[go: up one dir, main page]

WO2000039105A1 - 1,4-diazacycloheptane derivatives useful in the treatment of neurological disorders - Google Patents

1,4-diazacycloheptane derivatives useful in the treatment of neurological disorders Download PDF

Info

Publication number
WO2000039105A1
WO2000039105A1 PCT/GB1999/004329 GB9904329W WO0039105A1 WO 2000039105 A1 WO2000039105 A1 WO 2000039105A1 GB 9904329 W GB9904329 W GB 9904329W WO 0039105 A1 WO0039105 A1 WO 0039105A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
hydroxy
substituted
optionally substituted
homopiperazine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/GB1999/004329
Other languages
French (fr)
Inventor
Thomas Richard Simpson
Margaret Joyce Schooler
Sally Ann Walsh
Edward John Warawa
Charles David Mclaren
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AstraZeneca UK Ltd
AstraZeneca AB
Original Assignee
AstraZeneca UK Ltd
AstraZeneca AB
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB9828436.7A external-priority patent/GB9828436D0/en
Priority claimed from GBGB9914015.4A external-priority patent/GB9914015D0/en
Application filed by AstraZeneca UK Ltd, AstraZeneca AB filed Critical AstraZeneca UK Ltd
Priority to AU18745/00A priority Critical patent/AU1874500A/en
Priority to JP2000591016A priority patent/JP2002533447A/en
Priority to EP99962379A priority patent/EP1140863A1/en
Publication of WO2000039105A1 publication Critical patent/WO2000039105A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to chemical compounds, in particular 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. Background
  • Neurological disorders include stroke, head trauma, transient cerebral ischaemic attack, and chronic neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, diabetic neuropathy, amyotrophic lateral sclerosis, multiple sclerosis and AIDS-related dementia.
  • Emopamil has classically been thought of as a neuroprotective agent whose efficacy is 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. 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 [ H]-emopamil binding site is localised to the endoplasmic reticulum.
  • Neuroprotective compounds are known, for example emopamil and ifenprodil, that exhibit high affinity for the [ 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. It is thought that compounds that interact with either the VSCC or the NMDA receptor, are responsible for the side effects usually seen with emopamil, such as hypotension, or those seen with ifenprodil, such as behavioural manifestations. Summary of The Invention
  • R 1 at each occurrence is independently selected from hydrogen, halo, hydroxy, C ⁇ _ alkyl, C ⁇ - 6 alkoxy, haloC ⁇ _ 6 alkyl, cyano, nitro and C 2 . 6 alkenyl; q is 7 and R 2 at each occurrence is independently selected from hydrogen and C ⁇ _ alkyl and at least one R ⁇ group is hydrogen;
  • R 3 is selected from C ⁇ -8 alkyl, C 2 _ alkenyl and C 2 . 8 alkynyl, wherein: said Ci_ 8 alkyl, C 2 . 8 alkenyl or C 2 - 8 alkynyl may be substituted with one or more groups selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C ⁇ _ 6 alkoxy, C ⁇ -6alkanoyl, C ⁇ - 6 alkoxycarbonyl, C ⁇ _ 6 alkanoyloxy, N-(C ⁇ .
  • B is aryl, heteroaryl, heterocyclyl or C 3 _ ⁇ 2 cycloalkyl; r is an integer selected from the range 0 to 6; and X is a linking group selected from -C(O)-, -O-, -OC(O)-, -S-, -SO-, -SO 2 -, -SO 2 NR 4 -, -NR 4 SO 2 -, -NR 4 -, -C(O)O-, -C(O)NR 4 -, -NR 4 C(O)-, -OC(O)NR 4 -, -C(O)NR 4 SO 2 -, -NR 4 C(O)O-, -C(S)NR 4 -, -NR 4 C(S)NR 5 -, NR 4 C(O)NR 5 -, NR 4 C(O)NR 5 SO 2 -, -C(NOR 4 )- and -CH
  • alkyl means 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 means fluoro, chloro, bromo and iodo.
  • aryl means phenyl, naphthyl or biphenyl.
  • heteroaryl means, unless otherwise further specified, a monocyclic-, bicyclic- or tricyclic- 5-14 membered ring that is unsaturated or partially unsaturated, with up to five ring heteroatoms selected from nitrogen, oxygen and sulphur wherein a -CH 2 - group can optionally be replaced by a -C(O)-, and a ring nitrogen atom may be optionally oxidised to form the N-oxide.
  • 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 means, unless otherwise further specified, a mono- or bicyclic- 5-14 membered ring, that is totally saturated, with up to five ring heteroatoms selected from nitrogen, oxygen and sulphur wherein a -CH 2 - group can optionally be replaced by a -C(O)-.
  • heterocyclyls examples include morpholinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, homopiperidinyl, homopiperazinyl, 1 ,3-dioxolanyl, 1,4-dioxanyl, tetrahydropyranyl and quinuclidinyl.
  • C ⁇ _ 8 alkyl includes C
  • C ⁇ _ 6 alkoxycarbonyl includes C ⁇ _ alkoxycarbonyl, and such species as methoxycarbonyl, ethoxycarbonyl and n- and t-butoxycarbonyl;
  • C ⁇ - 6 alkoxy includes and such species as methoxy, ethoxy and propoxy; C ⁇ .
  • C ⁇ _ alkylSO a where a is an integer selected from the range 0 to 2, includes C ⁇ -6 alkylsulphonyl, and such species as methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl and ethylsulphonyl;
  • d- alkanoyl includes such species as propionyl and acetyl;
  • N-C ⁇ _ 6 alkylamino includes such species as N-methylamino and N-ethylamino;
  • N,N-(C ⁇ _ 6 alkyl) 2 amino includes such species as
  • C 3 _ ⁇ 2 cycloalkyl includes C . ⁇ 2 cycloalkyl and such species as cyclopentyl, cyclohexyl, cycloheptyl, cyclododecyl and adamantyl; C 2 .
  • alkenyl includes C 2- alkenyl, C -4 alkenyl and such species as vinyl, allyl and 1-propenyl;
  • C 2-8 alkynyl includes C 2- alkynyl, C 2-4 alkynyl and such species as ethynyl, 1-propynyl and 2-propynyl;
  • N-(C ⁇ - 6 alkyl)sulphamoyl includes such species as
  • C ⁇ _ 6 alkoxyC ⁇ _ 6 alkoxy includes C ⁇ _ alkoxyC ⁇ _ 4 alkoxy, and such species as methoxymethoxy, methoxyethoxy and ethoxypropoxy.
  • an integer selected from the range means an integral value that falls in the stated range, for example, 0 to 2, means 0, 1 and 2, and 0 to 6, means 0, 1, 2, 3, 4, 5 and 6.
  • R and R " are hydrogen.
  • R 3 is substituted C ⁇ - 8 alkyl, optionally substituted C 2 . alkenyl or optionally substituted C 2 . 8 alkynyl; where said substituents, when present, are at each occurrence independently selected from halo, cyano, hydroxy, carbamoyl, C ⁇ - 6 alkoxy, C ⁇ _ 6 alkanoyl, C ⁇ . 6 alkoxycarbonyl, C ⁇ . 6 alkanoyloxy, C ⁇ _ 6 alkoxyC ⁇ .
  • R 3 is substituted Cj- 6 alkyl, optionally substituted C 2- alkenyl or C 2-4 alkynyl; where said substituents, when present, are one or two groups independently selected at each occurrence from halo, cyano, hydroxy, carbamoyl, C ⁇ -4 alkoxy, C ⁇ -4 alkanoyl, C ⁇ .
  • R 3 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-diethyloxyethyl, 2-acetoxyethyl, 2-methoxycarbonylethyl, 2-ethoxycarbonylethyl, 2-phenoxyeth
  • 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 is 3-methyl-2-butenyl.
  • Particular compounds of the inventions are:
  • R 3 is substituted Ci-galkyl, 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 ⁇ _ 6 alkoxy, C ⁇ _ 6 alkanoyl, C ⁇ _ 6 alkoxycarbonyl, C ⁇ -6 alkanoyloxy, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl or a group of the formula IA as disclosed heretofore, wherein B is optionally substituted aryl, optionally substituted heterocyclyl or C 3 .
  • r is an integer selected from the range 0 to 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, C ⁇ _ 6 alkyl or C ⁇ -6 alkoxy; or a pharmaceutically-acceptable salt, or an in v vo-hydrolysable ester, amide or carbamate thereof; with the proviso that R 3 is not optionally substituted phenylCj.
  • R 3 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
  • R 3 is selected from 2-fluoroethyl, methoxyethyl, methoxyethoxyethyl, 2,2-dimethoxyethyl, 2-methoxycarbonylethyl, 2-ethoxycarbonylethyl, 2-phenoxyethyl, 2-(r,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 and 3,4,4-trifluoro-3-butenyl; or a pharmaceutically-acceptable salt, or an in v vo-hydrolysable ester, amide or carbamate thereof.
  • 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-ethylpiperidine, 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 interact with the [ H]-emopamil binding site.
  • the chiral centre is at the 1-position of the 1,2,3,4-tetrahydronaphthalene ring system and it is preferred 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.
  • esters, amides and carbamates are compounds that hydrolyse in the human body to produce the parent compound. Such esters, amides and carbamates can be identified by administering, for example intravenously to a test animal, the compound under test and subsequently examining the test animal's body fluids. Suitable in v vo-hydrolysable amides and carbamates include ⁇ -carbomethoxy and ⁇ -acetyl.
  • An in v/vo-hydrolysable ester of a compound of the formula I containing carboxy or hydroxy group is, for example, a pharmaceutically-acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol.
  • Suitable pharmaceutically-acceptable esters for carboxy include C ⁇ . 6 alkoxymethyl esters for example me thoxy methyl, C ⁇ _ 6 alkanoyloxymethyl esters for example pi valoyloxy methyl, phthalidyl esters, C 3 .
  • 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 yield the parent hydroxy group.
  • inorganic esters such as phosphate esters and -acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to yield the parent hydroxy group.
  • ⁇ -acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy.
  • a selection of in v/v ⁇ -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 carboxy acetyl.
  • Another aspect of the present invention provides a process for preparing a compound of formula I wherein R 1 , R 2 , R 3 , p and q are, unless otherwise specified, as defined in formula I, comprises: a) reacting a compound of the formula II:
  • 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 and suitable values for L are for example, halogeno or sulphonyloxy groups, such as chloro, bromo, methanesulphonyloxy or toluene-4-sulphonyloxy.
  • reaction conditions for reactions a) and b) are as follows: Compounds of formula II and III and compounds of formula IV and V are reacted together under standard alkylation conditions.
  • an organic solvent for example an anhydrous aprotic solvent such as dimethylformamide, dimethylacetamide or tetrahydrofuran, optionally in the presence of a catalyst, such as an iodide salt for example potassium iodide, and at a temperature in the range of 0 to 100 °C, preferably 40 to 80 °C.
  • Pg is an amino protecting group and suitable values for Pg as those as described hereinbelow.
  • Amines and ketones, aldehydes or carboxy lie acids are reacted together under standard reductive animation conditions.
  • a reducing agent such as hydrogen and a hydrogenation catalyst, for example palladium on carbon, zinc and hydrochloric acid, sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride, iron pentacarbonyl and alcoholic potassium hydroxide, 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 to 50 °C, preferably at or near room temperature.
  • a suitable solvent such as an alcohol, for example methanol or ethanol
  • aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid, the introduction of an acyl group using, for example, an acyl halide and Lewis acid, such as aluminium trichloride, under Friedel Crafts conditions; the introduction of an alkyl group using an alkyl halide and Lewis acid, such as aluminium trichloride, under Friedel Crafts conditions; and the introduction of a halogeno group.
  • modifications include the reduction of a nitro group to an amino group by for example, catalytic hydrogenation with a nickel catalyst or treatment with iron in the presence of hydrochloric acid with heating; and oxidation of alkylthio to alkylsulphinyl or alkylsulphonyl.
  • a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl.
  • the deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • an acyl group such as a t-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate).
  • a suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.
  • a suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl.
  • the deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • a suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • a base such as sodium hydroxide
  • a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • the protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art.
  • 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.
  • 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 preferred route of administration is intravenously in sterile isotonic solution.
  • the pharmaceutical composition of this invention may also contain, or be simultaneously or sequentially co-administered with, one or more pharmacological agents of value in treating one or more disease conditions referred to hereinabove.
  • the pharmaceutical compositions of this invention will normally be administered to humans so that, for example, a daily dose of 0.05 to 75 mg/kg body weight (and preferably of 0.1 to 30 mg/kg body weight) is received. This daily dose may be given in divided doses as necessary, the precise amount of the compound received and the route of administration depending on the weight, age and sex of the patient being treated and on the particular disease condition being treated according to principles known in the art.
  • 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 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 [ 3 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, for the manufacture of a medicament for use in a warm-blooded animal such as a human being in conditions benefited by the inhibition of the [ 3 H]-emopamil binding site.
  • 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.
  • Radioligand 0.96 nM (-)- 3 H-emopamil (Amersham).
  • Guinea pig liver membranes 40mg/mL original wet weight.
  • Guinea-pig liver membrane preparation Male guinea pigs were sacrificed by CO 2 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.
  • H-D-888 binding to rat brain cortical membranes was a modification of the method of Reynolds, I.J. ,
  • 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
  • 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 the pH, if needed. Forty-five minutes after dosing the gerbils are anaesthetised with halothane (3.3%) which is delivered along with oxygen (1.5 1/M) through a face mask. After the gerbils are anaesthetised, halothane is continued at a maintenance level of 1.5-2 % along with oxygen. The ventral surface of the neck is shaved and cleaned with alcohol.
  • Surgical procedures are carried out on a thermostat-controlled heating pad set to 37 °C.
  • An incision is made in the neck, the carotid arteries are dissected away from the surrounding tissue, and isolated with a 5 cm length of Silastic tubing.
  • both arteries have been isolated they are clamped with microaneurysm clips (Roboz Instruments).
  • the arteries are visually inspected to determine that the blood flow has been stopped. After 5 minutes the clips are gently removed from the arteries and blood flow begins again.
  • a sham control group is treated identically but is not subjected to carotid artery occlusion.
  • the incisions are closed with suture and the gerbils 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 Bonferroni post test. After each gerbil is tested it is returned to its home cage. At this time gerbils are also observed for any changes from normal behaviour.
  • microwave irradiation were performed using a kitchen grade 1000W microwave oven (Panasonic, the Genius Premier, model number NN-S567); and wherein the following abbreviations may be used:
  • DMSO dimethylsulphoxide
  • THF is tetrahydrofuran
  • NMP is N-methylpyrrolidone.
  • Chromatography was performed using 2.5% methanol in methylene chloride.
  • a 4-dram vial was charged with l-(l,2,3,4-tetrahydronaphthyl)homopiperazine (254 mg, 1.1 mmol) and 1 ,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 one minute at medium-high power (70%).
  • the resulting crude product was purified by column chromatography using a gradient from 0 to 2.5% methanol in diethyl ethe ⁇ hexane (1 : 1) to obtain the title compound as a colourless oil (383 mg).
  • This reaction was carried out by irradiating with microwaves for four minutes at medium- high power (70%).
  • N-l-(L2.3.4-Tetrahydronaphthyl)-N-4-(2-methoxy-3- benzyloxypropyDhomopiperazine A solution of N-l-(l,2,3,4-tetrahydronaphthyl)-N-4-(2-hydroxy-3-benzyloxypropyl) homopiperazine (601 mg, 1.5 mmol) in DMF (7 mL) was prepared in a 25 mL flask. The flask was immersed in an ice/water bath. The solution was treated with sodium hydride (60% dispersion in oil, 120 mg, 3.0 mmol) and allowed to stir for 15 minutes. The flask was then immersed in a 60 °C oil bath for 2.5 hours.
  • Example 64 illustrating the preparation of a salt of a compound of formula I is provided by way of illustration, and is not intended as a limitation to the scope of the invention.
  • Example 64 N- 1 -( 1 ,2,3,4-tetrahydronaphth- 1 -yl)-N-4-(3-methyl-2-butenyl)homopiperazine dimaleate salt.
  • 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.
  • N-l-(l,2,3,4-Tetrahvdronaphth-l-yl)-N-4-(2-hvdroxypiOpyl)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.
  • N- 1 -( 1 ,2,3,4-Tetrahydronaphth- 1 -yl)-N-4-(2,2,2-trifluoroethyI)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.
  • a 4 dram vial was charged with l-( 1,2,3,4 Tetrahydronaphthyl) homopiperazine (249mg, 1.08 mmol) and glycidyl 4-methoxyphenyl ether (450 mg, 2.44 mmol).
  • the vial was covered loosely and irradiated in the microwave at med-hi power for 1 minute.
  • the crude product was purified by column chromatography using a gradient from 0-25% methanol in diethyl ethe ⁇ hexane (1: 1) to obtain the title compound as a colorless oil (398mg).
  • Example 93 l-(l,2,3,4-tetrahvdronaphthyl)-4-(2,2-diphenylbutyronitrile)homopiperazine
  • a solution of l-(l,2,3,4-tetrahydronaphthyl)homopiperazine 761 mg, 3.3 mmol
  • Triethylamine (0.95 ml, 690 mg, 6.8 mmol)
  • 4- bromo-2,2-diphenyl butyronitrile (2.04 g, 6.8 mmol) were added.
  • the solution was immersed in a 60 °C oil bath for 36 hours during which time a precipitate formed.
  • 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.
  • HPMC Hydroxypropylmethylcellulose
  • a compound of Formula I is dissolved in an isotonic sterile solution (5 mg/mL).

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Psychology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Tetrahydronaphthylhomopiperazines of formula (I), wherein p is 4 and R1 at each occurrence is independently selected from hydrogen, halo, hydroxy, C¿1-6?alkyl, C1-6alkoxy, haloC1-6alkyl, cyano, nitro and C2-6alkenyl; q is 7 and R?2¿ at each occurrence is independently selected from hydrogen and C¿1-6?alkyl and at least one R?2¿ group is hydrogen and R3 is selected from substituted or unsubstituted C¿1-8?alkyl, C2-8alkenyl and C2-8alkynyl, together with processes for their manufacture and compositions containing them. Compounds of formula (I) are pharmacologically useful.

Description

1,4-DIAZACYCLOHEPTANE DERIVATIVES USEFUL IN THE TREATMENT OF
NEUROLOGICAL DISORDERS
Field of The Invention
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. Background
Neurological disorders, to which the present invention relates, include stroke, head trauma, transient cerebral ischaemic attack, and chronic neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, diabetic neuropathy, amyotrophic lateral sclerosis, multiple sclerosis and AIDS-related dementia. Emopamil has classically been thought of as a neuroprotective agent whose efficacy is 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 [ H]-emopamil binding site is localised to the endoplasmic reticulum.
Neuroprotective compounds are known, for example emopamil and ifenprodil, that exhibit high affinity for the [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. It is thought that compounds that interact with either the VSCC or the NMDA receptor, are responsible for the side effects usually seen with emopamil, such as hypotension, or those seen with ifenprodil, such as behavioural manifestations. Summary of The Invention
We have now found a class of compounds that selectively bind at the [3H] -emopamil binding site, such compounds are compounds of formula I:
Figure imgf000004_0001
wherein: p is 4 and R1 at each occurrence is independently selected from hydrogen, halo, hydroxy, Cι_ alkyl, Cι-6alkoxy, haloCι_6alkyl, cyano, nitro and C2.6alkenyl; q is 7 and R2 at each occurrence is independently selected from hydrogen and Cι_ alkyl and at least one R~ group is hydrogen;
R3 is selected from Cι-8alkyl, C2_ alkenyl and C2.8alkynyl, wherein: said Ci_8alkyl, C2.8alkenyl or C2-8alkynyl may be 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-(Cι.6alkyl)amino, N,N-(Cι-6alkyl)2amino, Cι.6alkanoylamino, N-(Cι_6alkyl)carbamoyl, N,N-(Cι.6alkyl)2carbamoyl, Cι.6alkoxyCι-6alkoxy, Cι-6alkylSOa where a is an integer selected from the range 0 to 2, N-(Cι.6alkyl)sulphamoyl, N,N-(C].6alkyl)2sulphamoyl, C3-ι2cycloalkyl, or a group of formula IA:
B-(CH2)rX-
IA wherein:
B is aryl, heteroaryl, heterocyclyl or C3_ι2cycloalkyl; r is an integer selected from the range 0 to 6; and X is a linking group selected from -C(O)-, -O-, -OC(O)-, -S-, -SO-, -SO2-, -SO2NR4-, -NR4SO2-, -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)- and -CH(OR4)-; wherein R4 and R5 are independently selected from hydrogen or Cι_4alkyl; and wherein any said aryl, heteroaryl and heterocyclyl may be 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, Cj.6alkanoyloxy, N-(Cι_6alkyl)amino, N,N-(Cι.6alkyl)2amino,
Figure imgf000005_0001
N-(Cι_ alkyl)carbamoyl,
N,N-(Cι.6alkyl)2carbamoyl, C|-6alkylSOa where a is an integer in the range 0 to 2, Cι_ alkoxycarbonyl, N-(Cι_6alkyl)sulphamoyl, N,N-(Cι_6alkyl)2sulphamoyl and phenylCι-6alkyl; and wherein any heterocyclyl or heteroaryl containing an -ΝH- moiety may be optionally substituted on this ring nitrogen with one or more groups selected from Cι_6alkyl, C2-6alkenyl, C2_6alkynyl, Cι_6alkanoyl, Cι_ alkylsulphonyl or phenylCι_ alkyl; or a pharmaceutically-acceptable salt, or an in v/vohydrolysable ester, amide or carbamate thereof; with the proviso that R3 is not optionally substituted phenylCι_8alkyl or C3_8cycloalkylCι-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 except fluoro. Detailed description of The Invention
As used herein, the term "alkyl" means 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.
As used herein, "halo" means fluoro, chloro, bromo and iodo. As used herein, "aryl" means phenyl, naphthyl or biphenyl.
As used herein, "heteroaryl" means, unless otherwise further specified, a monocyclic-, bicyclic- or tricyclic- 5-14 membered ring that is unsaturated or partially unsaturated, with up to five ring heteroatoms selected from nitrogen, oxygen and sulphur wherein a -CH2- group can optionally be replaced by a -C(O)-, and a ring nitrogen atom may be optionally oxidised to form the N-oxide. Examples of "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.
As used herein, "heterocyclyl" means, unless otherwise further specified, a mono- or bicyclic- 5-14 membered ring, that is totally saturated, with up to five ring heteroatoms selected from nitrogen, oxygen and sulphur wherein a -CH2- group can optionally be replaced by a -C(O)-. Examples of such heterocyclyls include morpholinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, homopiperidinyl, homopiperazinyl, 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.
As used herein, Cι_8alkyl includes C|.6alkyl, Cι. alkyl, and such species as methyl, ethyl, isopropyl and t-butyl; Cι_6alkoxycarbonyl includes Cι_ alkoxycarbonyl, and such species as methoxycarbonyl, ethoxycarbonyl and n- and t-butoxycarbonyl; Cι-6alkoxy includes
Figure imgf000006_0001
and such species as methoxy, ethoxy and propoxy; Cι.6alkanoylamino includes such species as formamido, acetamido and propionylamino; Cι_ alkylSOa where a is an integer selected from the range 0 to 2, includes Cι-6alkylsulphonyl, and such species as methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl and ethylsulphonyl; d- alkanoyl includes such species as propionyl and acetyl; N-Cι_6alkylamino includes such species as N-methylamino and N-ethylamino; N,N-(Cι_6alkyl)2amino includes such species as
N,N-dimethylamino, N,N-diethylamino and N-ethyl-N-methylamino; C3_ι2cycloalkyl includes C .ι2cycloalkyl and such species as cyclopentyl, cyclohexyl, cycloheptyl, cyclododecyl and adamantyl; C2.8alkenyl includes C2- alkenyl, C -4alkenyl and such species as vinyl, allyl and 1-propenyl; C2-8alkynyl includes C2- alkynyl, C2-4alkynyl and such species as ethynyl, 1-propynyl and 2-propynyl; N-(Cι-6alkyl)sulphamoyl includes such species as
N-methylsulphamoyl and N-ethylsulphamoyl; N,N-(Cι_6alkyl)2sulphamoyl includes such species as N,N-dimethylsulphamoyl and N-methyl-N-ethylsulphamoyl; N-(Cι_6alkyl)carbamoyl includes such species as N-methylcarbamoyl and N-ethylcarbamoyl; N,N-(Cι.6alkyl)2carbamoyl includes such species as N,N-dimethylcarbamoyl and N-methyl -N-ethylcarbamoyl; Cι_6alkanoyloxy includes C|.4alkanoyloxy and such species as propionyloxy, acetyloxy and formyloxy; Cι_6alkoxyCι_6alkoxy includes Cι_ alkoxyCι_4alkoxy, and such species as methoxymethoxy, methoxyethoxy and ethoxypropoxy.
As used herein, the phrase "an integer selected from the range" means an integral value that falls in the stated range, for example, 0 to 2, means 0, 1 and 2, and 0 to 6, means 0, 1, 2, 3, 4, 5 and 6.
In particular compounds of the present invention R and R" are hydrogen. In particular compounds of the present invention R3 is substituted Cι-8alkyl, optionally substituted C2. alkenyl or optionally substituted C2.8alkynyl; where said substituents, when present, are at each occurrence independently selected from halo, cyano, hydroxy, carbamoyl, Cι-6alkoxy, Cι_6alkanoyl, Cι.6alkoxycarbonyl, Cι.6alkanoyloxy, Cι_6alkoxyCι. alkoxy, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl or a group of the formula IA as described herein wherein B is optionally substituted aryl, optionally substituted heterocyclyl or C3_ι2cycloalkyl; r is an integer selected from the range 0 to 6; 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„ alkyl or C)_6alkoxy; with the proviso that R3 is not optionally substituted phenylC].8alkyl, and with the further proviso that when R3 is substituted _8alkyl, substituted C2.8alkenyl or substituted C2-8alkynyl the carbon atom adjacent to the homopiperazine ring is not directly substituted by any heteroatom other than fluoro.
In more particular compounds of the present invention, R3 is substituted Cj-6alkyl, optionally substituted C2- alkenyl or C2-4alkynyl; where said substituents, when present, are one or two groups independently selected at each occurrence from halo, cyano, hydroxy, carbamoyl, Cι-4alkoxy, Cι-4alkanoyl, Cι.4alkoxycarbonyl,
Figure imgf000007_0001
Figure imgf000007_0002
aryl, heterocyclyl, heteroaryl or a group of the formula IA as depicted above wherein B is optionally substituted aryl, heterocyclyl or C _ι2cycloalkyl; r is an integer in the range 0 to 4; 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,
Figure imgf000007_0003
or Cι-4alkoxy; with the proviso that R3 is not optionally substituted
Figure imgf000007_0004
and with the further proviso that when R3 is substituted Cι_6alkyl, substituted C2. alkenyl or substituted C -4alkynyl the carbon atom adjacent to the homopiperazine ring is not directly substituted by any heteroatom other than fluoro.
In other particular compounds of the present invention, 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-diethyloxyethyl, 2-acetoxyethyl, 2-methoxycarbonylethyl, 2-ethoxycarbonylethyl, 2-phenoxyethyl, 2-(4'-chlorophenoxy)ethyl,
2-( 1 ',3'-dioxolan-2'-yl)ethyl, 2-( 1 ',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-phenoxy butyl, 5-cyano-5-methylhexyl, 3-methoxycarbonylallyl, 3-phenylallyl, 3-butenyl, 3-methyl-2-butenyl, 3,4,4-trifluoro-3-butenyl and 2-propynyl.
In still more particular compounds of the present invention, 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 a particularly compound of the invention R is 3-methyl-2-butenyl. Particular compounds of the inventions are:
1 -( 1 -(3-methyl-but-2-enyl)-4-( 1 ,2,3,4-tetrahydro- 1 (R)-naphthyl)homopiperazine;
1 -( 1 -(3-methyl-but-2-enyl)-4-( 1 ,2,3,4-tetrahydro- 1 (S)-naphthyl)homopiperazine;
1 -( 1 -(2(S)-hydroxy-propyl)-4-( 1 ,2,3,4-tetrahydro- 1 (R)-naphthyl)homopiperazine;
1 -( 1 -(2(R)-hydroxy-propy l)-4-( 1,2,3 ,4-tetrahydro- 1 (R)-naphthyl)homopiperazine; 1 -( 1 -(2(S)-hydroxy-propyl)-4-( 1 ,2,3,4-tetrahydro- 1 (S)-naphthyl)homopiperazine;
1 -( 1 -(2(R)-hydroxy-propyl)-4-( 1 ,2,3,4-tetrahydro- 1 (S)-naphthyl)homopiperazine;
1 -( 1 -(3-hydroxy-propyl)-4-( 1 ,2,3,4-tetrahydro- 1 (S)-naphthyl)homopiperazine; 1 -( 1 -(3-hydroxy-propyl)-4-( 1 ,2,3,4-tetrahydro- 1 (R)-naphthyl)homopiperazine;
1 -( 1 -(2(S)-hydroxy-3-benzyloxy-propyl)-4-( 1 ,2,3 ,4-tetrahydro- 1 (R)- naphthyl)homopiperazine;
1 -( 1 -(2(R)-hydroxy-3-benzyloxy-propyl)-4-( 1 ,2,3 ,4-tetrahydro- 1 (R)- naphthyl)homopiperazine;
1 -( 1 -(2(S)-hydroxy-3-benzyloxy-propyl)-4-( 1 ,2,3,4-tetrahydro- 1 (S)- naphthyl)homopiperazine, and
1 -( 1 -(2(R)-hydroxy-3-benzyloxy-propyl)-4-( 1,2,3 ,4-tetrahydro- 1 (S)- naphthyl)homopiperazine. A particular aspect of the invention provides compounds of formula IB
Figure imgf000009_0001
LB wherein:
R3 is substituted Ci-galkyl, 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_6alkoxy, Cι_6alkanoyl, Cι_6alkoxycarbonyl, Cι-6alkanoyloxy,
Figure imgf000009_0002
optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl or a group of the formula IA as disclosed heretofore, wherein B is optionally substituted aryl, optionally substituted heterocyclyl or C3.12cycloalkyl; r is an integer selected from the range 0 to 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; or a pharmaceutically-acceptable salt, or an in v vo-hydrolysable ester, amide or carbamate thereof; with the proviso that R3 is not optionally substituted phenylCj.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.
A more particular aspect of the invention provides compounds of formula IB 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, 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 and 2-propynyl; or a pharmaceutically-acceptable salt, or an in v/vo-hydrolysable ester, amide or carbamate thereof. A still more particular aspect of the invention, provides compounds of formula IB wherein:
R3 is selected from 2-fluoroethyl, methoxyethyl, methoxyethoxyethyl, 2,2-dimethoxyethyl, 2-methoxycarbonylethyl, 2-ethoxycarbonylethyl, 2-phenoxyethyl, 2-(r,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 and 3,4,4-trifluoro-3-butenyl; or a pharmaceutically-acceptable salt, or an in v vo-hydrolysable ester, amide or carbamate thereof.
Particular compounds of the invention are those disclosed in the 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-ethylpiperidine, 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 interact with the [ H]-emopamil binding site. The chiral centre is at the 1-position of the 1,2,3,4-tetrahydronaphthalene ring system and it is preferred 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 unsolvated as well as solvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms.
In v vo-hydrolysable esters, amides and carbamates are compounds that hydrolyse in the human body to produce the parent compound. Such esters, amides and carbamates can be identified by administering, for example intravenously to a test animal, the compound under test and subsequently examining the test animal's body fluids. Suitable in v vo-hydrolysable amides and carbamates include Ν-carbomethoxy and Ν-acetyl.
An in v/vo-hydrolysable ester of a compound of the formula I containing carboxy or hydroxy group is, for example, a pharmaceutically-acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol.
Suitable pharmaceutically-acceptable esters for carboxy include Cι.6alkoxymethyl esters for example me thoxy methyl, Cι_6alkanoyloxymethyl esters for example pi valoyloxy methyl, 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 -acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to yield the parent hydroxy group. Examples of α-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. A selection of in v/vσ-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 carboxy acetyl.
Another aspect of the present invention provides a process for preparing a compound of formula I wherein R1, R2, R3, p and q are, unless otherwise specified, as defined in formula I, comprises: a) reacting a compound of the formula II:
Figure imgf000012_0001
π wherein L is a suitable displaceable group, with a compound of the formula III:
Figure imgf000012_0002
m or b) for compounds of formula I wherein R >3 i •s not hydrogen, reacting a compound of formula IV:
Figure imgf000012_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 imgf000013_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 imgf000013_0002
VII 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.
As described herein, L is a displaceable group and suitable values for L are for example, halogeno or sulphonyloxy groups, such as chloro, bromo, methanesulphonyloxy or toluene-4-sulphonyloxy.
Specific reaction conditions for reactions a) and b) are as follows: Compounds of formula II and III and compounds of formula IV and V are reacted together under standard alkylation conditions. For example in an organic solvent, for example an anhydrous aprotic solvent such as dimethylformamide, dimethylacetamide or tetrahydrofuran, optionally in the presence of a catalyst, such as an iodide salt for example potassium iodide, and at a temperature in the range of 0 to 100 °C, preferably 40 to 80 °C.
Compounds of formula II, III and V are commercially available compounds, are described in the literature, or are prepared by standard processes known in the art.
Compounds of formula IV may be prepared according to the following scheme:
Figure imgf000014_0001
In the scheme above, Pg is an amino protecting group and suitable values for Pg as those as described hereinbelow.
Compounds of formula IVA are commercially available compounds, are disclosed in the literature, or are prepared by standard processes known in the art.
Specific reaction conditions for reactions c) and d) are as follows:
Amines and ketones, aldehydes or carboxy lie acids are reacted together under standard reductive animation conditions. For example in the presence of a reducing agent such as hydrogen and a hydrogenation catalyst, for example palladium on carbon, zinc and hydrochloric acid, sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride, iron pentacarbonyl and alcoholic potassium hydroxide, 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 to 50 °C, preferably at or near room temperature. Compounds of formula VI and VII are commercially available compounds, are described in the literature, 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; and oxidation of alkylthio to alkylsulphinyl or alkylsulphonyl.
It will also be appreciated that in some of the reactions described herein it may be necessary or desirable to protect any sensitive groups in the compounds. The instances where protection is necessary or desirable and suitable methods for protection are known to those skilled in the art. Conventional protecting groups may be used in accordance with standard practice (for illustration see T.W. Greene, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991). Thus, if reactants include groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein.
A suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a t-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.
A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
The protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art.
In order to use a compound of the formula I or a pharmaceutically-acceptable salt or in v vo-hydrolysable ester, amide or carbamate thereof for the therapeutic treatment (including prophylactic treatment) of mammals including humans, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
The pharmaceutical compositions of compounds of this invention may be administered in standard manner for the disease condition that it is desired to treat, for example by oral, topical, parenteral, buccal, nasal, vaginal or rectal administration or by inhalation. For these purposes the compounds of this invention may be formulated by means known in the art into the form of, for example, tablets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, finely divided powders or aerosols for inhalation, and for parenteral use (including intravenous, intramuscular or infusion) sterile aqueous or oily solutions or suspensions or sterile emulsions. A preferred route of administration is intravenously in sterile isotonic solution. In addition to the compounds of the present invention the pharmaceutical composition of this invention may also contain, or be simultaneously or sequentially co-administered with, one or more pharmacological agents of value in treating one or more disease conditions referred to hereinabove. The pharmaceutical compositions of this invention will normally be administered to humans so that, for example, a daily dose of 0.05 to 75 mg/kg body weight (and preferably of 0.1 to 30 mg/kg body weight) is received. This daily dose may be given in divided doses as necessary, the precise amount of the compound received and the route of administration depending on the weight, age and sex of the patient being treated and on the particular disease condition being treated according to principles known in the art.
Typically unit dosage forms will contain about 1 mg to 500 mg of a compound of this invention.
According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the formula I 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 [3H]-emopamil binding site in a warm-blooded animal such as a human being.
Thus according to a further aspect of the invention there is provided the use of a compound of the formula I, or a pharmaceutically-acceptable salt or an in v vo-hydrolysable ester, amide or carbamate thereof, for the manufacture of a medicament for use in a warm-blooded animal such as a human being in conditions benefited by the inhibition of the [3H]-emopamil binding site. 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 (-)-' H-emopamil binding was a modification of the method of Zech, C,
Staudinger R., Muhlbacher, J. and Glossmann, H. Novel sites for phenylalkylamines: characterisation of a sodium-sensitive drug receptor with (-)-3H-emopamil. Eur. J. Pharm. (1991) 208 1 19-130. 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. Compounds of the invention bound to the 3H- emopamil binding site of guinea pig liver membranes with an KA below 300 nM. For example, the IC50 of the compound of Example 32 was 9 nM, the IC50 of the compound of Example 43 was 25 nM and the IC50 of the compound of Example 13 was 48 nM.
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 H-D-888 binding was a modification of the method of Reynolds, I.J.,
Snowman, A.M. and Synder, S.H. (-)-[3H] Desmethoxy verapamil labels multiple calcium channel modular receptors in brain and skeletal muscle membranes: differentiation by temperature and dihydropyridines. J. Pharmacol. Exp. Ther. (1986) 237: no.3, 731-738. 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 MgCl2, pH 7.4. Specific binding was measured with 10 μM methoxy verapamil (D-600). This assay was used to determine in vitro selectivity of compounds vs. L-type voltage sensitive calcium channels, i.e. high affinity for the Η-D888 binding site would show a lack of selectivity. The IC50 for compounds of the invention at the Η-D888 binding site was between 347 nM and 55432 nM.
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 the pH, if needed. Forty-five minutes after dosing the gerbils are anaesthetised with halothane (3.3%) which is delivered along with oxygen (1.5 1/M) through a face mask. After the gerbils are anaesthetised, halothane is continued at a maintenance level of 1.5-2 % along with oxygen. The ventral surface of the neck is shaved and cleaned with alcohol. Surgical procedures are carried out on a thermostat-controlled heating pad set to 37 °C. An incision is made in the neck, the carotid arteries are dissected away from the surrounding tissue, and isolated with a 5 cm length of Silastic tubing. When both arteries have been isolated they are clamped with microaneurysm clips (Roboz Instruments). The arteries are visually inspected to determine that the blood flow has been stopped. After 5 minutes the clips are gently removed from the arteries and blood flow begins again. A sham control group is treated identically but is not subjected to carotid artery occlusion. The incisions are closed with suture and the gerbils 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 Bonferroni post test. After each gerbil is tested it is returned to its home cage. At this time gerbils are also observed for any changes from normal behaviour.
For the next two days no specific testing is performed, but the gerbils are observed two to three times per day for any unusual behaviours or obvious neurological symptoms (i.e. ataxia, convulsions, stereotypic behaviour). Four days post ischaemia the gerbils are sacrificed by decapitation and their brains removed and preserved in 10% buffered formalin. Brains were removed, fixed and stained with hematoxylin and eosin. Under a light microscope, hippocampal fields were observed and graded for damage to the CA1 subfield: 0 to 4 scale, with 0 representing no damage and 4 representing extensive damage. Transient focal ischaemia in rats The method was performed as described by Lin, T-N., He, Y.Y., Wu, G., Khan, M. And Hsu, C.Y. Effect of brain edema on infarct volume in a focal model cerebral ischaemia model in rats. Stroke (1993) 24 1 17-121, 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 anesthesia by intracardiac perfusion with 200 mL of 0.9% NaCl. The brain was removed and processed with 2% triphenyltetrazolium chloride to identify and quantitate the infarcted brain region. Compounds were administered by intravenous infusion for 4 hours. Examples The 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 vacuo; (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 ICN 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 NMR and mass spectral techniques [proton magnetic resonance spectra were determined in CDC1 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); and wherein the following abbreviations may be used:
DMF is N,N-dimethylformamide
DMSO is dimethylsulphoxide
CDC13 is deuterated chloroform m/s is mass spectroscopy
THF is tetrahydrofuran
NMP is N-methylpyrrolidone.
Example 1
N- 1 -( 1 ,2 A4-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 4-bromo-2-mefhyl-2-butene (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 crude product was purified by column chromatography using dichloromethane:methanol (95:5) to obtain the title compound as a yellow oil (520 mg). NMR: 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, IH), 3.24 (m, 2H), 3.52 (d, 2H), 3.95 (m, IH), 5.51 (m, IH), 7.05 -7.21 (bm, 3H), 7.65 (d, lH); m/s: M+H+ 299.
Examples 2 - 52
Using an analogous procedure to that described in Example 1 , the appropriate substituted halo alkane was reacted with l-(l,2,3,4-tetrahydronaphthyl)homopiperazine to give the compounds of formula IB described in the following table.
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
Footnotes:
1 This reaction was carried out at room temperature for 16 hours. " Chromatography was performed using ethyl acetate :hexane (1:3).
3 Chromatography was performed using methanol :dichloromethane (1: 19).
4 Chromatography was not performed in this case.
5 Chromatography was performed using methanokdiethyl etheπhexane (1:4:16). This reaction was carried out at room temperature for 30 minutes.
7 Chromatography was performed using 2.5% methanol in diethyl ether: hexane (1:1).
8 This reaction was carried out at room temperature for 45 minutes.
10 9 Chromatography was performed using diethyl ether: hexane (3:2).
10 This reaction was carried out at 60 °C for 2 days.
" Chromatography was performed using 2.5% methanol in methylene chloride.
12 This reaction was carried out at 40 °C for 16 hours.
13 Chromatography was performed using 5% methanol in diethyl etheπhexane (1: 1).
15 14 This reaction was carried out at 60 °C for 16 hours and then room temperature for 1 day.
15 Chromatography was performed using 5% ethanol in diethyl etheπhexane (1:1).
16 This reaction was carried out at room temperature for 2 hours.
17 Chromatography was performed using 1% methanol in diethyl ether: hexane (1: 1).
18 This reaction was carried out at room temperature for 1 hour.
20 19 This reaction was carried out at 40 °C for 16 hours and then room temperature for 2 days.
20 This reaction was carried out at 40 °C for 2 days. 21 This reaction was carried out at 60 °C for 3 hours.
Example 53
25 N- 1 -( 1 ,2,3,4-Tetrahydronaphth- 1 -yl)-N-4-(2-hvdroxyethyl)homopiperazine
A solution of [4-(l,2,3,4-tetrahydronaphthalen-l-yl)-[l,4]diazepan-l-yl]-acetic acid ethyl ester (3.5 g) in THF (55 mL) was cooled to 0 °C in an ice/water bath and lithium aluminium hydride (1.05 g) was added in portions. The reaction mixture was then stirred for 4 hours at room temperature. The reaction mixture was then cooled to 0 °C in an ice/water bath
30 and quenched with aqueous Νa2SO4. The mixture was then filtered through celite and concentrated. The residue was taken up in ether and dried over anhydrous MgSO4. This mixture was filtered and concentrated to give a yellow oil. This crude product was purified by column chromatography using dichloromethane:methanol (95:5) to obtain the title compound as a yellow oil (1.5 g). NMR: 1.63 (m, 2H), 1.80 (m, 2H), 1.92-2.10 (bm, 2H), 2.66-2.89 (bm, 12H), 3.24 (bs, IH), 3.57 (t, 2H), 3.90 (m, IH), 7.03-7.18 (bm, 3H), 7.75 (d, IH); m/s: M+H+
275.
Example 54 N- 1 -( 1 ,2.3.4-Tetrahvdronaphth- 1 -yl)-N-4-(2-hvdroxy-3- phenoxypropyPhomopiperazine
A 4-dram vial was charged with l-(l,2,3,4-tetrahydronaphthyl)homopiperazine (254 mg, 1.1 mmol) and 1 ,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 one minute at medium-high power (70%). The resulting crude 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.
Examples 55 - 62
Using an analogous procedure to that described in Example 54, the appropriate substituted epoxide was reacted with N-l-(l,2,3,4-tetrahydronaphth-l-yl)homopiperazine to give the compounds of formula IB described in the following table, wherein (R) and (S) refer to the stereochemistry at the 1-position of the 1,2,3,4-tetrahydronaphthyl ring.
Figure imgf000031_0001
Figure imgf000032_0001
Footnotes:
1 This reaction was carried out by irradiating with microwaves for four minutes at medium- high power (70%).
2 This reaction was carried out by irradiating with microwaves for three minutes at medium- high power (70%). Example 63
N-l-(L2.3.4-Tetrahydronaphthyl)-N-4-(2-methoxy-3- benzyloxypropyDhomopiperazine A solution of N-l-(l,2,3,4-tetrahydronaphthyl)-N-4-(2-hydroxy-3-benzyloxypropyl) homopiperazine (601 mg, 1.5 mmol) in DMF (7 mL) was prepared in a 25 mL flask. The flask was immersed in an ice/water bath. The solution was treated with sodium hydride (60% dispersion in oil, 120 mg, 3.0 mmol) and allowed to stir for 15 minutes. The flask was then immersed in a 60 °C oil bath for 2.5 hours. The flask was then immersed in an ice/water bath and methyl iodide (284 mg, 2.00 mmol) was added. The flask was removed from the ice/water bath and stirred at room temperature for 3 days. Water (1.0 mL) was carefully added to quench the reaction. The mixture was poured into ethyl acetate (50 mL) and extracted with water (3 x 50 mL). The ethyl acetate layer was dried over anhydrous MgSO4, filtered and concentrated. The resulting crude product was purified by column chromatography using gradient from 0 to 5% methanol in diethyl etheπhexane (1:1) to obtain the title compound as a yellow oil (264 mg). ΝMR: 1.58 - 1.73 (m, 4H), 1.93 - 2.08 (m, 2H), 2.60 - 2.77 (m, 10H), 2.82 (m, 2H), 3.44 - 3.54 (m, 2H), 3.47 (s, 3H), 3.61 (m, IH), 3.87 (m, IH), 4.57 (s, 2H), 7.03 - 7.17 (m, 3H), 7.24 - 7.35 (m, 5H), 7.76 (d, IH); m/s: M+H+ 409.
Example 64, illustrating the preparation of a salt of a compound of formula I is provided by way of illustration, and is not intended as a limitation to the scope of the invention.
Example 64 N- 1 -( 1 ,2,3,4-tetrahydronaphth- 1 -yl)-N-4-(3-methyl-2-butenyl)homopiperazine dimaleate salt.
A solution of N-l-( 1,2,3, 4-tetrahydronaphth-l-yl)-N-4-(3-methyl-2- butenyl)homopiperazine (490 mg) in ethanol (3 mL) was prepared in a flask. A solution of maleic acid (420 mg) in diethyl ether was added and a precipitate began to form. Ethanol was then added until the precipitate dissolved. The mixture was placed in a 0 °C refrigerator for 16 hours during which time a precipitate formed. The mixture was filtered and the resulting white solid was died in vacuo at 48 °C for 16 hours to give the title compound (402 mg). Mp 130-134 °C; NMR: (DMSO-d6) 1.54 (m, 2H), 1.72 (s, 3H), 1.79 (s, 3H), 1.90-2.02 (bm, 4H), 2.70-2.90 (m, 7H), 3.10-3.40 (m, 3H), 3.79 (m, 2H), 4.00 (m, IH), 5.30 (m, IH), 6.16 (s, 4H (CH=CH, maleic acid)), 7.06-7.25 (bm, 3Η), 7.71 (d, IH); Anal; Calcd. for C2oH30N2-2C4H4O2-0.6H2O: C, 62.12; H, 7.30; N, 5.17. Found: C, 62.26; H, 7.07; N, 5.29; m/s: M+H+ 299.
Examples 65 - 71
Using an analogous procedure to that described in Example 1 , the appropriate substituted halo alkane was reacted with l-(l,2,3,4-tetrahydronaphthyl)homopiperazine to give the compounds of formula IB described in the following table.
Figure imgf000034_0001
Figure imgf000035_0001
Footnotes:
1 Chromatography was performed using 1% methanol in diethyl ether : hexane (1 : 1).
2 Chromatography was performed using a gradient from 0 to 100% diethyl ether in hexane followed by 2.5% methanol in diethyl ether. 3 Chromatography was performed using 5% methanol in diethyl ether : hexane (1 :9)
4 Chromatography was performed using a gradient from 0 to 5% methanol in diethyl ether : hexane (1: 1)
Example 72 N- 1 -( 1 ,2,3,4-Tetrahvdronaphth- 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 crude product was purified by column chromatography using hexane to elute high Rf impurities followed by diethyl ether : methanol (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, IH), 3.98 (m, IH), 6.72 (bs, IH), 7.01-7.18 (bm, 3H), 7.75 (d, IH); m/s: M+H+ 303.
Examples 73 - 77
Using an analogous procedure t,o that described in Example 72, the appropriate ketone was reduced to give the compounds of formula IB described in the following table.
Figure imgf000036_0001
Chromatography was performed using a gradient from 0 to 5% methanol in diethyl ether hexane (1: 1). 2 Chromatography was performed using 5% methanol in diethyl ether : hexane (1:1).
Example 78
N- 1 -( 1,2 ,3 ,4-Tetrahvdronaphth- 1 -yl)-N-4-(3-hvdroxy-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 crude 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, IH), 7.02-7.17 (bm, 3H), 7.75 (d, IH); m/s: M+H+ 317.
Example 79 N-l-(l,2.3,4-Tetrahvdronaphth-l-yl)-N-4-(3-hvdroxypropyl)homopiperazine
A solution of N-l-(l,2,3,4-tetrahydronaphth-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 crude product as a light purple oil. This crude product was purified by column chromatography using a gradient from 0 to 5% methanol in diethyl ether : hexane (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, IH), 7.03-7.20 (bm, 3H), 7.76 (d, IH); m/s: M+H+ 289.
Examples 80 - 87
Using an analogous procedure to that described in Example 79, the following compounds of formula IB were prepared.
Figure imgf000037_0001
Figure imgf000038_0001
* Indicates stereochemistry at the 1 -position of the 1,2,3,4-tetrahydronaphthyl ring
Example 82
N-l-(l,2,3,4-Tetrahvdronaphth-l-yl)-N-4-(2-hvdroxypiOpyl)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, 1 IH), 3.72 (m, IH), 3.89 (m, 2H), 7.03-7.18 (bm, 3H), 7.76 (d, IH); m/s: M+H+ 289.
Examples 83 - 87 Using an analogous procedure to that described in Example 82, the following compounds of formula IB were prepared.
Figure imgf000038_0002
Figure imgf000039_0001
Example 88
N- 1 -( 1 ,2.3 ,4-Tetrahvdronaphth- 1 -yl)-N-4-(2-hvdroxy-3- phenoxypropyDhomopiperazine
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 crude product was purified by column chromatography using a gradient from 0 to 2.5% methanol in diethyl ether : hexane (1: 1) to obtain the title compound as a colourless oil (383 mg). NMR: 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 89
Using an analogous procedure to that described in Example 88, the appropriate substituted epoxide was reacted with N-l-(l,2,3,4-tetrahydronaphth-l-yl)homopiperazine to give the compound of formula IB described in the following table.
Figure imgf000040_0001
Example 90
N- 1 -( 1 ,2,3,4-Tetrahydronaphth- 1 -yl)-N-4-(2,2,2-trifluoroethyI)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). ΝMR: 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.
Example 91 1 -(4-Methoxy-phenoxy)-3-r 1 ,2,3,4-tetrahydro-naphthalen- 1 -yl)[ 1 ,41diazepan- 1 -yll- propan-2-ol
A 4 dram vial was charged with l-( 1,2,3,4 Tetrahydronaphthyl) homopiperazine (249mg, 1.08 mmol) and glycidyl 4-methoxyphenyl ether (450 mg, 2.44 mmol). The vial was covered loosely and irradiated in the microwave at med-hi power for 1 minute. The crude product was purified by column chromatography using a gradient from 0-25% methanol in diethyl etheπhexane (1: 1) to obtain the title compound as a colorless oil (398mg). NMR: 1.63 (m, 2H), 1.79 (m, 2H), 1.96-2.05 (m, 2H), 2.69-2.95 (m, 12H), 3.76 (s, 3H), 3.89-4.00 (m, 5H), 6.74-6.92 (m, 4H), 7.03 (d, IH), 7.13 (m, 2H), 7.75 (d, IH); m/s: M+H 411.
Example 92
Using an analogous procedure to that described in Example 91, the appropriate substituted epoxide was reacted with N-l-(l,2,3,4-tetrahydronaphth-l-yl)homopiperazine to give the compound of formula IB described in the following table.
Figure imgf000041_0001
Example 93 l-(l,2,3,4-tetrahvdronaphthyl)-4-(2,2-diphenylbutyronitrile)homopiperazine A flask was charged with a solution of l-(l,2,3,4-tetrahydronaphthyl)homopiperazine (761 mg, 3.3 mmol) in THF (25 mL). Triethylamine (0.95 ml, 690 mg, 6.8 mmol) and 4- bromo-2,2-diphenyl butyronitrile (2.04 g, 6.8 mmol) were added. The solution was immersed in a 60 °C oil bath for 36 hours during which time a precipitate formed. The resulting mixture was filtered and the filtrate was concentrated to give an orange oil. This crude product was purified by column chromatography using methylene chloride:methanol (95:5) to obtain the title compound as a yellow oil (781 mg). Η NMR (CDC13, 300MHz) δ 1.59-1.73 (m, 4H), 1.99 (m, 2H), 2.56-2.83 (m, 14H), 3.86 (m, IH), 7.02 (d, IH), 7.12 (m, 2H), 7.27-7.41 (m, 1 OH), 7.71 (d, IH)
Examples 94 - 96
Using an analogous procedure to that described in Example 93, the appropriate substituted epoxide was reacted with N-l-(l,2,3,4-tetrahydronaphth-l-yl)homopiperazine to give the compounds of formula IB described in the following table.
Figure imgf000042_0001
Preparation of Starting Materials:
Method A
1 -( 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 0.1 1; 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), 6.1 1 (3.44Η, CH=CH, maleic acid), 7.05-7.18 (m, 3H), 7.72 (d, IH); Anal. Calcd. for C,5H22N2-1.70 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- 1 -chloronaphthalene
A one litre 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 -vDhomopiperazine
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:.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). [α]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; [α]22 +44.7° (c = 0.38, methanol); anal: Calcd.
for Cι5H22Ν2-2C4H4O4: 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-l-yl)homopiperazine 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:.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). [α]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; [α]22 -41.6° (c = 0.60, methanol); anal, calcd. for C,5H2 N2- 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-Tetrahvdronaphth- 1 -yl)-N-4-(3-(t-butyldimethylsilyloxy)propyn homopiperazine
A flask was charged with a solution of N-l-( 1,2,3,4-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 crude product was purified by column chromatography using a gradient from 0 to 5% methanol in diethyl ether : hexane (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 97
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 mg/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

ClaimsWe Claim:
1. Any compound according to formula I:
Figure imgf000047_0001
wherein: p is 4 and R1 at each occurrence is independently selected from hydrogen, halo, hydroxy, Cι.6alkyl, Ci.όalkoxy, haloCι.6alkyl, cyano, nitro and C2_6alkenyl; q is 7 and R2 at each occurrence is independently selected from hydrogen and C|.6alkyl and at least one R" group is hydrogen;
R3 is selected from Cι_8alkyl, C2.8alkenyl and C2.8alkynyl, wherein: said Cι_8alkyl, C?-8alkenyl or C2.8alkynyl may be substituted with one or more groups selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Cι_ alkoxy, Cι-6alkanoyl, C],6alkoxycarbonyl,
Figure imgf000047_0002
N-(C].6alkyl)amino, N,N-(Cι.6alkyl)2amino, Cι.6alkanoylamino, N-(Cι-6alkyl)carbamoyl, N,N-(Cι-6alkyl)2carbamoyl, Cι-6alkoxyCι_6alkoxy, Cι.6alkylSOa where a is an integer selected from the range 0 to 2, N-(Cι.6alkyl)sulphamoyl, N,N-(Cι-6alkyl)2sulphamoyl, C3.12cycloalkyl, or a group of formula IA:
B-(CH2)-X-
IA wherein:
B is aryl, heteroaryl, heterocyclyl or C3.i2cycloalkyl; r is an integer selected from the range 0 to 6; and X is a linking group selected from -C(O)-, -O-, -OC(O)-, -S-, -SO-, -SO2-, -SO2NR4-, -NR4SO2-, -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)- and -CH(OR4)-; wherein R4 and R5 are independently selected from hydrogen or Cι_4alkyl; and wherein any said aryl, heteroaryl and heterocyclyl may be 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, C^alkanoyloxy, N-(Cι.6alkyl)amino, N,N-(Cι-6alkyl)2amino, Cι_6alkanoylamino, N-(Cι.6alkyl)carbamoyl,
N,N-(Cι-6alkyl)2carbamoyl, Cι-6alkylSOa where a is an integer in the range 0 to 2, Cι. alkoxycarbonyl, N-(Cι-6alkyl)sulphamoyl, N,N-(C|_6alkyl)2sulphamoyl and phenylCι.6alkyl; and wherein any heterocyclyl or heteroaryl containing an -ΝH- moiety may be optionally substituted on this ring nitrogen with one or more groups selected from Cι.6alkyl, C2_6alkenyl, C2.6alkynyl, C|.6alkanoyl, Cι- alkylsulphonyl or phenylCi_6alkyl; or a pharmaceutically-acceptable salt, or an in v/vo-hydrolysable ester, amide or carbamate thereof; with the proviso that R3 is not optionally substituted phenylC|,8alkyl or C3.8cycloalkylCj_8alkyl and with the further proviso that when R3 is substituted Cι_8alkyl, substituted C .8alkenyl or substituted C2-8alkynyl the carbon atom adjacent to the homopiperazine ring is not directly substituted by any heteroatom except fluoro.
2. A compound according to Claim 1, wherein R1 and R2 are hydrogen.
3. A compound according to Claim 1, wherein R3 is substituted Cι-8alkyl, optionally substituted C2-8alkenyl or optionally substituted C2-8alkynyl; where said substituents, when present, are at each occurrence independently selected from halo, cyano, hydroxy, carbamoyl,
Figure imgf000048_0001
Cι„6alkoxycarbonyl, Cι_ alkanoyloxy, Cι-6alkoxyCι.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 an integer selected from the range 0 to 6; 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 is not optionally substituted phenylCι_8alkyl, and with the further proviso that when R3 is substituted Ci-salkyl, 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.
4. A compound according to Claim 1, wherein R3 is substituted Cι_6alkyl, optionally substituted C2- alkenyl or C2- alkynyl; where said substituents, when present, are one or two groups independently selected at each occurrence from halo, cyano, hydroxy, carbamoyl, Ct_4alkoxy, C).4alkanoyl, Cι_4alkoxycarbonyl, C).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_ι2cycloalkyl; r is an integer in the range 0 to 4; 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, Cι_ alkyl or C(.4alkoxy; with the proviso that R3 is not optionally substituted phenylCι-6alkyl, and with the further proviso that when R is substituted Cι_6alkyl, substituted C .4alkenyl or substituted C _4alkynyl the carbon atom adjacent to the homopiperazine ring is not directly substituted by any heteroatom other than fluoro.
5. A compound according to Claim 1, 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-diethyloxyethyl, 2-acetoxyethyl, 2-methoxycarbonylethyl, 2-ethoxycarbonylethyl, 2-phenoxyethyl, 2-(4'-chlorophenoxy)ethyl, 2-( l',3'-dioxolan-2'-yl)ethyl, 2-( 1 ',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 and 2-propynyl.
6. A compound according to Claim 1 , wherein R is selected from 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, 3-methyl-2-butenyl and 3,4,4-trifluoro-3-butenyl.
7 A compound according to Claim 2, wherein R is substituted Cj_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, C].6alkoxy, C]. alkanoyl, Cι.6alkoxycarbonyl, Cι.6alkanoyloxy, Cι_6alkoxyCι.6alkoxy, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl or a group of the formula IA as disclosed heretofore, wherein B is optionally substituted aryl, optionally substituted heterocyclyl or C3.j2cycloalkyl; r is an integer selected from the range 0 to 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 ^alkoxy; or a pharmaceutically-acceptable salt, or an in v/vo-hydrolysable ester, amide or carbamate thereof; with the proviso that R3 is not optionally substituted phenylC)-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.
8. A compound according to Claim 7, wherein R 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,
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 and 2-propynyl; or a pharmaceutically-acceptable salt, or an in v/vo-hydrolysable ester, amide or carbamate thereof.
9. A compound according to Claim 8, wherein R" is selected from 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 and 3,4,4-trifluoro-3-butenyl; or a pharmaceutically-acceptable salt, or an in v/vo-hydrolysable ester, amide or carbamate thereof.
10. A compound according to Claim 1, selected from: 1 -( 1 -(3-methyl-but-2-enyl)-4-( 1 ,2,3,4-tetrahydro- 1 (R)-naphfhyl)homopiperazine;
1 -( 1 -(3-methyl-but-2-enyl)-4-( 1 ,2,3,4-tetrahydro- 1 (S)-naphthyl)homopiperazine; l-( l-(2(S)-hydroxy-propyl)-4-( 1 ,2,3,4-tetrahydro- 1 (R)-naphthyl)homopiperazine; l-( l-(2(R)-hydroxy-propyl)-4-( 1 ,2,3,4-tetrahydro- 1 (R)-naphthyl)homopiperazine;
1 -( 1 -(2(S)-hydroxy-propyl)-4-( 1 ,2,3 ,4-tetrahydro- 1 (S)-naphthyl)homopiperazine; 1 -( 1 -(2(R)-hydroxy-propy l)-4-( 1 ,2,3 ,4-tetrahydro- 1 (S)-naphthyl)homopiperazine;
1 -( 1 -(3-hydroxy-propyl)-4-( 1 ,2,3,4-tetrahydro- 1 (S)-naphthyl)homopiperazine; l-(l-(3-hydroxy-propyl)-4-(l,2,3,4-tetrahydro-l(R)-naphthyl)homopiperazine; 1 -( 1 -(2(S)-hydroxy-3-benzyloxy-propyl)-4-( 1 ,2,3,4-tetrahydro- 1 (R)- naphthyl)homopiperazine;
1 -( 1 -(2(R)-hydroxy-3-benzyloxy-propyl)-4-( 1 ,2,3 ,4-tetrahydro- 1 (R)- naphthyl)homopiperazine; 5 1 -( 1 -(2(S)-hydroxy-3-benzyloxy-propyl)-4-( 1 ,2,3,4-tetrahydro- 1 (S)- naphfhyl)homopiperazine, and
1 -( 1 -(2(R)-hydroxy-3-benzyloxy-propyl)-4-( 1,2,3 ,4-tetrahydro- 1 (S)- naphthyl)homopiperazine .
10 11. A pharmaceutical composition comprising as an active ingredient an effective amount of a compound according to any of Claims 1 to 9, together with a pharmaceutically-acceptable carrier.
12. Use of a pharmaceutical composition according to Claim 10, for the therapy or 15 treatment of stroke, head trauma, transient cerebral ischaemic attack, Alzheimer's disease, Parkinson's disease, diabetic neuropathy, amyotrophic lateral sclerosis, multiple sclerosis or AIDS-related dementia.
13. A method for treating or preventing neurological diseases by inhibition of the 0 [[ HH]]--eemmooppaammiill b biinnddiinngg s siittee,, ccoommpprriissiinngg a addmmiinistering to a mammal an effective amount of a compound according to any of Claims 1 to 9.
14. Use of a compound according to any of Claims 1 to 9, for preparation of a therapeutic agent or prophylactic agent for diseases treatable by inhibition of the [3H] -emopamil binding 5 site.
15. A method for treating or preventing diseases treatable by inhibition of the [ 3 HH]]--eemmooppaammiill bbiinnddiinngg s siittee,, ccoommpprriissiinngg aaddmm:inistering to a mammal an effective amount of a compound according to any of Claims 1 to 9. 0
16. A method of making a compound according to Claim 1, said method comprising: a) reacting a compound of the formula II:
Figure imgf000053_0001
π wherein L is a suitable displaceable group, with a compound of the formula III:
Figure imgf000053_0002
in or b) for compounds of formula I wherein R is not hydrogen, reacting a compound of formula IV:
Figure imgf000053_0003
IV with a compound of formula V:
R3-L
wherein L is a suitable displaceable group; or c) reacting a compound of the formula VI:
Figure imgf000053_0004
VI with a compound of the formula III; or d) for compounds of formula I wherein R is substituted C -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 imgf000054_0001
VII wherein Ra is Cj- alkyl 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.
PCT/GB1999/004329 1998-12-24 1999-12-20 1,4-diazacycloheptane derivatives useful in the treatment of neurological disorders Ceased WO2000039105A1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU18745/00A AU1874500A (en) 1998-12-24 1999-12-20 1,4-diazacycloheptane derivatives useful in the treatment of neurological disorders
JP2000591016A JP2002533447A (en) 1998-12-24 1999-12-20 1,4-Diazacycloheptane derivatives useful for treating neurological diseases
EP99962379A EP1140863A1 (en) 1998-12-24 1999-12-20 1,4-diazacycloheptane derivatives useful in the treatment of neurological disorders

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB9828436.7 1998-12-24
GBGB9828436.7A GB9828436D0 (en) 1998-12-24 1998-12-24 Chemical compounds
GBGB9914015.4A GB9914015D0 (en) 1999-06-17 1999-06-17 Chemical compounds
GB9914015.4 1999-06-17

Publications (1)

Publication Number Publication Date
WO2000039105A1 true WO2000039105A1 (en) 2000-07-06

Family

ID=26314903

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1999/004329 Ceased WO2000039105A1 (en) 1998-12-24 1999-12-20 1,4-diazacycloheptane derivatives useful in the treatment of neurological disorders

Country Status (5)

Country Link
EP (1) EP1140863A1 (en)
JP (1) JP2002533447A (en)
AU (1) AU1874500A (en)
GB (1) GB9930014D0 (en)
WO (1) WO2000039105A1 (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000078736A1 (en) * 1999-06-17 2000-12-28 Astrazeneca Uk Limited 1,4-diazacycloheptane derivatives as neuroprotective agents
US9024071B2 (en) 2009-05-05 2015-05-05 University Of Florida Research Foundation, Inc. Therapeutic compounds

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
WO1997031887A1 (en) * 1996-03-01 1997-09-04 Zeneca Limited Aminotetralin derivatives and compositions and method of use thereof
WO1998000412A1 (en) * 1996-07-01 1998-01-08 Schering Corporation Muscarinic antagonists
WO1999032461A1 (en) * 1997-12-18 1999-07-01 Astrazeneca Uk Limited 1,4-diazacycloheptane derivatives

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
WO1997031887A1 (en) * 1996-03-01 1997-09-04 Zeneca Limited Aminotetralin derivatives and compositions and method of use thereof
WO1998000412A1 (en) * 1996-07-01 1998-01-08 Schering Corporation Muscarinic antagonists
WO1999032461A1 (en) * 1997-12-18 1999-07-01 Astrazeneca Uk Limited 1,4-diazacycloheptane derivatives

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000078736A1 (en) * 1999-06-17 2000-12-28 Astrazeneca Uk Limited 1,4-diazacycloheptane derivatives as neuroprotective agents
US9024071B2 (en) 2009-05-05 2015-05-05 University Of Florida Research Foundation, Inc. Therapeutic compounds
US10017458B2 (en) 2009-05-05 2018-07-10 University Of Florida Research Foundation, Incorporated Therapeutic tetrahydronaphthalene compounds

Also Published As

Publication number Publication date
JP2002533447A (en) 2002-10-08
EP1140863A1 (en) 2001-10-10
GB9930014D0 (en) 2000-02-09
AU1874500A (en) 2000-07-31

Similar Documents

Publication Publication Date Title
TWI242004B (en) 1-(1-substituted-4-piperidinyl)methyl-4-piperidine derivatives, process for producing the same, medicinal compositions containing the same and intermediates of these compounds
CN101180050B (en) Novel thiophene derivatives as sphingosine-1-phosphate-1 receptor agonists
US4879300A (en) Novel piperidine derivatives
EP0784055B1 (en) Pyrimidinylpyrazole derivative
WO2000035882A1 (en) 1,2,3,4-tetrahydronaphthalenes and their pharmaceutical use
EP1192146A1 (en) Chroman derivatives resisting neurological disorders
EP1140863A1 (en) 1,4-diazacycloheptane derivatives useful in the treatment of neurological disorders
WO1999032461A1 (en) 1,4-diazacycloheptane derivatives
EP1192141A1 (en) 1,4-diazacycloheptane derivatives as neuroprotective agents
EP1204641A1 (en) 4-aminopiperidine derivatives of tetrahydronaphthalene, chromans and thiochromans
JPH0725851A (en) Piperidine and piperazine
SK6412000A3 (en) Biphenyl derivatives as pharmaceuticals
EP1140891A1 (en) 1,4-diazacycloheptane compounds, process for their preparation, and their use as medicaments
US6407093B1 (en) 1,4-Diazacycloheptane derivatives for the treatment of neurological disorders
WO2000039110A1 (en) Homopiperazine derivatives as selective emopamil inhibitors
WO2000078751A2 (en) Compounds for use in treatment of neurological disorders
EP1192148A1 (en) Thiochroman derivatives resisting neurological disorders
JPS6012357B2 (en) Alicyclic derivative
RU2146675C1 (en) Derivatives of pyrimidinylpyrazole and antitumor agent
JPWO1997003963A1 (en) Indole derivatives
JP2002201177A (en) Tricyclic condensed heterocyclic derivative, method for producing the same and application of the same
WO2002051793A1 (en) Sterol isomerase inhibitors

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AL AM AT AU AZ BA BB BG BR BY CA CH CN CR CU CZ DE DK DM EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
ENP Entry into the national phase

Ref country code: JP

Ref document number: 2000 591016

Kind code of ref document: A

Format of ref document f/p: F

WWE Wipo information: entry into national phase

Ref document number: 1999962379

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1999962379

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWW Wipo information: withdrawn in national office

Ref document number: 1999962379

Country of ref document: EP