3H), 1.95-2.20 (bm, 4H), 2.68-2.92 (bm, 7H), 3.05 (m, 1H), 3.24 (m, 2H), 3.52 (d, 2H), 3.95 (m, 1H), 5.51 (m, 1H), 7.05 -7.21 (bm, 3H), 7.65 (d, 1H); m/s: M+H+ 299.
Using an analogous procedure to that described in Example 1, Examples 2-8 were prepared by reacting an appropriate substituted halo alkane with 1-(1, 2,3,4- tetrahydronaphthyl)homopiperazine. Example 2
N-l-(l,2,3.4-Tetrahydronaphth-l-yl)-N-4-(3,3,4,4,tetrafluoro-4-bromobutyl)homopiperazine The product was purified by chromatography performed using a gradient from 0 to 100% diethyl ether in hexane followed by 2.5% methanol in diethyl ether. ΝMR: 1.58-1.82 (bm, 4H), 1.93-2.07 (bm, 2H), 2.29 (m, 2H), 2.63-2.89 (bm, 12H), 3.90 (m, 1H), 7.03-7.18 (bm, 3H), 7.75 (d, 1H); m s: M+H+ 437, 439. Example 3 N-l-(L2,3,4-Tetrahvdronaphth-l-yl)-N-4-(3-oxo-butyl)homopiperazine
The product was purified by chromatography performed using 5% methanol in diethyl etheπhexane (1 :9). ΝMR: 1.54-1.77 (bm, 4H), 1.94-2.06 (bm, 2H), 2.17 (s, 3H), 2.58- 2.86 (bm, 14H), 3.89 (1H), 7.03-7.18 (bm, 3H), 7.75 (d, 1H); m s: M+H+ 301. Example 4 N- 1 -( 1 ,2,3 ,4-Tetrahydronaphth- 1 -yl)-N-4-(3-oxo-pentyl)homopiperazine
ΝMR: 1.06 (t, 3H) 1.58-1.77 (bm, 4H), 1.94-2.06 (bm, 2H), 2.46 (q, 2H), 2.56-2.86 (bm, 14H), 3.89 (1H), 6.99-7.18 (bm, 3H), 7.75 (d, 1H); m s: M+H+ 315. Example 5 N-l-(L2,3,4-Tetrahvdronaphth-l-yl)-N-4-(3-oxo-3-phenyl-propyl)homopiperazine
The product was purified by chromatography performed using a gradient from 0 to 5% methanol in diethyl etheπhexane (1:1). ΝMR: 1.64 (m, 2H), 1.76 (m, 2H), 1.94-2.07 (bm, 2H), 2.67-2.79 (bm, 8H), 2.84 (m, 2H), 3.01 (m, 2H), 3.18 (m,2H), 3.89 (m, 1H), 7.03-7.18 (bm, 3H), 7.46 (m, 2H), 7.56 (m, 1H), 7.76 (d, 1H), 7.97 (m, 2H); m/s: M+H+ 363. Example 6
N- 1 -( 1 ,2,3,4-Tetrahydronaphth- 1 -yl)-N-4-(3-oxo-3-(4-fluorophenyl)-propyl)homopiperazine The product was purified by chromatography performed using 1% methanol in diethyl etheπhexane (1 :1). ΝMR: 1.63 (m, 2H), 1.77 (m, 2H), 1.94-2.08 (bm, 2H), 2.66-2.85 (bm, 10H), 3.00 (m, 2H), 3.14 (m, 2H), 3.89 (m, 1H), 7.03-7.19 (bm, 5H), 7.76 (d, 1H), 7.99 (m, 2H): m s: M+H+ 381.
Example 7 N-l-(l,2,3,4-Tetrahvdronaphth-l-yl)-N-4-(3-oxo-3-(4-chloro-phenyl)-propyl)homopiperazine The product was purified by chromatography performed using 1% methanol in diethyl etheπhexane (1:1). ΝMR: 1.57-1.82 (bm, 4H), 1.95-2.07 (bm, 2H), 2.65-2.85 (bm, 10H), 3.00 (m, 2H), 3.13 (m, 2H), 3.89 (m, 1H), 7.03-7.18 (bm, 3H), 7.44 (d, 2H), 7.75 (d, 1H), 7.90 (d, 2H): m/s: M+H+ 397, 399. Example 8
N-l-(l,2,3,4-Tetrahvdronaphth-l-yl)-N-4-(3-oxo-3-(4-bromo-phenyl)-propyl)homopiperazine The product was purified by chromatography performed using 1 % methanol in diethyl etheπhexane (1 : 1). ΝMR: 1.57-1.82 (bm, 4H), 1.95-2.09 (bm, 2H), 2.65-2.84 (bm, 10H), 2.99 (m, 2H), 3.13 (m, 2H), 3.89 (m, 1H), 7.03-7.18 (bm, 3H), 7.61 (d, 2H), 7.75 (d, 1H), 7.83 (d, 2H): m/s: M+H+ 441, 443. Example 9 N- 1 -( 1 ,2,3 ,4-Tetrahydronaphth- 1 -yl)-N-4-(3-hvdroxybutyl)homopiperazine
A flask was charged with a solution of Example 3 (620 mg, 2.1 mmol) in diethyl ether (12 mL) and methanol (12 mL). A pellet of sodium borohydride (450 mg, 12 mmol) was added. After stirring for 40 minutes the reaction was quenched by the careful addition of water and then poured into water (100 mL). The resulting mixture was extracted with ether (2 x 100 mL) and the combined organic extracts were washed with brine (200 mL), dried over anhydrous magnesium sulphate, filtered and concentration to give an orange oil. This product was purified by column chromatography using hexane to elute high Rf impurities followed by diethyl efheπmefhanol (95:5) to obtain the title compound as a yellow oil (450 mg). ΝMR: 1.17 (m, 3H), 1.39-1.80 (bm, 6H), 1.92-2.05 (bm, 2H), 2.54-2.92 (bm, 12H), 3.88 (m, 1H), 3.98 (m, 1H), 6.72 (bs, 1H), 7.01-7.18 (bm, 3H), 7.75 (d, 1H); m/s: M+H+ 303.
Using an analogous procedure to that described in Example 9, Examples 10-14 were prepared by reducing an appropriate ketone. Example 10 N- 1 -( 1 ,2,3 ,4-Tetrahydronaphth- 1 -yl)-N-4-(3-hvdroxy-pentyl)homopiperazine Reduction of the compound of Example 4 yielded the title compound. ΝMR: 0.94
(m, 3H), 1.43-1.80 (bm, 8H), 1.92-2.05 (bm, 2H), 2.53-2.93 (bm, 12H), 3.71 (m, 1H), 3.88 (m, 1H), 6.77 (bs, 1H), 7.01-7.18 (bm, 3H), 7.75 (d, 1H); m/s: M+H+ 317.
Example 11 N-l-( 2,3,4-Tetrahvdronaphth-l-yl)-N-4-(3-hvdroxy-3-phenyl-propyl)homopiperazine
Reduction of the compound of Example 5 yielded the title compound. The product was purified by chromatography performed using a gradient from 0 to 5%> methanol in diethyl etheπhexane (1 :1). NMR: 1.62 (m, 2H), 1.83 (m, 4H), 1.95-2.08 (bm, 2H), 2.63-2.90 (bm, 12H), 3.90 (m, 1H), 4.97 (m, 1H), 7.03-7.41 (bm, 9H), 7.77 (t, 1H); M+H+ 365.
Example 12 N-l-(l,2.3,4-Tetrahvdronaphth-l-yl)-N-4-(3-hydroxy-3-(4-fluoro-phenyl)- propyl))homopiperazine
Reduction of the compound of Example 6 yielded the title compound. The product was purified by chromatography performed using 5% methanol in diethyl etheπhexane (1:1).
ΝMR: 1.56-2.07 (bm, 8H), 2.63-2.92 (bm, 12H), 3.91 (m, 1H), 4.94 (m, 1H), 6.98-7.18 (bm, 5H), 7.34 (m, 2H), 7.48 (bs, 1H), 7.76 (t, 1H); M+H+ 383.
Example 13
N- 1 -( 1 ,2.3,4-Tetrahvdronaphth- 1 -yl -N-4-(3-hvdroxy-3-(4-chloro-phenyl)- propyl))homopiperazine
Reduction of the compound of Example 7 yielded the title compound. The product was purified by chromatography performed using 5% methanol in diethyl etheπhexane (1 : 1).
ΝMR: 1.57-2.06 (bm, 8H), 2.64-2.90 (bm, 12H), 3.91 (m, 1H), 4.95 (m, 1H), 7.03-7.20 (bm,
3H), 7.24-7.37 (bm, 4H), 7.54 (bs, 1H), 7.76 (t, 1H); M+H+ 399, 401.
Example 14
N- 1 -( 1.2.3.4-Tetrahvdronaphth- 1 -yl)-N-4-(3 -hvdroxy-3-(4-bromo-phenyl)- propyl))homopiperazine
Reduction of the compound of Example 8 yielded the title compound. The product was purified by chromatography performed using 5% methanol in diethyl etheπhexane (1 :1).
ΝMR: 1.55-2.06 (bm, 8H), 2.64-2.92 (bm, 12H), 3.91 (m, 1H), 4.93 (m, 1H), 7.03-7.21 (bm,
3H), 7.26 (m, 2H), 7.46 (m, 2H), 7.54 (bs, 1H), 7.76 (t, 1H); M+H+ 443, 445. Example 15
N- 1 -(1 ,2,3,4-Tetrahydronaphth- 1 -yl)-N-4-(3-hydroxy-3-methylbutyl)homopiperazine
A flask was charged with a solution of Example 3 (418 mg, 1.4 mmol) in THF (10 mL) and cooled to -78 °C. A solution of methyl magnesium bromide (1.4 mL, 3.0 M in diethyl ether, 4.2 mmol) was added and the solution was allowed to come to room temperature. After stirring for an additional 30 minutes the reaction was quenched by the careful addition of water (50 mL) and then extracted with ether (3 x 100 mL). The combined organic extracts were washed with brine (200 mL), dried over anhydrous magnesium sulphate, filtered and concentration to give an orange oil. This product was purified by column chromatography using hexane to elute high Rf impurities followed by 2.5% methanol in diethyl ether to obtain the title compound as an orange oil (269 mg). NMR: 1.21 (s, 3H), 1.22 (s, 3H), 1.55-1.82 (m, 6H), 1.95-2.04 (bm, 2H), 2.63-2.83 (bm, 12H), 3.88 (m, 1H), 7.02-7.17 (bm, 3H), 7.75 (d, 1H); m/s: M+H+ 317. Example 16 N- 1 -( 1 ,2,3 ,4-Tetrahydronaphth- 1 -yl)-N-4-(3-hvdroxypropyl)hornopiperazine
A solution of N-l-(l,2,3,4-tetrahydronaphfh-l-yl)-N-4-(3-(t- butyldimethylsilyloxy)propyl)homopiperazine (1.45 g, 3.6 mmol) in THF (12 mL) was cooled to 0 °C and tetrabutylammonium fluoride (7.2 mL, 1.0 M in THF) was added over 5 minutes. The solution was allowed to warm to room temperature while stirring for 16 hours. The mixture was quenched by the addition of water (100 mL) and then extracted with diethyl ether (2 x 100 mL). The combined extracts were washed with brine (200 mL), dried over anhydrous magnesium sulphate, filtered and concentrated to obtain the product as a light purple oil. This 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 light purple oil (518 mg). ΝMR: 1.56-1.80 (m, 7H), 1.94-2.07 (m, 2H), 2.63-2.83 (bm, 12H), 3.82-3.91 (bm, 3H), 5.97 (bs, 1H), 7.03-7.20 (bm, 3H), 7.76 (d, 1H); m/s: M+H+ 289.
Compounds of Examples 17-18 were prepared using a procedure analogous to that of Example 16. Example 17
N-l -(1 ,2,3,4-Tetrahvdronaphth-l-yl)-N-4-(3-hydroxy-propyl)homopiperazine (S enantiomer) ΝMR: 1.56-1.80 (m, 7H), 1.95-2.05 (m, 2H), 2.63-2.83 (bm, 12H), 3.82-3.91 (bm,
3H), 5.96 (bs, 1H), 7.05-7.18 (bm, 3H), 7.74 (d, 1H); M^ +66-7° (c = 2-25> methanol). M+H+ 289. Example 18
N-l-(l,2,3,4-Tetrahydronaphth-l-yl)-N-4-(3-hydroxy-propyl)homopiperazine (R enantiomer) ΝMR: 1.56-1.80 (m, 7H), 1.95-2.05 (m, 2H), 2.63-2.82 (bm, 12H), 3.82-3.91 (bm,
3H), 5.97 (bs, 1H), 7.03-7.18 (bm, 3H), 7.74 (d, 1H); M^ -67.8° (c = 2.45, methanol).
M+H+ 289. Example 19
N- 1 -( 1 ,2 ,3 ,4-Tetrahydronaphth- 1 -yl)-N-4-(2-hvdroxypropyl)homopiperazine
A flask was charged with a solution of N-l-( 1,2,3, 4-tetrahydronaphthyl) homopiperazine (505 mg, 2.19 mmol) in a solution of t-butanol (5.0 mL) and toluene (5.0 mL). Propylene oxide (0.31 mL, 257 mg, 4.43 mmol) was added via syringe. The solution was immersed in a 30-35 °C oil bath for 16 hours. The resulting mixture was concentrated and purified by column chromatography using 5% methanol in diethyl etheπhexane (1 : 1) to obtain the title compound as a colourless oil (460 mg). ΝMR: 1.12 (d, 3H), 1.56-1.79 (bm, 4H), 1.95-2.09 (bm, 2H), 2.20 (m, IH), 2.59-2.92 (bm, 11H), 3.72 (m, IH), 3.89 (m, 2H), 7.03-7.18 (bm, 3H), 7.76 (d, IH); m/s: M+H+ 289.
Compounds of Examples 20-24 were prepared using a procedure analogous to that described in Example 19. Example 20
N- 1 (S)-( 1 ,2 ,3 ,4-Tetrahydronaphth- 1 -yl)-N-4-(2(S)-hydroxy-propyl)homopiperazine ΝMR: 1.12 (d, 3H), 1.56-1.79 (bm, 4H), 1.95-2.09 (bm, 2H), 2.20 (m, IH), 2.59-
2.92 (bm, 1 IH), 3.72 (m, IH), 3.89 (m, 2H), 7.03-7.18 (bm, 3H), 7.76 (d, IH); W^2 +89° (c
= 2.40, methanol). m/g. M+H+ 289. Example 21
N- 1 (R)-( 1.2,3 ,4-Tetrahydronaphth- 1 -yl)-N-4-(2(S)-hydroxy-propyl)homopiperazine ΝMR: 1.12 (d, 3H), 1.58-1.73 (bm, 4H), 1.93-2.07 (bm, 2H), 2.18 (m, IH), 2.60-
2.89 (bm, 11H), 3.73 (m, IH), 3.89 (m, 2H), 7.03-7.18 (bm, 3H), 7.76 (d, IH); Mp -49° (c
= 2.25, methanol); m/s: M+H+ 289. Example 22
N- 1 (S)-( 1.2,3 ,4-Tetrahydronaphth- 1 -yl)-N-4-(2(R)-hvdroxy-propyl)homopiperazine ΝMR: 1.12 (d, 3H), 1.57-1.80 (bm, 4H), 1.94-2.07 (bm, 2H), 2.18 (m, IH), 2.60-
2.92 (bm, 11H), 3.74 (m, IH), 3.89 (m, 2H), 7.03-7.18 (bm, 3H), 7.76 (d, IH); [a] +55° (c
= 2.35, methanol); m/s: M+H+ 289.
Example 23
N- 1 (R)-( 1 ,2,3 ,4-Tetrahydronaphth- 1 -yl)-N-4-(2(R)-hydroxy-propyl)homopiperazine NMR: 1.12 (d, 3H), 1.58-1.79 (bm, 4H), 1.94-2.07 (bm, 2H), 2.21 (m, IH), 2.59-
,2 222
2.94 (bm, 11H), 3.70 (m, IH), 3.89 (m, 2H), 7.03-7.18 (bm, 3H), 7.75 (d, IH); [aL JD -87° (c
= 2.12, methanol); m/s: M+H+ 289.
Example 24 N- 1 -( 1.2.3 ,4-Tetrahydronaphth- 1 -yl)-N-4-(2-hydroxy-butyl)homopiperazine
ΝMR: 0.98 (dt, 3H), 1.43 (m, 2H), 1.58-1.80 (bm, 4H), 1.96-2.09 (bm, 2H), 2.22
(m, IH), 2.58-2.94 (bm, 11H), 3.49 (m, IH), 3.90 (m, 2H), 7.03-7.18 (bm, 3H), 7.75 (d, IH); m/s: M+H+ 303.
Example 25 N- 1 -( 1 ,2.3 ,4-Tetrahydronaphth- 1 -yl)-N-4-(2-hydroxy-3-phenoxypropyl)homopiperazine
A 4-dram vial was charged with l-(l,2,3,4-tetrahydronaphthyl)homopiperazine (254 mg, 1.1 mmol) and l,2-epoxy-3-phenoxypropane (0.30 mL, 333 mg, 2.2 mmol). A loose cover was placed over the vial and the vial was irradiated with microwaves for 1 :00 minutes at medium-hi power (70%). The resulting product was purified by column chromatography using a gradient from 0 to 2.5% methanol in diethyl etheπhexane (1 :1) to obtain the title compound as a colourless oil (383 mg). ΝMR: 1.55-1.69 (m, 5H), 1.94 - 2.07 (m, 2H), 2.51 -
2.98 (m, 12H), 3.87 - 4.04 (m, 4H), 6.89 - 6.97 (m, 3H), 7.03 - 7.18 (m, 3H), 7.26 - 7.32 (m,
2H), 7.76 (d, IH); m s: M+H+ 381.
Example 26 N-l-(l,2.3,4-Tetrahvdronaphth-l-yl)-N-4-(2-hydroxy-3-phenoxy-propyl)homopiperazine Using an analogous procedure to that described in Example 25, an appropriate substituted epoxide was reacted with N-l-(l,2,3,4-tetrahydronaphth-l-yl)homopiperazine to give the title compound. ΝMR: 1.57 (m, 2H), 1.79 (m, 2H), 2.01 (m, 2H), 2.50 (m, IH), 2.64-
3.0 (bm, 11H), 3.48 (m, 2H), 3.80-3.92 (bm, 2H), 4.52 (m, 2H), 6.33 (m, 2H), 7.03-7.18 (bm, 3H), 7.40 (m, IH), 7.73 (d, IH); m s: M+H+ 385.
Example 27
N-l-(l,2.3.4-Tetrahvdronaphth-l-yl)-N-4-(2,2,2-trifluoroethyl)homopiperazine
A mixture of l-(l,2,3,4-tetrahydronaphth-l-yl)homopiperazine (1.07 g, 4.63 mmol) and trifluoroacetic acid (15.8 g, 10.7 mL, 139 mmol) was heated to 50 °C and then sodium borohydride pellets (857 mg, 22.7 mmol) were added in portions. After stirring at 50 °C for 16 hours the mixture was cooled to 0 °C and made basic by the addition of aqueous sodium hydroxide. This mixture was extracted with ethyl acetate (2 x 200 mL). The combined organics were extracted with hydrogen chloride (400 mL, 10%), aqueous). The aqueous portion was made basic by the addition of sodium hydroxide pellets and then extracted with ethyl acetate (2 x 300 mL). The combined organics were washed with brine (400 mL), dried over anhydrous magnesium sulphate, filtered, and concentrated to give an orange oil (433 mg). Column chromatography using hexane followed by 2.5% methanol in diethyl ether provided the title compound as a colourless oil (66 mg). NMR: 1.43-1.75 (bm, 4H), 1.93-2.09 (bm, 2H), 2.63-3.03 (bm, 10H), 3.19 (m, IH), 3.90 (m, IH), 7.03-7.19 (bm, 3H), 7.76 (d, IH); m/s: M+H+ 313. Preparation of Starting Materials. Method A l-(1.2.3,4-Tetrahydronaphthyl)homopiperazine
A 250 mL 3-necked flask equipped with a condenser and magnetic stirring bar and under a nitrogen atmosphere was charged with a solution of homopiperazine (19.2 g, 186 mmol) in DMF (90 mL). Potassium iodide (100 mg) was added followed by the addition by pipette of a solution of 1,2,3,4-tetrahydro-l-chloronaphthalene (6.35 g, 38.1 mmol) in DMF (20 mL). This solution was then heated in an oil bath at 55 °C for 43 hours. The reaction mixture was partitioned between water and ethyl acetate, washed with brine and dried with magnesium sulphate. Filtration and evaporation of solvent gave an amber liquid (7.5 g) which was purified by Kugelrohr distillation to give the title compound as a pale yellow oil (5.3 g) bp (air bath temperature) 120-140 °C at 90 mtorr; tic analysis on silica gel (CH2Cl2:CH3OH: NH4OH, 89:10:1) showed a single component, Rf 0.11 ; NMR: 3.90-3.95 (m, IH, benzylic CHN), 7.03-7.37 (m, 3Η), 7.77-7.80 (d, IH).
An ethanolic solution (21 mL) containing this base (1.00 g) was treated dropwise with an ethereal solution (43 mL) saturated with maleic acid to the cloud point. A gum formed on standing very slowly solidified. This white solid was collected by filtration, washed with ether and dried at 60 °C at high vacuum to yield the salt of the title compound (0.95 g). Mp 107-109.4°C; NMR (DMSO-d6): 3.96 (m, IH, benzylic CHN), 6.11 (3.44Η, CH=CH, maleic acid), 7.05-7.18 (m, 3Η), 7.72 (d, IH); Anal. Calcd. for Cι5H22N 1.70 C4H4O4: C, 61.22; H, 6.79; N, 6.55. Found: C, 61.06; H, 6.91; N, 6.73. Method B 1,2,3,4-Tetrahydro-l-chloronaphthalene A IL 3 -necked flask equipped with a condenser, electronic thermocouple, mechanical stirrer and under a nitrogen atmosphere was charged with 1,2,3,4-tetrahydro-l- naphthol (34.3 g, 0.23 mol) in dry diethyl ether (420 mL). Pyridine (4.7 mL) was added and the flask was cooled to 16 °C in a bath of water and ice. A solution of thionyl chloride (50.7 mL, 0.70 mol) in ether (140 mL) was then added dropwise in 25 minutes and stirring continued overnight while allowing the bath to warm to room temperature. The reaction mixture was then poured into cold brine (400 g ice and 800 mL brine) and the organic phase was separated. The aqueous phase was extracted with diethyl ether (2 x 150 mL) and the combined organic extract was dried with sodium sulphate. Filtration and removal of solvent in vacuo gave 1,2,3,4-tetrahydro-l-chloronaphthalene (36.9 g) as an oil. This material was used without further purification. Method C S-(+)-N-( 1 ,2,3 ,4-Tetrahydronaphth- 1 -yPhomopiperazine
S-(+)-N-(l,2,3,4-Tetrahydronaphth-l-yl)homopiperazine was obtained as the first material to elute on subjecting racemic material (5.3 g), prepared as in Method A, to preparative Chiral Pak AD HPLC resolution using a hexane/ethanol mixture with modification with diethylamine. The enantiomeric purity was determined on an analytical scale using hexane:ethanol:diethylamine (90:5:0.05, v/v) and detection at 220 nm. The solution containing this enantiomer was concentrated using a rotary evaporator to give the title compound (2.35 g). [a]22 +108° (c = 0.50, methanol); 98% ee.
To a solution of this base (1.0 g, 4.35 mmol), in ethanol (25 mL) was added by pipette a solution of maleic acid (1.1 g, 9.47 mmol) in ether (40 mL). Addition of ether (5 mL) resulted in a cloudiness and, on standing, the formation of a white precipitate. This solid was collected by filtration and dried in a drying pistol (50 °C, 70 mtorr) to yield the dimaleate of the title compound (0.76 g). Mp 106-107.5 °C; [a]22 +44.7° (c = 0.38, methanol); anal:
Calcd. for Ci5H22Ν2-2C4H4O4: C, 59.73; H, 6.53; N, 6.05. Found: C, 59.83; H, 6.52; N, 6.00.
Method D
R-(-)-N-( 1.2,3 ,4-Tetrahydronaphth- 1 -yPhomopiperazine
R-(-)-Ν-(l,2,3,4-tetrahydronaphth-l-yl)homopiperazine was obtained as the second material to elute on subjecting racemic material (5.3 g), prepared as in Method A, to preparative Chiral Pak AD HPLC resolution using a hexane/ethanol mixture with modification with diethylamine. The enantiomeric purity was determined on an analytical scale using hexane:ethanol:diethylamine (90:5:0.05, v:v) and detection at 220 nm. The solution containing this enantiomer was concentrated using a rotary evaporator to give the title compound (2.65 g). [a]22 -94° (c = 0..64, methanol); 98.5% ee.
To a solution of this base (1.1 g: 4.78 mmol) in ethanol (25 mL) was added by pipette a solution of maleic acid (1.2 g; 10.33 mmol) in ether (40 mL) and the formation of a white solid was promoted by scratching. This solid was collected by filtration and dried in a drying pistol (50 °C, 70 mtorr) to yield the dimaleate salt of the title compound (1.2 g). Mp
108-110 °C; [a]22 -41.6° (c = 0.60, methanol); anal, calcd. for Cι5H22N2- 2C4H4O4: C, 59.73;
H, 6.53; N, 6.05; Found: C, 59.62; H, 6.56; N, 6.09.
Method E
N- 1 -( 1.2,3 ,4-Tetrahydronaphth- 1 -vP-N-4-(3-(t-butyldimethylsilyloxy)propyl) homopiperazine A flask was charged with a solution of N-l-(l,2,3,4-tetrahydronaphthyl) homopiperazine (1018 mg, 4.4 mmol) in THF (25 mL). Triethylamine (0.61 mL, 443 mg, 4.4 mmol) and l-bromo-3-(t-butyldimethylsilyloxy)propane (0.38 mL, 490 mg, 3.3 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 product was purified by column chromatography using a gradient from 0 to
5%o methanol in diethyl etheπhexane (2:8) to obtain the title compound as a yellow oil (940 mg). ΝMR: 0.05 (s, 6H), 0.89 (s, 9H), 1.62-1.78 (bm, 6H), 1.93-2.08 (bm, 2H), 2.54-2.78
(bm, 12H), 3.65 (t, 2H), 3.89 (m, IH), 7.03-7.18 (bm, 3H), 7.77 (d, IH); m/s: M+H+ 403.
Using the above method and R-(-)-N-(l,2,3,4-tetrahydronaphth-l-yl)homopiperazine or S-(+)-N-(l,2,3,4-tetrahydronaphth-l-yl)homopiperazine the corresponding enantiomers of the title compound were also prepared. Example 28
Following conventional procedures well known in the pharmaceutical art the following representative pharmaceutical dosage forms containing a compound of formula (I) can be prepared:
(a) Tablet mg/tablet Compound of formula (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 ms/capsule
Compound of formula (I) 10.0
Mannitol, USP 488.5
Croscarmellose sodium 15.0
Magnesium stearate 1.5
(c) Injection
For intravenous administration, a compound of formula (I) is dissolved in an isotonic sterile solution (5 mg/mL).

Claims

1. A method of treating neurological disorders comprising administration of a therapeutically-effective amount of any compound according to formula (I):
Figure imgf000034_0001
(I) wherein:
R1 is halo, hydroxy, Cι-6alkyl, Cι-6alkoxy, haloCι.6alkyl, cyano, nitro or C2-6alkenyl; p is 0, 1, 2, 3 or 4 wherein R1 may be the same or different;
R2 is C,.6alkyl; q is 0, 1 or 2 wherein R2 may be the same or different; and
R3 is C]-8alkyl, C2-8alkenyl or C2-8alkynyl, wherein said Cι-8alkyl, C2-8alkenyl or C2- 8alkynyl are optionally substituted with one or more groups selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Cι-6alkoxy, Cι-6alkanoyl, Cι-6alkoxycarbonyl,
Figure imgf000034_0002
6alkyl)amino, N,N-(Cι-6alkyl)2amino,
Figure imgf000034_0003
6alkyl)2carbamoyl, Cι-6alkoxyCι-6alkoxy, Cι.6alkylS(O)a wherein a is 0, 1 or 2, N-(C . 6alkyl)sulphamoyl, N,N-(Cι-6alkyl)2Sulphamoyl, C3_i2cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl or a group of the formula: B- (CH2)-X-
(IA) wherein B is aryl, heteroaryl, heterocyclyl or C3-i2Cycloalkyl; r is 0, 1, 2, 3, 4, 5 or 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-, -NR4C(S)-, -NR4C(S)NR5-, NR4C(O)NR5-, -NR4C(O)NR5SO2-, - C(NOR4)- or -CH(OR4)-; wherein R4 and R5 are independently selected from hydrogen )or C\. alkyl; and wherein said foregoing aryl, heteroaryl heterocyclyl are optionally substituted on a ring carbon with one or more groups selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Ci- 6alkyl, C2-6alkenyl, C2-6alkynyl, Cι.6alkoxy, Ci ^alkanoyl, Cι-6alkanoyloxy, N-(Cι_ 6alkyl)amino, NN-(Cι-6alkyl) amino, Ci-όalkanoylamino, N-(Cι_6alkyl)carbamoyl, N,N-(C\. 6alkyl) carbamoyl, Cι.6alkylS(O)a wherein a is 0, 1 or 2, Cι-6alkoxycarbonyl, N-(Cι- 6alkyl)sulphamoyl, N,N-(Cι_6alkyl)2sulphamoyl or phenylCι-6alkyl; and wherein any heterocyclyl or heteroaryl containing an -ΝH- moiety is optionally substituted on this ring nitrogen with one or more groups selected from Cι-6alkyl, C2-6alkenyl, C2-6alkynyl, Cι_ 6alkanoyl, C i -6alkylsulphonyl or phenylC i -6alkyl; or a pharmaceutically-acceptable salt, or an in v/vo-hydrolysable ester, amide or carbamate thereof.
2. The method according to Claim 1, for treating 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 ALDS-related dementia.
3. The method according to Claim 1, for treating neurological disorders treatable by inhibition of the the [3H]-emopamil binding site.
4. A pharmaceutical composition comprising any compound according to formula (I), or an in v/vo-hydrolysable ester, amide or carbamate thereof, together with a pharmaceutically-acceptable carrier, wherein, in a compound of formula (I):
Figure imgf000035_0001
Figure imgf000036_0001
R1 is halo, hydroxy, Cι-6alkyl, Cι- alkoxy, haloCι-6alkyl, cyano, nitro or C2-6alkenyl; p is 0, 1 , 2, 3 or 4 wherein R1 may be the same or different; R2 is Ci-ealkyl; q is 0, 1 or 2 wherein R2 may be the same or different; and
R3 is Cι-8alkyl, C2-8alkenyl or C2-8alkynyl, wherein said Cι-8alkyl, C2-8alkenyl or C2- 8alkynyl are optionally substituted with one or more groups selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Cι- alkoxy, Cι-6alkanoyl, Ci
Figure imgf000036_0002
6alkyl)amino, NN-(Cι-6alkyl)2amino, Cι-6alkanoylamino, N-(Cι-6alkyl)carbamoyl, N,N-(C\. 6alkyl)2carbamoyl, Cι-6alkoxyCι-6alkoxy, Cι-6alkylS(O)a wherein a is 0, 1 or 2, N-(Cι- 6alkyl)sulphamoyl, N,N-(Cι-6alkyl)2sulphamoyl, C3-i2cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl or a group of the formula:
B- (CH2)-X- (IA) wherein B is aryl, heteroaryl, heterocyclyl or C3.i2cycloalkyl; r is 0, 1, 2, 3, 4, 5 or 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-, -NR4C(S)-, -NR4C(S)NR5-, NR4C(O)NR5-, -NR4C(O)NR5SO2-, - C(NOR4)- or -CH(OR4)-; wherein R4 and R5 are independently selected from hydrogen or Cj. 4alkyl; and wherein said foregoing aryl, heteroaryl heterocyclyl are optionally substituted on a ring carbon with one or more groups selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C\. 6alkyl, C2-6alkenyl, C2-6alkynyl,
Figure imgf000036_0003
Cι-6alkanoyl, Cι-6alkanoyloxy, N-(Cι- 6alkyl)amino, N,N-(Cι-6alkyl)2amino, Cι.6alkanoylamino, N-(Cι-6alkyl)carbamoyl, N,N-(C\. 6alkyl)2carbamoyl, Cj. -6alkylS(O)a wherein a is 0, 1 or 2, Ci-όalkoxycarbonyl, N-(Cι_ 6alkyl)sulphamoyl, N,N-(C1 -6alkyl)2 sulphamoyl or phenylCi-βalkyl; and wherein any heterocyclyl or heteroaryl containing an -ΝH- moiety is optionally substituted on this ring nitrogen with one or more groups selected from Cι-6alkyl, C2-6alkenyl, C2-6alkynyl, C\. 6alkanoyl,
Figure imgf000037_0001
or phenylCi-δalkyl.
5. A pharmaceutical composition according to Claim 4, comprising any compound in accord with formula (I), wherein: p and q are both 0; and
R3 is selected from Cι-8alkyl, C2-8alkenyl or C2-8alkynyl; wherein said Cι-8alkyl, C2- 8alkenyl or C2-8alkynyl are optionally substituted with one or more groups selected from halo, cyano, hydroxy, carbamoyl, Ci-όalkoxy, Cι-6alkanoyl, Ci ^alkoxycarbonyl, Cι.6alkanoyloxy, Cι- alkoxyCι-6alkoxy, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl or a group of the formula (IA) wherein B is optionally substituted aryl, optionally substituted heterocyclyl or C3-ι2cycloalkyl; r is 0, 1, 2, 3, 4, 5 or 6; and X is a linking group selected from -C(O)-, -O-, -OC(O)-; and wherein any foregoing aryl, heteroaryl or heterocyclyl is optionally substituted on a ring carbon with one or more groups selected from halo,
Figure imgf000037_0002
or Cι-6alkoxy.
6. A pharmaceutical composition according to Claim 5, comprising any compound in accord with formula (I), wherein:
R3 is selected from carbamoylmethyl, isopropoxycarbonylmethyl, t- butoxycarbonylmethyl, t-butylcarbonylmethyl, benzoylmethyl, 4-methylbenzoylmethyl, 4- methoxybenzoylmethyl, 4-chlorobenzoylmethyl, 4-bromobenzoylmethyl, 4- phenylbenzoylmethyl, 2,4-dimethoxybenzoylmethyl, phenoxycarbonylmethyl, tetrahydropyran-2-ylmethyl, adamant-3-ylcarbonylmethyl, 2-fluoroethyl, 2-hydroxyethyl, 2- cyanoethyl, methoxyethyl, methoxyethoxyethyl, 2,2-dimethoxyethyl, 2,2-diethyoxyethyl, 2- acetoxyethyl, 2-methoxycarbonylethyl, 2-ethoxycarbonylethyl, 2-phenoxyethyl, 2-(4'- chlorophenoxy)ethyl, 2-(r,3'-dioxolan-2'-yl)efhyl, 2-(l',3'-dioxan-2'-yl)ethyl, 2-hydroxy-2- phenylethyl, 2,2,2-trifluoroethyl, 2-hydroxypropyl, 3-hydroxypropyl, 3-fluoropropyl, 3- cyanopropyl, 3-ethoxycarbonylpropyl, 3-phenoxypropyl, 3-benzyloxypropyl, 3- (tetrahydropyran-2'-yloxy)propyl, 3-(phthalimid-2'-yl)propyl, 2-hydroxy-3-phenoxypropyl, 2- hydroxy-3 -benzyloxypropyl, 2-methoxy-3-benzyloxypropyl, 2-hydroxy-3-isopropoxypropyl, 3-phenyl-3-oxopropyl, 3-(4-fluorophenyl)-3-oxopropyl, 3-(4-chlorophenyl)-3-oxopropyl, 3-(4- bromophenyl)-3-oxopropyl, 3-phenyl-3-hydroxypropyl, 3-(4-fluorophenyl)-3-hydroxypropyl, 3-(4-chlorophenyl)-3-hydroxypropyl, 3-(4-bromophenyl)-3-hydroxypropyl, 3-fur-2- ylmethoxy-2-hydroxypropyl, 3-hydroxy-3-methylbutyl, 2-hydroxybutyl, 3-hydroxybutyl, 2- hydroxy-3-phenylpropyl, 4-fluorobutyl, 4-cyanobutyl, 4-acetoxybutyl, 4-ethoxycarbonylbutyl, 4-phenoxybutyl, 3-oxobutyl, 4-bromo-3,3,4,4-tetrafluorobutyl, 3-oxopentyl, 3-hydroxypentyl, 5-cyano-5-methylhexyl, 3-methoxycarbonylallyl, 3-phenylallyl, 3-butenyl, 3-methyl-2- butenyl, 3,4,4-trifluoro-3-butenyl or 2-propynyl.
7. Any compound according to formula (I):
Figure imgf000038_0001
(I) wherein:
R is halo, hydroxy,
Figure imgf000038_0002
Cι- alkoxy, haloCι-6alkyl, cyano, nitro or C2-6alkenyl; p is 0, 1, 2, 3 or 4 wherein R1 may be the same or different;
R2 is C,-6alkyl; q is 0, 1 or 2 wherein R may be the same or different; and
R3 is d-8alkyl, C2-salkenyl or C2-8alkynyl, wherein said Cι-8alkyl, C2-8alkenyl or C2- 8alkynyl are optionally substituted with one or more groups selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Cι-6alkoxy, Cι_6alkanoyl, Cι_6alkoxycarbonyl, Cι-6alkanoyloxy, N-(C\. 6alkyl)amino, NN-(Cι-6alkyl)2amino, Cι-6alkanoylamino, N-(Cι-6alkyl)carbamoyl, N,N-(C\. 6alkyl)2carbamoyl, Cι- alkoxyCι-6alkoxy, Cι_6alkylS(O)a wherein a is 0, 1 or 2, N-(C\. 6alkyl)sulphamoyl, NN-(Cι_6alkyl)2Sulphamoyl, C3_i2cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl or a group of the formula:
B-(CH2)-X-
(LA) wherein B is aryl, heteroaryl, heterocyclyl or C3-i2cycloalkyl; r is 0, 1, 2, 3, 4 or 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(0)-, -OC(O)NR4-, -C(O)NR4SO2-, - NR4C(O)O-, -C(S)NR4-, -NR4C(S)-, -NR4C(S)NR5-, NR4C(O)NR5-, -NR4C(O)NR5SO2-, - C(NOR4)- or -CH(OR4)-; wherein R4 and R5 are independently selected from hydrogen )or Cj. 4alkyl; and wherein said foregoing aryl, heteroaryl heterocyclyl are optionally 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-6alkanoyloxy, N-(C\. alkyl)amino, N,N-(Cι- alkyl)2amino, Cι-6alkanoylamino, N-(Ci-6alkyl)carbamoyl, N,N-(C\. 6alkyl)2carbamoyl, Cι-6alkylS(O)a wherein a is 0, 1 or 2, Cι-6alkoxycarbonyl,
Figure imgf000039_0001
6alkyl)sulphamoyl, NN-(Cι-6alkyl)2sulphamoyl or phenylCι-6alkyl; and wherein any heterocyclyl or heteroaryl containing an -ΝH- moiety is optionally substituted on this ring nitrogen with one or more groups selected from Cι-6alkyl, C2-6alkenyl, C2- alkynyl, Ci- 6alkanoyl, Cι-6alkylsulphonyl or phenylCι-6alkyl; or a pharmaceutically-acceptable salt, or an in v/vo-hydrolysable ester, amide or carbamate thereof, with a proviso wherein in such compounds:
R is not optionally substituted phenylCι-8alkyl or C3-8cycloalkylCι-8alkyl, or if R is substituted Cι-8alkyl, substituted C2-8alkenyl or substituted C2-8alkynyl then the carbon atom adjacent to the homopiperazine ring is not directly substituted by any other than a fluoro heteroatom.
8. A compound according to Claim 7, wherein: p and q are both 0; and
R3 is selected from Ci-salkyl, C2-8alkenyl or C2-8alkynyl; wherein said Cι-8alkyl, C2- 8alkenyl or C2-salkynyl are optionally substituted with one or more groups selected from halo, cyano, hydroxy, carbamoyl, Cι-6alkoxy, Cι-6alkanoyl, Ci ^alkoxycarbonyl, Cι-6alkanoyloxy, Cι-6alkoxyCι-6alkoxy, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl or a group of the formula (LA) wherein B is optionally substituted aryl, optionally substituted heterocyclyl or C3-ι2cycloalkyl; r is 0, 1, 2, 3, 4, 5 or 6; and X is a linking group selected from -C(O)-, -O-, -OC(O)-; and wherein any foregoing aryl, heteroaryl or heterocyclyl is optionally substituted on a ring carbon with one or more groups selected from halo, Cι-6alkyl or Cι-6alkoxy.
9. A compound according to Claim 8, wherein:
R3 is selected from carbamoylmethyl, isopropoxycarbonylmethyl, t- butoxycarbonylmethyl, t-butylcarbonylmethyl, benzoylmethyl, 4-methylbenzoylmethyl, 4- methoxybenzoylmethyl, 4-chlorobenzoylmethyl, 4-bromobenzoylmethyl, 4- phenylbenzoylmethyl, 2,4-dimethoxybenzoylmethyl, phenoxycarbonylmethyl, tetrahydropyran-2-ylmethyl, adamant-3-ylcarbonylmethyl, 2-fluoroethyl, 2-hydroxyethyl, 2- cyanoethyl, methoxyethyl, methoxyethoxyethyl, 2,2-dimethoxyethyl, 2,2-diethyoxyethyl, 2- acetoxyethyl, 2-methoxycarbonylethyl, 2-ethoxycarbonylethyl, 2-phenoxyethyl, 2-(4'- chlorophenoxy)ethyl, 2-(l',3'-dioxolan-2'-yl)ethyl, 2-(l',3'-dioxan-2'-yl)ethyl, 2-hydroxy-2- phenylethyl, 2,2,2-trifluoroethyl, 2-hydroxypropyl, 3-hydroxypropyl, 3-fluoropropyl, 3- cyanopropyl, 3-ethoxycarbonylpropyl, 3-phenoxypropyl, 3 -benzyloxypropyl, 3- (tetrahydropyran-2'-yloxy)propyl, 3-(phthalimid-2'-yl)propyl, 2-hydroxy-3-phenoxypropyl, 2- hydroxy-3-benzyloxypropyl, 2-methoxy-3 -benzyloxypropyl, 2-hydroxy-3-isopropoxypropyl, 3-phenyl-3-oxopropyl, 3-(4-fluorophenyl)-3-oxopropyl, 3-(4-chlorophenyl)-3-oxopropyl, 3-(4- bromophenyl)-3-oxopropyl, 3-phenyl-3-hydroxypropyl, 3 -(4-fluorophenyl)-3 -hydroxypropyl, 3-(4-chlorophenyl)-3-hydroxypropyl, 3 -(4-bromophenyl)-3 -hydroxypropyl, 3-fur-2- ylmethoxy-2-hydroxypropyl, 3-hydroxy-3-methylbutyl, 2-hydroxybutyl, 3-hydroxybutyl, 2- hydroxy-3-phenylpropyl, 4-fluorobutyl, 4-cyanobutyl, 4-acetoxybutyl, 4-ethoxycarbonylbutyl, 4-phenoxybutyl, 3-oxobutyl, 4-bromo-3,3,4,4-tetrafluorobutyl, 3-oxopentyl, 3-hydroxypentyl, 5-cyano-5-methylhexyl, 3-methoxycarbonylallyl, 3-phenylallyl, 3-butenyl, 3-methyl-2- butenyl, 3,4,4-trifluoro-3-butenyl or 2-propynyl.
10. A compound according to Claim 7, selected from: N-l-(l,2,3,4-tetrahydronaphth-l-yl)-N-4-(3-methyl-2-butenyl)homopiperazine;
N- 1 -( 1 ,2,3 ,4-tetrahydronaphth- 1 -yl)-N-4-(3 ,3,4,4,tetrafluoro-4-bromobutyl)homopiperazine; N- 1 -( 1 ,2,3 ,4-tetrahydronaphth- 1 -yl)-N-4-(3-oxo-butyl)homopiperazine; N- 1 -(1 ,2,3 ,4-tetrahydronaphth- 1 -yl)-N-4-(3-oxo-pentyl)homopiperazine;
N- 1 -( 1 ,2,3,4-tetrahydronaphth- 1 -yl)-N-4-(3-oxo-3-phenyl-propyl)homopiperazine;
N-l-(l,2,3,4-tetrahydronaphth-l-yl)-N-4-(3-oxo-3-(4-fluorophenyl)-propyl)homopiperazine;
N- 1 -(1 ,2,3,4-tetrahydronaphth- 1 -yl)-N-4-(3-oxo-3-(4-chloro-phenyl)-propyl)homopiperazine; N-l-(l,2,3,4-tetrahydronaphth-l-yl)-N-4-(3-oxo-3-(4-bromo-phenyl)-propyl)homopiperazine;
N- 1 -(1 ,2,3,4-tetrahydronaphth- 1 -yl)-N-4-(3-hydroxybutyl)homopiperazine;
N- 1 - ( 1 , 2 , 3 ,4-tetrahydronaphth- 1 -yl)-N-4- (3 -hydroxy-p entyl)homopip erazine ;
N-l-(l,2,3,4-tetrahydronaphth-l-yl)-N-4-(3-hydroxy-3-phenyl-propyl)homopiperazine;
N- 1 -( 1 ,2,3,4-tetrahydronaphth- 1 -yl)-N-4-(3-hydroxy-3-(4-fluoro-phenyl)- propyl))homopiperazine;
N- 1 -( 1 ,2,3,4-tetrahydronaphth- 1 -yl)-N-4-(3-hydroxy-3-(4-chloro-phenyl)- propyl))homopiperazine;
N- 1 -( 1 ,2,3 ,4-tetrahydronaphth- 1 -yl)-N-4-(3-hydroxy-3-(4-bromo-phenyl)- propyl))homopiperazine; N- 1 -( 1 ,2,3,4-tetrahydronaphth- 1 -yl)-N-4-(3-hydroxy-3-methylbutyl)homopiperazine;
N- 1 -( 1 ,2,3 ,4-tetrahydronaphth- 1 -yl)-N-4-(3-hydroxypropyl)homopiperazine;
N- 1 (S)-( 1 ,2,3 ,4-tetrahydronaphth- 1 -yl)-N-4-(3-hydroxy-propyl)homopiperazine;
N-l(R)-(l,2,3,4-tetrahydronaphth-l-yl)-N-4-(3-hydroxy-propyl)homopiperazine;
N- 1 -( 1 ,2 ,3 ,4-tetrahydronaphth- 1 -yl)-N-4-(2-hydroxypropyl)homopiperazine; N- 1 (S)-( 1 ,2,3 ,4-tetrahydronaphth- 1 -yl)-N-4-(2(S)-hydroxy-propyl)homopiperazine;
N- 1 (R)-( 1 ,2,3 ,4-tetrahydronaphth- 1 -yl)-N-4-(2(S)-hydroxy-propyl)homopiperazine;
N- 1 (S)-( 1 ,2,3 ,4-tetrahydronaphth- 1 -yl)-N-4-(2(R)-hydroxy-propyl)homopiperazine;
N- 1 (R)-( 1 ,2,3 ,4-tetrahydronaphth- 1 -yl)-N-4-(2(R)-hydroxy-propyl)homopiperazine;
N- 1 -( 1 ,2,3 ,4-tetrahydronaphth- 1 -yl)-N-4-(2-hydroxy-butyl)homopiperazine; N- 1 -( 1 ,2,3 ,4-tetrahydronaphth- 1 -yl)-N-4-(2-hydroxy-3-phenoxypropyl)homopiperazine;
N- 1 -( 1 ,2,3,4-tetrahydronaphth- 1 -yl)-N-4-(2-hydroxy-3-phenoxy-propyl)homopiperazine, and
N-l-(l,2,3,4-tetrahydronaphth-l-yl)-N-4-(2,2,2-trifluoroethyl)homopiperazine.
11. A method of making a compound of formula (I) according to Claim 7, wherein R1 ,
RR ,, pp,, aanndd qq uunnlleessss ootthheerrwwiissee ddeeffiinneedd aarree aass ddeefined in Claim 7, said method comprising: a) reacting a compound of the formula (II):
Figure imgf000042_0001
(II)
wherein L is a suitable displaceable group, with a compound of the formula (III):
Figure imgf000042_0002
(HI) or b) for compounds of formula (I) wherein R3 is not hydrogen, reacting a compound of formula (TV):
Figure imgf000042_0003
(IV)
with a compound of formula (V):
R3-L (V) wherein L is a suitable displaceable group; or c) reacting a compound of the formula (VI):
Figure imgf000043_0001
(VI)
with a compound of the formula (III); or d) for compounds of formula (I) wherein R3 is substituted C2-8alkyl with no substitution on the carbon adjacent to the homopiperazine ring, reacting a compound of formula (IV) with a compound of formula (VII):
Figure imgf000043_0002
(Nil) wherein Ra is Cι- alkyl substituted with one or more of the substituents listed under R3 above and Q is hydrogen or hydroxy; and thereafter if necessary: converting a compound of the formula (I) into another compound of the formula (I); removing any protecting groups, and forming a pharmaceutically-acceptable salt or in v/vo-hydrolysable ester, amide or carbamate.
PCT/GB2000/002308 1999-06-17 2000-06-14 1,4-diazacycloheptane derivatives as neuroprotective agents WO2000078736A1 (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0343830A2 (en) * 1988-05-23 1989-11-29 Eli Lilly And Company Ring-substituted 2-amino-1,2,3,4-tetrahydronaphthalenes
WO1999021834A1 (en) * 1997-10-27 1999-05-06 Neurosearch A/S Heteroaryl diazacycloalkanes as cholinergic ligands at nicotinic acetylcholine receptors
WO1999032461A1 (en) * 1997-12-18 1999-07-01 Astrazeneca Uk Limited 1,4-diazacycloheptane derivatives
WO2000039105A1 (en) * 1998-12-24 2000-07-06 Astrazeneca Ab 1,4-diazacycloheptane derivatives useful in the treatment of neurological disorders

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0343830A2 (en) * 1988-05-23 1989-11-29 Eli Lilly And Company Ring-substituted 2-amino-1,2,3,4-tetrahydronaphthalenes
WO1999021834A1 (en) * 1997-10-27 1999-05-06 Neurosearch A/S Heteroaryl diazacycloalkanes as cholinergic ligands at nicotinic acetylcholine receptors
WO1999032461A1 (en) * 1997-12-18 1999-07-01 Astrazeneca Uk Limited 1,4-diazacycloheptane derivatives
WO2000039105A1 (en) * 1998-12-24 2000-07-06 Astrazeneca Ab 1,4-diazacycloheptane derivatives useful in the treatment of neurological disorders

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