+

WO2000078742A1 - Chroman derivatives against neurological disorders - Google Patents

Chroman derivatives against neurological disorders Download PDF

Info

Publication number
WO2000078742A1
WO2000078742A1 PCT/GB2000/002304 GB0002304W WO0078742A1 WO 2000078742 A1 WO2000078742 A1 WO 2000078742A1 GB 0002304 W GB0002304 W GB 0002304W WO 0078742 A1 WO0078742 A1 WO 0078742A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
formula
chroman
amino
carbamoyl
Prior art date
Application number
PCT/GB2000/002304
Other languages
French (fr)
Inventor
Deborah Weng Chun Chen
Janet Marie Forst
Original Assignee
Astrazeneca Uk Limited
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
Application filed by Astrazeneca Uk Limited filed Critical Astrazeneca Uk Limited
Priority to AU54141/00A priority Critical patent/AU5414100A/en
Priority to JP2001504908A priority patent/JP2003502415A/en
Priority to EP00938917A priority patent/EP1192146A1/en
Publication of WO2000078742A1 publication Critical patent/WO2000078742A1/en

Links

Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C07D311/68—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with nitrogen atoms directly attached in position 4

Definitions

  • the present invention relates to chemical compounds, in particular chromans, to processes for their preparation and to chemical intermediates useful in such processes.
  • the present invention further relates to chromans, to pharmaceutical compositions containing them and to their use in methods of therapeutic treatment of animals including man, in particular in the treatment of neurological disorders.
  • Neurological disorders for which the present compounds are useful, include stroke, head trauma, transient cerebral ischaemic attack, and chronic neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, diabetic neuropathy, amyotrophic lateral sclerosis, multiple sclerosis and AIDS-related dementia.
  • the compounds useful in the present invention act by selectively binding to the [ 3 H]-emopamil binding site.
  • Compounds with selective action at the [ 3 H]-emopamil binding site exhibit fewer associated side effects such as hypotension seen with emopamil or behavioural manifestations seen with ifenprodil. Background
  • Emopamil has classically been thought of as a neuroprotective agent whose efficacy is most likely derived from actions at either voltage-sensitive calcium channels (VSCC) or 5- HT 2 receptors.
  • VSCC voltage-sensitive calcium channels
  • 5- HT 2 receptors 5- HT 2 receptors.
  • verapamil although chemically and pharmacologically very similar to emopamil, is not neuroprotective. While the lack of neuroprotective efficacy by verapamil was initially explained by lack of CNS penetration, recent studies suggest other factors may be involved (Keith et al., Br. J. Pharmacol. 113: 379- 384, 1994).
  • [ 3 H]-Emopamil binding defines a unique high affinity site that is not related to VSCC, is found in the brain, but is most prevalent in the liver (Moebius et al., Mol. 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 [ 3 H]-emopamil binding site is localised to the endoplasmic reticulum.
  • Neuroprotective compounds are known, for example emopamil and ifenprodil, that exhibit high affinity for the [ 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. Summary of the Invention
  • a new method for using compounds having selective action at the [ 3 H]-emopamil binding site and that are neuroprotective without acting directly at either VSCC or NMDA receptors is disclosed.
  • R 1 is hydrogen, C,. 6 alkyl, C 2 . 6 alkenyl or C 2 . 6 alkynyl;
  • R 2 and R 3 are independently selected from hydrogen, C,. 6 alkyl, C 2 . 6 alkenyl, C 2. 6 alkynyl, aryl, a carbon linked heteroaryl, a carbon-linked heterocycle, C 3 . 12 cycloalkyl and C 3. 12 cycloalkyl fused to a benzene ring, wherein said C,. 6 alkyl, C ⁇ alkenyl and C 2 . 6 alkynyl are optionally substituted with one or more groups selected from halo, nitro, hydroxy, C,.
  • any aryl, heteroaryl, heterocycle, C 3 . I2 cycloalkyl and C 3 . 12 cycloalkyl fused to a benzene ring may be optionally substituted on a ring carbon with one or more groups selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C,. 6 alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C,. 6 alkoxy, C,_ 6 alkanoyl, C,.
  • R 4 at each occurrence is selected from halo, hydroxy, C,. 6 alkyl, C,. 6 alkoxy, haloC,. 6 alkyl, cyano, nitro or C 2 . 6 alkenyl;
  • R 5 is C,- 6 alkyl; n is 1 or 2; r is 0, 1 , 2, 3 or 4, wherein at each occurrence the value of R 4 may be the same or different; and s is 0, 1 , 2 or 3 wherein at each occurrence the value of R 5 may be the same or different; or a pharmaceutically-acceptable salt or an in vzvo-hydrolysable ester, amide or carbamate thereof.
  • new pharmaceutical compositions containing compounds of formula (I), or in v/v ⁇ -hydrolysable esters, amides or carbamates thereof, together with a pharmaceutically-acceptable carrier such as an excipient, diluent or stabilizer or combinations thereof as further defined herein are disclosed.
  • a pharmaceutically-acceptable carrier such as an excipient, diluent or stabilizer or combinations thereof as further defined herein.
  • the use of a compound of the formula (I), or a pharmaceutically-acceptable salt or an in vzvo-hydrolysable ester, amide or carbamate thereof, in the manufacture of a medicament for use in the inhibition of the [ 3 H]-emopamil binding site in a warm-blooded animal is disclosed.
  • novel compounds which are compounds of formula (I) with a proviso wherein in such compounds: if r is 1, R 4 is a 6-linked cyano moiety, s is 2 and both R 5 moieties are 2-linked methyl, n is 1, and R 1 and R 2 are both H, then R 3 is not phenyl or benzyl; if r and s are both 0, R 1 is H and n is 2, then R 1 and R 2 are not both ethyl or not both H, or if r and s are both 0, R 1 is H and n is 1, then R 1 and R 2 are not both ethyl.
  • alkyl includes both straight and branched chain alkyl groups but references to individual alkyl groups such as “propyl” are specific for the straight chain version only.
  • alkenyl alkynyl
  • alkynyl alkynyl
  • 6 alkyl includes 2-phenylethyl, 2-phenylpropyl and 3-phenylpropyl.
  • halo refers to fluoro, chloro, bromo and iodo.
  • aryl refers to an unsaturated carbon ring.
  • aryl is phenyl, naphthyl or biphenyl. More preferably aryl is phenyl.
  • heteroaryl or “heteroaryl ring” refers to, unless otherwise further specified, a monocyclic-, bicyclic- or tricyclic-, 5- to 14-membered ring that is unsaturated or partially unsaturated, with up to five ring heteroatoms selected from nitrogen, oxygen and sulphur wherein a -CH 2 - group can optionally be replaced by a -C(O)-, and a ring nitrogen atom may be optionally oxidised to form the N-oxide.
  • heteroaryls examples include thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, pyridyl, pyridyl-N-oxide, oxopyridyl, oxoquinolyl, pyrimidinyl, pyrazinyl, oxopyrazinyl, pyridazinyl, indolinyl, benzofuranyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolinyl, quinazolinyl, xanthenyl, quinoxalinyl, indazolyl, benzofuranyl and cinnolinolyl.
  • heterocyclyl or “heterocyclic ring” refers to, unless otherwise further specified, a mono- or bicyclic-, 5- to 14-membered ring, that is totally saturated, with up to five ring heteroatoms selected from nitrogen, oxygen and sulphur wherein a -CH 2 - group can optionally be replaced by a -C(O)-.
  • heterocyclyls include morpholinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, homopiperidinyl, homopiperazinyl and quinuclidinyl.
  • examples of C ⁇ a-kyl include C alkyl such as methyl, ethyl, isopropyl and t-butyl;
  • examples of phenylC ⁇ alkyl include phenylC 2 . 6 alkyl such as phenylC,. 4 alkyl such as phenylC 2. 4 alkyl such as benzyl, phenylethyl and phenylpropyl;
  • examples of C,. 6 alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, n- and t- butoxycarbonyl; examples of C,.
  • examples of C,_ 6 alkanoylamino include formamido, acetamido and propionylamino
  • examples of C,. 6 alkylS(O) a where a is 0, 1 or 2 include C,. 6 alkylsulphonyl, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl and ethylsulphonyl
  • examples of C,. 6 alkylsulphonyl include mesyl and ethylsulphonyl
  • examples of C,. 6 alkylsulphonyl include mesyl and ethylsulphonyl
  • 6 alkanoyl include propionyl and acetyl; examples of N-C,. 6 alkylamino include N-methylamino and N-ethylamino; examples of N,N-(C,. 6 alkyl) 2 amino include N-N-dimethylamino, N,N-diethylamino and N- ethyl-N-methylamino ; examples of C 3.]2 cycloalkyl include cyclopropyl and cyclohexyl; examples of C 3 . 12 cycloalkyl fused to a benzene ring are 1,2,3,4-tetrahydronaphthyl and 2,3- dihydroindenyl; examples of C 2 .
  • 6 alkenyl include vinyl, allyl and 1-propenyl
  • examples of C 2.6 alkynyl include ethynyl, 1-propynyl and 2-propynyl
  • examples of haloC 2 . 6 alkyl include 2-chloroethyl and 2-bromopropyl
  • examples of N-(C,. 6 alkyl)sulphamoyl include N-methylsulphamoyl and N-ethylsulphamoyl
  • examples of N,N-(C,. 6 alkyl) 2 sulphamoyl include N,N-dimethylsulphamoyl and N-methyl-N- ethylsulphamoyl
  • 6 alkyl)carbamoyl include N-methylcarbamoyl and N-ethylcarbamoyl; examples of N,N-(C,. 6 alkyl) 2 carbamoyl include N,N-dimethylcarbamoyl and N-methyl-N- ethylcarbamoyl, and examples of C
  • . 6 alkanoyloxy include propionyloxy, acetyloxy and formyloxy.
  • R ! is hydrogen or C,. 6 alkyl
  • R 1 is hydrogen or C,. 4 alkyl. Particularly R' is hydrogen or methyl. More particularly R 1 is methyl.
  • R 2 and R 3 are independently selected from hydrogen, C,. 6 alkyl, aryl, a carbon linked heteroaryl, a carbon-linked heterocycle, C 3.
  • R 2 and R 3 and the nitrogen atom to which they are attached in combination form a ring selected from 1,2,3,4- tetrahydroisoquinolinyl, morpholinyl, piperidinyl, pyrrolidinyl, homopiperidinyl and wherein said ring may be optionally substituted on a ring carbon with one or more groups selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C,. 6 alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C,.
  • R 2 and R 3 are independently selected from hydrogen, aryl and C,. 6 alkyl optionally substituted with aryl; or R 2 and R 3 and the nitrogen atom to which they are attached in combination form a heterocyclic ring.
  • R 2 and R 3 are independently selected from methyl, ethyl or benzyl, or R 2 and R 3 and the nitrogen atom to which they are attached in combination form a pyrrolidin-1-yl, piperidin-1-yl or morpholino ring.
  • R 2 and R 3 are independently selected from methyl or benzyl, or R 2 and R 3 and the nitrogen atom to which they are attached in combination form a pyrrolidin-1-yl or piperidin-1-yl ring.
  • r is 0.
  • s is 0.
  • n 1
  • n is 2. Therefore in a preferred aspect of the invention there is provided an compound of formula (I) as depicted above wherein:
  • R 1 is hydrogen or C,. 6 alkyl
  • R 2 and R 3 are independently selected from hydrogen, aryl and C,. 6 alkyl optionally substituted with aryl; or R 2 and R 3 and the nitrogen atom to which they are attached in combination form a heterocyclic ring; r is 0; s is 0; n is 1 or 2; or a pharmaceutically-acceptable salt or an in vzvo-hydrolysable ester, amide or carbamate thereof.
  • R 1 is hydrogen or methyl
  • R 2 and R 3 are independently selected from methyl, ethyl or benzyl; or R 2 and R 3 and the nitrogen atom to which they are attached in combination form a pyrrolidin-1-yl, piperidin-1-yl or morpholino ring
  • r is 0
  • s is 0
  • n is 1 or 2
  • R 2 and R 3 are independently selected from methyl or benzyl, or R 2 and R 3 and the nitrogen atom to which they are attached in combination form a pyrrolidin-1-yl or piperidin-1-yl ring; r is 0; s is 0; n is 1 or 2; or a pharmaceutically-acceptable salt or and in vzvo-hydrolysable ester, amide or carbamate thereof.
  • Preferred compounds of the invention are those of Examples.
  • a preferred aspect of the invention relates to any one of the Examples.
  • Preferred aspects of the invention relate to a compound according to formula (I) or a pharmaceutically-acceptable salt 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 a chiral centre at the 4-position of the chroman ring. Certain compounds of formula (I) may also have other chiral centres, for example certain of the values of R 2 , R 3 , R 4 , R 5 and certain of the optional substituents may possess chiral centres. It is to be understood that the invention encompasses all such optical isomers and diasteroisomers of compounds of formula (I) that inhibit the [ 3 H]-emopamil binding site.
  • the invention further relates to all tautomeric forms of the compounds of formula
  • esters, amides and carbamates are compounds that hydrolyse in the human body to produce the parent compound. Such esters, amides and carbamates can be identified by administering, for example intravenously to a test animal, the compound under test and subsequently examining the test animal's body fluids. Suitable in vzvo-hydrolysable amides and carbamates include N-carbomethoxy and N-acetyl.
  • An in vzvo-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 methoxymethyl, C ] - 6 alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, C 3 . g cycloalkoxy-carbonyloxyC,.
  • alkyl esters for example 1-cyclohexylcarbonyloxyethyl
  • l,3-dioxolen-2-onylmethyl esters for example 5-methyl-l,3- dioxolen-2-onylmethyl
  • C ⁇ alkoxycarbonyloxy ethyl esters for example 1- methoxycarbonyloxyethyl and may be formed at any carboxy group in the compounds of this invention.
  • An in vzvo-hydrolysable ester of a compound of the formula (I) containing a hydroxy group includes inorganic esters such as phosphate esters and ⁇ -acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group.
  • inorganic esters such as phosphate esters and ⁇ -acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group.
  • ⁇ -acyloxyalkyl ethers include acetoxymethoxy and 2,2- dimethylpropionyloxymethoxy.
  • a selection of in vzvo-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) or a pharmaceutically-acceptable salt or an in vzvo-hydrolysable ester, amide or carbamate thereof which process (wherein R 1 , R 2 , R 3 , R 4 , R 5 , n, r and s are, unless otherwise specified, as defined in formula (I)) comprises of: a) reacting a ketone of formula (II):
  • R b and R c are R 2 and R 3 respectively, unless the value of R 2 and/or R 3 is hydrogen, in which case the appropriate R b and/or R c is a suitable amino protecting group such as those defined below; or b) reacting an amine of formula (IV):
  • L is a suitable displaceable group, with an amine of formula (VII); or h) if R 1 is not hydrogen, reacting a compound of formula (VIII) with a compound of formula (XIII):
  • L is a displaceable group, suitable values for L are for example, a halogeno or sulphonyloxy group, for example a chloro, bromo, methanesulphonyloxy or toluene-4- sulphonyloxy group.
  • G is a suitable displaceable group
  • suitable values for G are C ⁇ alkoxy, for example methoxy or ethoxy.
  • Ketones or aldehydes may be reacted with amines under standard reductive animation conditions. Imine formation may optionally be assisted with a Lewis acid for example titanium tetrachloride, in an inert solvent for example toluene. The reduction may occur for example in the presence of a reducing agent such as hydrogen and a hydrogenation catalyst (for example palladium on carbon), or zinc and hydrochloric acid, or sodium cyanoborohydride, or sodium triacetoxyborohydride, or sodium borohydride, iron pentacarbonyl and alcoholic potassium hydroxide, or borane and pyridine or formic acid.
  • a reducing agent such as hydrogen and a hydrogenation catalyst (for example palladium on carbon), or zinc and hydrochloric acid, or sodium cyanoborohydride, or sodium triacetoxyborohydride, or sodium borohydride, iron pentacarbonyl and alcoholic potassium hydroxide, or borane and pyridine or formic acid.
  • reaction is preferable carried out in the presence of a suitable solvent such as an alcohol, for example methanol or ethanol, and at a temperature in the range of 0-50 °C, preferably at or near room temperature.
  • a suitable solvent such as an alcohol, for example methanol or ethanol
  • Compounds of formula (II), (III), (IV), (V), (VII) and (IX) are commercially available compounds, or they are known in the literature, or they are prepared by standard processes known in the art.
  • Amines and compounds with suitable leaving groups are reacted together under standard alkylation conditions.
  • a base such as an inorganic base for example sodium carbonate or sodium hydroxide or in the presence of excess amine
  • an inert solvent for example tetrahydrofuran, acetonitrile or toluene and at a temperature in the range of 50-120 °C, preferably at or near reflux.
  • an optically active form of a compound of the formula (I) When an optically active form of a compound of the formula (I) is required, it may be obtained, for example, by carrying out one of the aforesaid procedures using an optically active starting material or by resolution of a racemic form of said compound using a conventional procedure.
  • An example of converting one compound of formula (I) into another compound of formula (I) is the conversion of R 1 , R 2 or R 3 when they are hydrogen to a different R 1 , R 2 , or R 3 .
  • an alkyl group could be introduced by standard alkylation or reductive amination techniques, such as those described above.
  • aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid, the introduction of an acyl group using, for example, an acyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; the introduction of an alkyl group using an alkyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; and the introduction of a halogeno group.
  • modifications include the reduction of a nitro group to an amino group by for example, catalytic hydrogenation with a nickel catalyst or treatment with iron in the presence of hydrochloric acid with heating; oxidation of alkylthio to alkylsulphinyl or alkylsulphonyl.
  • a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl.
  • the deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • an acyl group such as a t-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate).
  • a suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.
  • a suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl.
  • the deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • a suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • a base such as sodium hydroxide
  • a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • a pharmaceutical composition which comprises a compound of the formula (I).
  • a pharmaceutical composition which comprises a compound of the formula (I).
  • compounds of formula (I) or a pharmaceutically-acceptable salt or in vzvo-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.
  • 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.
  • composition of this invention may also contain, or be co-administered (simultaneously or sequentially) with, one or more pharmacological agents of value in treating one or more disease conditions referred to hereinabove.
  • compositions of this invention will normally be administered to humans so that, for example, a daily dose of 0.05 to 75 mg/kg body weight (and preferably of 0.1 to 30 mg/kg body weight) is received.
  • This daily dose may be given in divided doses as necessary, the precise amount of the compound received and the route of administration depending on the weight, age and sex of the patient being treated and on the particular disease condition being treated according to principles known in the art.
  • unit dosage forms will contain about 1 mg to 500 mg of a compound of this invention 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 vzvo-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 vzvo-hydrolysable ester, amide or carbamate thereof, in the manufacture of a medicament for use in the inhibition of the [ 3 H]-emopamil binding site in a warm-blooded animal such as a human being.
  • a method of inhibiting of the [ 3 H]-emopamil binding site in a warm-blooded animal, such as a human being, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I) or a pharmaceutically-acceptable salt or an in vivo- hydrolysable ester, amide or carbamate thereof, as defined hereinbefore.
  • 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.
  • Assay buffer 10 mM Tris-HCl, 0.1 mM phenylmethylsulfonyl fluoride (PMSF), 0.2% bovine serum albumin (BSA), pH 7.4 at 4 °C.
  • Radioligand 0.96 nM (-)- 3 H-emopamil (Amersham).
  • Guinea pig liver membranes 40mg/mL original wet weight. Compounds: 1-300 nM. Total volume: 500 ⁇ l. 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 MgCl 2 , 0.2% BSA, pH 7.4 at 25 °C. Specific binding was defined with 10 ⁇ M emopamil. In general compounds with an IC 50 below 300nM in this test were of interest. Guinea-pig liver membrane preparation:
  • the method of 3 H-D-888 binding was a modification of Reynolds, I.J., Snowman, A.M. and Synder, S.H. (-)-[ 3 H] Desmethoxyverapamil labels multiple calcium channel modular receptors in brain and skeletal muscle membranes: differentiation by temperature and dihydropyridines. J. Pharmacol. Exp. Ther. 237: no.3, 731-738, 1986.
  • the assay tubes contained the following: assay buffer: 50 mM Hepes, 0.2% BSA, pH 7.4 radioligand: l ⁇ M H-D888 (Amersham) rat cortical membranes: 6 mg/mL original wet weight compounds: 0.3-100 ⁇ M Total volume: 1000 ⁇ l
  • This mixture was incubated for 60 minutes at 25 °C.
  • the assay was terminated by filtering with a Brandel Cell Harvester over Whatman GF/C filters that had been soaked for at least 120 minutes in 0.3% polyethylenamine (PEI) and washed three times with 5 mL of wash buffer containing 20 mM Hepes, 20 mM MgCl 2 , pH 7.4. Specific binding was measured with 10 ⁇ M methoxyverapamil (D-600).
  • This assay was used to determine in vitro selectivity of compounds vs. L-type voltage sensitive calcium channels, i.e. high affinity for the 3 H-D888 binding site would show a lack of selectivity.
  • Rat brain cortical membrane preparation Male Sprague-Dawley Rats were sacrificed by decapitation and the brains were quickly excised. The cerebellum and brain stem were removed and discarded; and the rest of the brain was rinsed in 320 mM sucrose. The brain was then homogenised in a 10-fold volume of 320 mM sucrose with a motor driven Teflon-glass homogeniser using 10 strokes on ice. The homogenate was spun at 1000 x g for 10 minutes at 4 °C in a SS-34 rotor. The supernatant was then spun at 29,000 x g for 20 minutes. The resulting pellet was resuspended in membrane buffer (5 mM Hepes, 0.2% BSA, pH 7.4) to a final concentration of 60 mg original wet weight/ mL.
  • Gerbil Global Model of Cerebral Ischaemia Gerbil Global Model of Cerebral Ischaemia
  • mice Male Mongolian gerbils (Charles River) weighing 60-70 grams are used in these experiments. They are housed in individual cages with food (Purina Rodent Chow) and water available ad libitum. The animal room is maintained at 23 ⁇ 2 °C, and is on an automatic 12 hour light cycle.
  • the gerbils are brought to the surgical suite and dosed intraperitoneally with the test agent or vehicle, forty five minutes prior to surgery. Drugs are administered at a volume of 5 mL/kg (intraperitoneal). Vehicle is generally saline, with sodium phosphate added to adjust pH, if needed. Forty-five minutes after dosing the gerbils are anaesthetised with halothane (3.3%) 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.
  • THF is tetrahydrofuran
  • DCM is dichloromethane
  • Com Av is commercially available.
  • reaction mixture was partitioned between IN sodium hydroxide solution and DCM.
  • the aqueous portion was extracted with additional DCM.
  • the combined organic portions were washed (water, brine), dried, and evaporated to a white solid.
  • the solid was dissolved in DCM and purified by chromatography, eluting with 10% 2.0 M ammonia in methanol:90% DCM (v/v), to give the product as a white solid (2.50 g, 89%).
  • reaction mixture was filtered through diatomaceous earth and the filtrate was evaporated to a purple oil which was purified by chromatography, eluting with 5% 2.0 M ammonia in methanol: 95% DCM (v/v), to give te title compound as a tan oil (1.03 g, 82%).
  • Example 10 (S)-chroman-4-yl-[2-(3,4-dihydro-lH-isoquinolin-2-yl)ethyl]amine, 1.81-2.12 (m, 3 ⁇ ), 2.53-2.92 (m, 8H), 3.57 (s, 2H), 3.68-3.78 (m, IH), 4.07-4.29 (m, 2H), 6.72 (d, IH), 6.77-6.85 (m, IH), 7.00-7.17 (m, 5H), 7.24 (d, IH).
  • Example 11 N-chroman-4-yl-NN.N-trimethylpropane-1.3-diamine
  • Example 12 N'-chroman-4-yl-N-methyl-N-phenylpropane-l,3-diamine, 1.58-1.75 (m, 2H), 1.80-2.00 (m, 3H), 2.45-2.77 (m, 2H), 2.86 (s, 3H), 3.27-3.50 (m, 2H), 3.65 (s, IH), 4.07-4.30 (m, 2H), 6.57 (t, IH), 6.64-6.77 (m, 3H), 6.83 (t, IH), 7.05-7.20 (m, 3H), 7.26-7.33 (m, IH).
  • Example 13 N'-chroman-4-yl-N,N-dimethylethane-l,2-diamine, 1.70-2.00 (m, 3H), 2.14 (s, 6H), 2.33 (t, 2H), 2.55-2.78 (m, 2H), 3.68 (t, IH), 4.06-4.30 (m, 2H), 6.67-6.90 (m, 2H), 7.04- 7.27 (m, 2H).
  • Example 14 chroman-4-yl-(2-mo holin-4-ylethyl)amine, 1.75-1.95 (m, 3H), 2.27-2.47 (m, 6H), 2.60-2.81 (m, 2H), 3.56 (t, 4H), 3.69 (t, IH), 4.07-4.30 (m, 2H), 6.73 (d, IH), 6.84 (t, lH), 7.11 (t, IH), 7.25 (d, IH).
  • Example 15 chroman-4-yl-(3-morpholin-4-ylpropyl)amine, 1.47-1.68 (m, 2H), 1.82-2.00 (m, 3H), 2.23-2.43 (m, 6H), 2.50-2.76 (m, 2H), 3.54 (t, 4H), 3.66 (t, IH), 4.06-4.30 (m, 2H), 6.72 (d, IH), 6.83 (t, IH), 7.10 (t, IH), 7.27 (d, IH).
  • Example 16 N-benzyl-N-chroman-4-ylethane-l,2-diamine, 1.83-1.91 (m, 2H), 1.94-2.20 (m, 2H), 2.52-2.90 (m, 4H), 3.61-3.73 (m, 3H), 4.06-4.30 (m, 2H), 6.72 (d, IH), 6.83 (t, IH), 7.10 (t, lH), 7.17-7.40 (m, 6H).
  • Example 17 chroman-4-yl-(3-piperidin-l-ylpropyl)amine, 1.23-1.67 (m, 8H), 1.80-2.02 (m, 3H), 2.17-2.40 (m, 6H), 2.50-2.73 (m, 2H), 3.65 (t, IH), 4.07-4.32 (m, 2H), 6.71 (d, IH), 7.09 (t, IH), 7.26 (d, IH).
  • Example 18 chroman-4-yl-(3-pyrrolidin-l-ylpropyl)amine, 1.51-2.00 (m, 10H), 2.30-2.80 (m, 7H), 3.62-3.72 (m, IH), 4.07-4.32 (m, 2H), 6.71 (d, IH), 6.83 (t, IH), 7.10 (t, IH), 7.26 (d, IH).
  • Example 19 chroman-4-yl-(2-pyrrolidin-l-ylethyl)amine, 1.60-1.77 (m, 4H), 1.80-2.00 (m, 3H), 2.34-2.57 (m, 6H), 2.60-2.82 (m, 2H), 3.69 (t, IH), 4.07-4.31 (m, 2H), 6.72 (d, IH), 6.84 (t, IH), 7.11 (t, IH), 7.24 (d, IH).
  • Example 20 N-chroman-4-yl-N,N-dimethylethane-l,2-diamine, 1.82-2.00 (m, 2H), 2.10 (s, 6H), 2.16 (s, 3H), 2.23-2.56 (m, 4H), 3.90-4.12 (m, 2H), 4.24-4.37 (m, IH), 6.68 (d, IH), 6.83 (t, IH), 7.08 (t, IH), 7.43 (d, IH).
  • Example 21 Chroman-4-yl-(N-methyl-2-piperidin- 1 -ylethvDamine bismaleate salt
  • Example 23 2.00-2.20 (m, 2H), 3.02-3.24 (m, 5H), 4.09-4.33 (m, 6H), 6.09 (s, 4H), 6.83 (d, IH), 6.94 (t, IH), 7.24 (t, IH), 7.35-7.58 (m, 6H).
  • Example 24 1.80-2.30 (m, 8H), 2.89-3.60 (m, 9H, H 2 O), 4.27 (t, 2H), 4.42 (s, IH), 6.04 (s,
  • Example 25 1.85-2.02 (m, 7H), 2.16 (s, 3H), 2.65-2.87 (m, 2H), 3.15-3.43 (m, 5H, H 2 O),
  • Example 28 (S)-N-chroman-4-yl-2-(3 ,4-dihydro- 1 H-isoquinolin-2-yl)-N-methylacetamide, 1.84-2.20 (m, 2 ⁇ ), 2.59-2.97 (m, 6H), 3.26-3.80 (m, 5H), 4.07-4.37 (m, 2H), 5.51-5.61 (m, 0.5H), 5.80-5.89 (m, 0.5H), 6.73-7.20 (m, 8H).
  • Example 29 (S)-N-chroman-4-yl-N-methyl-2-pyrrolidin-l-ylacetamide, 1.61-1.78 (m, 4H), 1.82-2.20 (m, 2H), 2.40-2.64 (m, 5.2H), 2.70 (s, 1.8H), 3.27-3.48 (m, 2H), 4.08-4.37 (m, 2H), 5.43-5.53 (m, 0.4H), 5.74-5.84 (m, 0.6H), 6.75-6.98 (m, 3H), 7.08-7.19 (m, IH).
  • Example 30 (5)-2-azepan-l-yl-N-chroman-4-ylacetamide, 1.43-1.65 (m, 8H), 1.87-2.11 (m, 2H), 2.57-2.70 (m, 4H), 3.12 (s, 2H), 4.1 1-4.26 (m, 2H), 4.97-5.09 (m, IH), 6.77 (d, IH), 6.80-6.93 (m, IH), 7.07-7.20 (m, 2H), 8.00 (d, IH).
  • Example 31 (S)-N-chroman-4-yl-2-(3 ,4-dihydro- lH-isoquinolin-2-yl)acetamide, 1.90-2.09 (m, 2 ⁇ ), 2.70-2.93 (m, 4H), 3.13-3.24 (m, 2H), 3.67 (s, 2H), 4.13-4.25 (m, 2H), 5.02-5.13 (m, 1H),6.75 (d, IH), 6.82-6.92 (m, IH), 7.00-7.20 (m, 6H), 8.21 (d, IH).
  • Reference Example 1 (S)-N-chroman-4-yl-2-(3 ,4-dihydro- lH-isoquinolin-2-yl)acetamide, 1.90-2.09 (m, 2 ⁇ ), 2.70-2.93 (m, 4H), 3.13-3.24 (m, 2H), 3.67 (s, 2H), 4.13-4.25 (m, 2H), 5.02-5.13 (m,
  • the starting materials for the Examples above are either commercially available or are readily prepared by standard methods from known materials. For example the following reactions are illustrations but not limitations of the preparation of the starting materials used in the above reactions.
  • HPMC Hydroxypropylmethylcellulose
  • a compound of Formula I is dissolved in an isotonic sterile solution (5 mg/mL).

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Neurology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Hospice & Palliative Care (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Psychiatry (AREA)
  • Psychology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyrane Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Methods for the use of compounds of formula (I) for treatment of neurological disorders, wherein n, r and s are as defined in the specification and R?1, R2, R3, R4 and R5¿ are various substituents, also as defined in the specification, such compounds and pharmaceutical compositions containing such compounds.

Description

-ι_
CHROMAN DER IVATIVES AGAINST NEUROLOGICAL DISORDERS
The present invention relates to chemical compounds, in particular chromans, to processes for their preparation and to chemical intermediates useful in such processes. The present invention further relates to chromans, to pharmaceutical compositions containing them and to their use in methods of therapeutic treatment of animals including man, in particular in the treatment of neurological disorders.
Neurological disorders, for which the present compounds are useful, include stroke, head trauma, transient cerebral ischaemic attack, and chronic neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, diabetic neuropathy, amyotrophic lateral sclerosis, multiple sclerosis and AIDS-related dementia. The compounds useful in the present invention act by selectively binding to the [3H]-emopamil binding site. Compounds with selective action at the [3H]-emopamil binding site exhibit fewer associated side effects such as hypotension seen with emopamil or behavioural manifestations seen with ifenprodil. Background
Emopamil has classically been thought of as a neuroprotective agent whose efficacy is most likely derived from actions at either voltage-sensitive calcium channels (VSCC) or 5- HT2 receptors. An apparent paradox to this logic is that verapamil, although chemically and pharmacologically very similar to emopamil, is not neuroprotective. While the lack of neuroprotective efficacy by verapamil was initially explained by lack of CNS penetration, recent studies suggest other factors may be involved (Keith et al., Br. J. Pharmacol. 113: 379- 384, 1994).
[3H]-Emopamil binding defines a unique high affinity site that is not related to VSCC, is found in the brain, but is most prevalent in the liver (Moebius et al., Mol. Pharmacol. 43: 139-148, 1993). Moebius et al. have termed this the "anti-ischaemic" binding site on the basis of high affinity displacement by several chemically disparate neuroprotective agents. In liver, the [3H]-emopamil binding site is localised to the endoplasmic reticulum.
Neuroprotective compounds are known, for example emopamil and ifenprodil, that exhibit high affinity for the [3H] -emopamil binding site. However these are not selective inhibitors and exhibit activity either at neuronal VSCC, the polyamine site of the NMDA receptor (N-Methyl-D-aspartate) and/or the sigma-1 binding site. Summary of the Invention
In one aspect of the present invention a new method for using compounds having selective action at the [3H]-emopamil binding site and that are neuroprotective without acting directly at either VSCC or NMDA receptors is disclosed.
Compounds of the invention that have selective action at the [3H]-emopamil binding site are compounds of formula (I):
Figure imgf000003_0001
wherein:
R1 is hydrogen, C,.6alkyl, C2.6alkenyl or C2.6alkynyl; R2 and R3 are independently selected from hydrogen, C,.6alkyl, C2.6alkenyl, C2. 6alkynyl, aryl, a carbon linked heteroaryl, a carbon-linked heterocycle, C3.12cycloalkyl and C3. 12cycloalkyl fused to a benzene ring, wherein said C,.6alkyl, C^alkenyl and C2.6alkynyl are optionally substituted with one or more groups selected from halo, nitro, hydroxy, C,.6alkoxy, cyano, amino, trifluoromethyl, trifluoromethoxy, carboxy, carbamoyl, mercapto, sulphamoyl, mesyl, N-C,.6alkylamino, N,N-(C,.6alkyl)2amino, C,.6alkoxycarbonyl, N-C,.6alkylcarbamoyl, N,N-(Cι_6alkyl)2carbamoyl, aryl, a carbon linked heteroaryl, a carbon-linked heterocycle, C3. 12cycloalkyl and C3.12cycloalkyl fused to a benzene ring; and wherein any aryl, heteroaryl, heterocycle, C3.I2cycloalkyl and C3.12cycloalkyl fused to a benzene ring may be optionally substituted on a ring carbon with one or more groups selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C,.6alkyl, C2.6alkenyl, C2.6alkynyl, C,.6alkoxy, C,_6alkanoyl, C,.6alkanoyloxy, N- (C,.6alkyl)amino, N,N-(C,.6alkyl)2amino, C,.6alkanoylamino, N-(C,.6alkyl)carbamoyl, N,N-(C 6alkyl)2carbamoyl, C,.6alkylS(O)a wherein a is 0, 1 or 2, Cι.6alkoxycarbonyl, N-(C,. 6alkyl)sulphamoyl, N,N-(C,.6alkyl)2sulphamoyl and phenylC,.6alkyl; and a heterocycle or a heteroaryl ring containing an -ΝH- group may be optionally substituted on this nitrogen with C,_6alkyl, C2.6alkenyl, C2.6alkynyl, C,.6alkanoyl, C,.6alkylsulphonyl or phenylC,.6alkyl; or R2 and R3 and the nitrogen atom to which they are attached in combination form a heterocyclic or heteroaryl ring and wherein said heterocyclic or heteroaryl ring is optionally substituted on a ring carbon with one or more groups selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C,.6alkyl, C2.6alkenyl, C2_6alkynyl, C,.6alkoxy, C,.6alkanoyl, C,.6alkanoyloxy, N- (C|.6alkyl)amino, N,N-(C,.6alkyl)2amino, C,.6alkanoylamino, N-(C,.6alkyl)carbamoyl, N,N-(C,_ 6alkyl)2carbamoyl, C,.6alkylS(O)a wherein a is 0, 1 or 2, C,.6alkoxycarbonyl, N-(C,. 6alkyl)sulphamoyl, N,N-(C,.6alkyl)2sulphamoyl or phenylC,.6alkyl; and a heterocyclic or a heteroaryl ring containing an -ΝH- group is optionally substituted on this nitrogen with C,_ 6alkyl, C2.6alkenyl, C2-6alkynyl, C,.6alkanoyl or C,.6alkylsulphonyl;
R4 at each occurrence is selected from halo, hydroxy, C,.6alkyl, C,.6alkoxy, haloC,. 6alkyl, cyano, nitro or C2.6alkenyl;
R5 is C,-6alkyl; n is 1 or 2; r is 0, 1 , 2, 3 or 4, wherein at each occurrence the value of R4 may be the same or different; and s is 0, 1 , 2 or 3 wherein at each occurrence the value of R5 may be the same or different; or a pharmaceutically-acceptable salt or an in vzvo-hydrolysable ester, amide or carbamate thereof.
In another aspect of the present invention, new pharmaceutical compositions containing compounds of formula (I), or in v/vø-hydrolysable esters, amides or carbamates thereof, together with a pharmaceutically-acceptable carrier such as an excipient, diluent or stabilizer or combinations thereof as further defined herein are disclosed. In a further aspect of the present invention, the use of a compound of the formula (I), or a pharmaceutically-acceptable salt or an in vzvo-hydrolysable ester, amide or carbamate thereof, in the manufacture of a medicament for use in the inhibition of the [3H]-emopamil binding site in a warm-blooded animal is disclosed.
In yet a further aspect of the present invention, novel compounds are disclosed which are compounds of formula (I) with a proviso wherein in such compounds: if r is 1, R4 is a 6-linked cyano moiety, s is 2 and both R5 moieties are 2-linked methyl, n is 1, and R1 and R2 are both H, then R3 is not phenyl or benzyl; if r and s are both 0, R1 is H and n is 2, then R1 and R2 are not both ethyl or not both H, or if r and s are both 0, R1 is H and n is 1, then R1 and R2 are not both ethyl. Detailed Description of the Invention
In this specification the term "alkyl" includes both straight and branched chain alkyl groups but references to individual alkyl groups such as "propyl" are specific for the straight chain version only. A similar convention applies to "alkenyl", "alkynyl" and other radicals, for example "phenylC,.6alkyl" includes 2-phenylethyl, 2-phenylpropyl and 3-phenylpropyl. The term "halo" refers to fluoro, chloro, bromo and iodo.
The term aryl refers to an unsaturated carbon ring. Preferably aryl is phenyl, naphthyl or biphenyl. More preferably aryl is phenyl.
The term "heteroaryl" or "heteroaryl ring" refers to, unless otherwise further specified, a monocyclic-, bicyclic- or tricyclic-, 5- to 14-membered ring that is unsaturated or partially unsaturated, with up to five ring heteroatoms selected from nitrogen, oxygen and sulphur wherein a -CH2- group can optionally be replaced by a -C(O)-, and a ring nitrogen atom may be optionally oxidised to form the N-oxide. Examples of such heteroaryls include thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, pyridyl, pyridyl-N-oxide, oxopyridyl, oxoquinolyl, pyrimidinyl, pyrazinyl, oxopyrazinyl, pyridazinyl, indolinyl, benzofuranyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolinyl, quinazolinyl, xanthenyl, quinoxalinyl, indazolyl, benzofuranyl and cinnolinolyl. The term "heterocyclyl" or "heterocyclic ring" refers to, unless otherwise further specified, a mono- or bicyclic-, 5- to 14-membered ring, that is totally saturated, with up to five ring heteroatoms selected from nitrogen, oxygen and sulphur wherein a -CH2- group can optionally be replaced by a -C(O)-. Examples of such heterocyclyls include morpholinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, homopiperidinyl, homopiperazinyl and quinuclidinyl.
Where optional substituents are chosen from "one or more" groups it is to be understood that this definition includes all substituents being chosen from one of the specified groups or the substituents being chosen from two or more of the specified groups.
In the present invention, examples of C^a-kyl include C alkyl such as methyl, ethyl, isopropyl and t-butyl; examples of phenylC^alkyl include phenylC2.6alkyl such as phenylC,.4alkyl such as phenylC2. 4alkyl such as benzyl, phenylethyl and phenylpropyl; examples of C,.6alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, n- and t- butoxycarbonyl; examples of C,.6alkoxy include methoxy, ethoxy and propoxy; examples of C,_6alkanoylamino include formamido, acetamido and propionylamino; examples of C,.6alkylS(O)a where a is 0, 1 or 2 include C,.6alkylsulphonyl, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl and ethylsulphonyl; examples of C,.6alkylsulphonyl include mesyl and ethylsulphonyl; examples of C,.6alkanoyl include propionyl and acetyl; examples of N-C,.6alkylamino include N-methylamino and N-ethylamino; examples of N,N-(C,.6alkyl)2amino include N-N-dimethylamino, N,N-diethylamino and N- ethyl-N-methylamino ; examples of C3.]2cycloalkyl include cyclopropyl and cyclohexyl; examples of C3.12cycloalkyl fused to a benzene ring are 1,2,3,4-tetrahydronaphthyl and 2,3- dihydroindenyl; examples of C2.6alkenyl include vinyl, allyl and 1-propenyl; examples of C2.6alkynyl include ethynyl, 1-propynyl and 2-propynyl; examples of haloC2.6alkyl include 2-chloroethyl and 2-bromopropyl; examples of N-(C,.6alkyl)sulphamoyl include N-methylsulphamoyl and N-ethylsulphamoyl; examples of N,N-(C,.6alkyl)2sulphamoyl include N,N-dimethylsulphamoyl and N-methyl-N- ethylsulphamoyl; examples of N-(C,.6alkyl)carbamoyl include N-methylcarbamoyl and N-ethylcarbamoyl; examples of N,N-(C,.6alkyl)2carbamoyl include N,N-dimethylcarbamoyl and N-methyl-N- ethylcarbamoyl, and examples of C|.6alkanoyloxy include propionyloxy, acetyloxy and formyloxy. Preferably R! is hydrogen or C,.6alkyl
More preferably R1 is hydrogen or C,.4alkyl. Particularly R' is hydrogen or methyl. More particularly R1 is methyl.
In one aspect of the invention, preferably R2 and R3 are independently selected from hydrogen, C,.6alkyl, aryl, a carbon linked heteroaryl, a carbon-linked heterocycle, C3.
12cycloalkyl and C3.12cycloalkyl fused to a benzene ring; wherein said C,.6alkyl, is optionally substituted with one or more groups selected from halo, nitro, hydroxy, C,.6alkoxy, cyano, amino, trifluoromethyl, trifluoromethoxy, carboxy, carbamoyl, mercapto, sulphamoyl, mesyl, N-C,.6alkylamino, N,N-(C,.6alkyl)2amino, C,.6alkoxycarbonyl, N-C,.6alkylcarbamoyl or N,N- (C,-6alkyl)2carbamoyl, aryl, a carbon linked heteroaryl, a carbon-linked heterocycle, C3_ 12cycloalkyl or C3.12cycloalkyl fused to a benzene ring; and wherein any aryl, heteroaryl or heterocycle may be optionally substituted on a ring carbon with one or more groups selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C,.6alkyl, C2.6alkenyl, C2.6alkynyl, C,.6alkoxy, C].6alkanoyl, C,.6alkanoyloxy, N-(C,.6alkyl)amino, N,N-(C,_6alkyl)2amino, C,.6alkanoylamino, N-(C,_ 6alkyl)carbamoyl, N,N-(C,.6alkyl)2carbamoyl, C,.6alkylS(O)a wherein a is 0, 1 or 2, C,. 6alkoxycarbonyl, N-(C,.6alkyl)sulphamoyl, N,N-(C].6alkyl)2sulphamoyl and phenylC,.6alkyl; and a heterocycle or a heteroaryl ring containing an -ΝH- group is optionally substituted on this nitrogen with C,.6alkyl, C2.6alkenyl, C2-6alkynyl, C,.6alkanoyl, C,.6alkylsulphonyl or phenylC,_6alkyl.
In another aspect of the invention preferably R2 and R3 and the nitrogen atom to which they are attached in combination form a ring selected from 1,2,3,4- tetrahydroisoquinolinyl, morpholinyl, piperidinyl, pyrrolidinyl, homopiperidinyl and wherein said ring may be optionally substituted on a ring carbon with one or more groups selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C,.6alkyl, C2.6alkenyl, C2.6alkynyl, C,.6alkoxy, C,.6alkanoyl, C,.6alkanoyloxy, N-(C,.6alkyl)amino, N.N-(C,.6alkyl)2amino, C,.6alkanoylamino, N-(C,. 6alkyl)carbamoyl, N,N-(C,.6alkyl)2carbamoyl, C,_6alkylS(O)a wherein a is 0, 1 or 2, C,_ 6alkoxycarbonyl, N-(C,.6alkyl)sulphamoyl, N,N-(C,.6alkyl)2sulphamoyl or phenylC,.6alkyl.
In a further aspect of the invention, preferably R2 and R3 are independently selected from hydrogen, aryl and C,.6alkyl optionally substituted with aryl; or R2 and R3 and the nitrogen atom to which they are attached in combination form a heterocyclic ring.
More preferably R2 and R3 are independently selected from methyl, ethyl or benzyl, or R2 and R3 and the nitrogen atom to which they are attached in combination form a pyrrolidin-1-yl, piperidin-1-yl or morpholino ring.
Particularly R2 and R3 are independently selected from methyl or benzyl, or R2 and R3 and the nitrogen atom to which they are attached in combination form a pyrrolidin-1-yl or piperidin-1-yl ring. Preferably r is 0.
Preferably s is 0.
In one aspect of the invention preferably n is 1.
In another aspect of the invention preferably n is 2. Therefore in a preferred aspect of the invention there is provided an compound of formula (I) as depicted above wherein:
R1 is hydrogen or C,.6alkyl;
R2 and R3 are independently selected from hydrogen, aryl and C,.6alkyl optionally substituted with aryl; or R2 and R3 and the nitrogen atom to which they are attached in combination form a heterocyclic ring; r is 0; s is 0; n is 1 or 2; or a pharmaceutically-acceptable salt or an in vzvo-hydrolysable ester, amide or carbamate thereof.
In a more preferred aspect of the invention there is provided a compound of the formula (I) as depicted above wherein:
R1 is hydrogen or methyl; R2 and R3 are independently selected from methyl, ethyl or benzyl; or R2 and R3 and the nitrogen atom to which they are attached in combination form a pyrrolidin-1-yl, piperidin-1-yl or morpholino ring; r is 0; s is 0; n is 1 or 2; or a pharmaceutically-acceptable salt or an in vzvo-hydrolysable ester, amide or carbamate thereof.
In a particular aspect of the invention there is provided a compound of formula (I) as depicted above wherein: R1 is hydrogen or methyl;
R2 and R3 are independently selected from methyl or benzyl, or R2 and R3 and the nitrogen atom to which they are attached in combination form a pyrrolidin-1-yl or piperidin-1-yl ring; r is 0; s is 0; n is 1 or 2; or a pharmaceutically-acceptable salt or and in vzvo-hydrolysable ester, amide or carbamate thereof.
Preferred compounds of the invention are those of Examples. A preferred aspect of the invention relates to any one of the Examples. Preferred aspects of the invention relate to a compound according to formula (I) or a pharmaceutically-acceptable salt 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. 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 a chiral centre at the 4-position of the chroman ring. Certain compounds of formula (I) may also have other chiral centres, for example certain of the values of R2, R3, R4, R5 and certain of the optional substituents may possess chiral centres. It is to be understood that the invention encompasses all such optical isomers and diasteroisomers of compounds of formula (I) that inhibit the [3H]-emopamil binding site.
The invention further relates to all tautomeric forms of the compounds of formula
(I).
It is also to be understood that certain compounds of the formula (I) can exist in solvated as well as unsolvated forms such as, for example, hydrated forms and that the invention encompasses all such solvated and unsolvated forms. In vzvo-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 vzvo-hydrolysable amides and carbamates include N-carbomethoxy and N-acetyl.
An in vzvo-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,.6alkoxymethyl esters for example methoxymethyl, C]-6alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, C3.gcycloalkoxy-carbonyloxyC,.6alkyl esters for example 1-cyclohexylcarbonyloxyethyl; l,3-dioxolen-2-onylmethyl esters for example 5-methyl-l,3- dioxolen-2-onylmethyl; and C^alkoxycarbonyloxy ethyl esters for example 1- methoxycarbonyloxyethyl and may be formed at any carboxy group in the compounds of this invention.
An in vzvo-hydrolysable ester of a compound of the formula (I) containing a hydroxy group includes inorganic esters such as phosphate esters and α-acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group. Examples of α-acyloxyalkyl ethers include acetoxymethoxy and 2,2- dimethylpropionyloxymethoxy. A selection of in vzvo-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) or a pharmaceutically-acceptable salt or an in vzvo-hydrolysable ester, amide or carbamate thereof which process (wherein R1, R2, R3, R4, R5, n, r and s are, unless otherwise specified, as defined in formula (I)) comprises of: a) reacting a ketone of formula (II):
Figure imgf000011_0001
(II) with an amine of formula (III):
Figure imgf000011_0002
(in); wherein Rb and Rc are R2 and R3 respectively, unless the value of R2 and/or R3 is hydrogen, in which case the appropriate Rb and/or Rc is a suitable amino protecting group such as those defined below; or b) reacting an amine of formula (IV):
Figure imgf000011_0003
(IV) with an aldehyde of formula (V):
Figure imgf000011_0004
(V) wherein Rb and Rc are as defined above; or c) reacting an aldehyde of formula (VI):
Figure imgf000011_0005
with an amine of formula:
R2 I HN^ R3
(Nil) wherein R is R1 unless the value of R1 is hydrogen, in which case Ra is a suitable amino protecting group such as those defined below; or d) if R1 is C].6alkyl, reacting a compound of formula (VIII):
R
Figure imgf000012_0001
wherein Rb and Rc are as defined above, with a compound of formula (IX);
Figure imgf000012_0002
(IX) wherein K is hydrogen or C,.5alkyl; or e) reacting a compound of formula (X):
Figure imgf000012_0003
(X) wherein L is a suitable displaceable group, with an amine of formula (III); or f) reacting an amine of formula (IV) with a compound of formula (XI):
Figure imgf000012_0004
(XI) wherein L is a suitable displaceable group and Rb and Rc are as defined above; or g) reacting a compound of formula (XII):
Figure imgf000013_0001
wherein L is a suitable displaceable group, with an amine of formula (VII); or h) if R1 is not hydrogen, reacting a compound of formula (VIII) with a compound of formula (XIII):
R'-L (XIII) wherein L is a suitable displaceable group; i) reducing a compound of formula (XIV):
Figure imgf000013_0002
or j) reducing a compound of formula (XV):
Figure imgf000013_0003
or k) if R1 is not hydrogen, reducing a compound of formula (XVI):
Figure imgf000014_0001
(XVI) wherein:
1) for preparing a compound wherein R1 is methyl, G is a suitable displaceable group; or 2) for preparing a compound wherein R1 is C2.6alkyl, G is C,.5alkyl; 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 vzvo-hydrolysable ester, amide or carbamate.
L is a displaceable group, suitable values for L are for example, a halogeno or sulphonyloxy group, for example a chloro, bromo, methanesulphonyloxy or toluene-4- sulphonyloxy group.
When G is a suitable displaceable group, suitable values for G are C^alkoxy, for example methoxy or ethoxy.
Specific reaction conditions for the above reactions a), b), c) and d) are as follows: Ketones or aldehydes may be reacted with amines under standard reductive animation conditions. Imine formation may optionally be assisted with a Lewis acid for example titanium tetrachloride, in an inert solvent for example toluene. The reduction may occur for example in the presence of a reducing agent such as hydrogen and a hydrogenation catalyst (for example palladium on carbon), or zinc and hydrochloric acid, or sodium cyanoborohydride, or sodium triacetoxyborohydride, or sodium borohydride, iron pentacarbonyl and alcoholic potassium hydroxide, or borane and pyridine or formic acid. The reaction is preferable carried out in the presence of a suitable solvent such as an alcohol, for example methanol or ethanol, and at a temperature in the range of 0-50 °C, preferably at or near room temperature. Compounds of formula (II), (III), (IV), (V), (VII) and (IX) are commercially available compounds, or they are known in the literature, or they are prepared by standard processes known in the art.
Compounds of formula (VI) may be prepared according to the following scheme:
(R4) ■ (VI)
Figure imgf000015_0001
(VIA) (VIB) (VIC)
Compounds of formula (VIII) may be prepared according to the following scheme:
Figure imgf000015_0002
Compounds of formula (VIA), (VIB) and (VIII A) are commercially available compounds, or they are known in the literature, or they are prepared by standard processes known in the art.
Specific reaction conditions for the above reactions e), f), g) and h) are as follows:
Amines and compounds with suitable leaving groups are reacted together under standard alkylation conditions. For example in the presence of a base, such as an inorganic base for example sodium carbonate or sodium hydroxide or in the presence of excess amine, in the presence of an inert solvent for example tetrahydrofuran, acetonitrile or toluene and at a temperature in the range of 50-120 °C, preferably at or near reflux.
Compounds of formula (X), (XI) and (XIII) are commercially available compounds, or they are known in the literature, or they are prepared by standard processes known in the art. Compounds of formula (XII) may be prepared according to the following scheme.
O
11 Sodium borohydride
(i ) + H H "n L Methanol. - (χπ)
(XIIA) Compounds of formula (XII A) are commercially available compounds, or they are known in the literature, or they are prepared by standard processes known in the art. Specific reaction conditions for the above reactions i), j) and k) are as follows:
Compounds of formula (XIV), (XV) and (XVI) are reduced under standard reduction conditions for reducing an amide to an amine. For example, in the presence of a reducing agent such as borane, sodium borohydride or lithium aluminium hydride, in an inert solvent such as toluene or tetrahydrofuran, and at a temperature in the range of 50-120 °C, preferably at or near reflux.
Compounds of formula (XIV) may be prepared according to the following scheme:
Figure imgf000016_0001
Compounds of formula (XV) may be prepared according to the following scheme:
Figure imgf000016_0002
(XVA) (XVB) wherein Ra, Rb and L are as hereinbefore defined.
Compounds of formula (XVI) may be prepared according to the following schemes:
Figure imgf000016_0003
( VI A)
Compounds of formula (XIVA) and (XVI A) are commercially available compounds, or they are known in the literature, or they are prepared by standard processes known in the art.
When an optically active form of a compound of the formula (I) is required, it may be obtained, for example, by carrying out one of the aforesaid procedures using an optically active starting material or by resolution of a racemic form of said compound using a conventional procedure.
An example of converting one compound of formula (I) into another compound of formula (I) is the conversion of R1, R2 or R3 when they are hydrogen to a different R1, R2, or R3. For example an alkyl group could be introduced by standard alkylation or reductive amination techniques, such as those described above.
It will be appreciated that certain of the various ring substituents in the compounds of the present invention may be introduced by standard aromatic substitution reactions or generated by conventional functional group modifications either prior to or immediately following the processes mentioned above, and as such are included in the process aspect of the invention. Such reactions and modifications include, for example, introduction of a substituent by means of an aromatic substitution reaction, reduction of substituents, alkylation of substituents and oxidation of substituents. The reagents and reaction conditions for such procedures are well known in the chemical art. Particular examples of aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid, the introduction of an acyl group using, for example, an acyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; the introduction of an alkyl group using an alkyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; and the introduction of a halogeno group. Particular examples of modifications include the reduction of a nitro group to an amino group by for example, catalytic hydrogenation with a nickel catalyst or treatment with iron in the presence of hydrochloric acid with heating; oxidation of alkylthio to alkylsulphinyl or alkylsulphonyl.
It will also be appreciated that in some of the reactions mentioned herein it may be necessary/desirable to protect any sensitive groups in the compounds. The instances where protection is necessary or desirable and suitable methods for protection are known to those skilled in the art. Conventional protecting groups may be used in accordance with standard practice (for illustration see T.W. Greene, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991). Thus, if reactants include groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein. A suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a t-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.
A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
The protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art. According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the formula (I). To use compounds of formula (I) or a pharmaceutically-acceptable salt or in vzvo-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 co-administered (simultaneously or sequentially) 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 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 vzvo-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 vzvo-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 vzvo-hydrolysable ester, amide or carbamate thereof, in the manufacture of a medicament for use in the inhibition of the [3H]-emopamil binding site in a warm-blooded animal such as a human being.
According to a further feature of the invention there is provided a method of inhibiting of the [3H]-emopamil binding site in a warm-blooded animal, such as a human being, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I) or a pharmaceutically-acceptable salt or an in vivo- 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 -H-Emopamil binding to guinea pig liver membranes The method of (-)-3H-emopamil binding was a modification of Zech, C, Staudinger
R., Miihlbacher, J. and Glossmann, H. Novel sites for phenylalkylamines: characterisation of a sodium-sensitive drug receptor with (-)-3H-emopamil. Eur. J. Pharm. 208: 119-130, 1991. The reaction mixture contained: Assay buffer: 10 mM Tris-HCl, 0.1 mM phenylmethylsulfonyl fluoride (PMSF), 0.2% bovine serum albumin (BSA), pH 7.4 at 4 °C.
Radioligand: 0.96 nM (-)-3H-emopamil (Amersham). Guinea pig liver membranes: 40mg/mL original wet weight. Compounds: 1-300 nM. Total volume: 500 μl. This mixture was incubated for 60 minutes at 37 °C. The incubation was terminated by filtering with a Brandel Cell Harvester over Whatman GF/C filters that had been soaked for at least 120 minutes in 0.3%) polyethylenimine (PEI) and washed three times with 5 mL of wash buffer containing 10 mM Tris-HCl, 10 mM MgCl2, 0.2% BSA, pH 7.4 at 25 °C. Specific binding was defined with 10 μM emopamil. In general compounds with an IC50 below 300nM in this test were of interest. Guinea-pig liver membrane preparation:
Male guinea pigs were sacrificed by CO2 asphyxiation with dry ice. The livers were quickly excised and weighed and rinsed in membrane preparation buffer containing 10 mM Hepes, 1 mM Tris base-EDTA, 250 mM sucrose, pH 7.4. The livers were then minced, homogenised in 10 times volume with a motor driven Teflon-glass homogeniser with three strokes on ice. The homogenate was centrifuged at 1000 x g in a SS34 rotor for 5 minutes at 4 °C. The supernatant was filtered through 4 layers of gauze and then centrifuged at 8000 x g for 10 minutes at 4 °C. This resulting supernatant was centrifuged at 40,000 x g for 15 minutes at 4 °C. The resulting pellet was resuspended in assay buffer and centrifuged again at 40,000 x g for 15 minutes at 4 °C. This pellet was resuspended in assay buffer (2.5 fold with respect to original wet weight) and homogenised with one stroke with the Teflon-glass homogeniser. Aliquots of 1 mL were stored at -70 °C. -H-D-888 binding to rat brain cortical membranes
The method of 3H-D-888 binding was a modification of Reynolds, I.J., Snowman, A.M. and Synder, S.H. (-)-[3H] Desmethoxyverapamil labels multiple calcium channel modular receptors in brain and skeletal muscle membranes: differentiation by temperature and dihydropyridines. J. Pharmacol. Exp. Ther. 237: no.3, 731-738, 1986. The assay tubes contained the following: assay buffer: 50 mM Hepes, 0.2% BSA, pH 7.4 radioligand: lηM H-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 methoxyverapamil (D-600). This assay was used to determine in vitro selectivity of compounds vs. L-type voltage sensitive calcium channels, i.e. high affinity for the 3H-D888 binding site would show a lack of selectivity. Rat brain cortical membrane preparation Male Sprague-Dawley Rats were sacrificed by decapitation and the brains were quickly excised. The cerebellum and brain stem were removed and discarded; and the rest of the brain was rinsed in 320 mM sucrose. The brain was then homogenised in a 10-fold volume of 320 mM sucrose with a motor driven Teflon-glass homogeniser using 10 strokes on ice. The homogenate was spun at 1000 x g for 10 minutes at 4 °C in a SS-34 rotor. The supernatant was then spun at 29,000 x g for 20 minutes. The resulting pellet was resuspended in membrane buffer (5 mM Hepes, 0.2% BSA, pH 7.4) to a final concentration of 60 mg original wet weight/ mL. Gerbil Global Model of Cerebral Ischaemia
Male Mongolian gerbils (Charles River) weighing 60-70 grams are used in these experiments. They are housed in individual cages with food (Purina Rodent Chow) and water available ad libitum. The animal room is maintained at 23 ± 2 °C, and is on an automatic 12 hour light cycle.
The gerbils are brought to the surgical suite and dosed intraperitoneally with the test agent or vehicle, forty five minutes prior to surgery. Drugs are administered at a volume of 5 mL/kg (intraperitoneal). Vehicle is generally saline, with sodium phosphate added to adjust pH, if needed. Forty-five minutes after dosing the gerbils are anaesthetised with halothane (3.3%) 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 as described by Lin, T-N., He, Y.Y., Wu, G., Khan, M. And Hsu,
C.Y. Effect of brain edema on infarct volume in a focal model cerebral ischaemia model in rats. Stroke 24:117-121, 1993, 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. Data
The following results were obtained in the 3H-Emopamil binding to guinea pig liver membranes test.
Figure imgf000024_0001
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, 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 Merck Kieselgel silica (Art. 9385) 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 DMSO- δ6 unless otherwise stated using a Varian Gemini 2000 spectrometer operating at a field strength of 300 MHz; chemical shifts are reported in parts per million downfield from tetramethylsilane as an internal standard (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 and unless otherwise stated Η NMR is quoted; fast- atom bombardment (FAB) mass spectral data were obtained using a Platform spectrometer (supplied by Micromass) run in electrospray and, where appropriate, either positive ion data or negative ion data were collected, in this application, (M+H)+ is quoted unless otherwise stated;
(vi) intermediates were not generally fully characterised and purity was in general assessed mass spectral (MS) or NMR analysis; and (vii) in which the following abbreviations (also used hereinabove) may be used :- DMSO is dimethylsulphoxide; m/s is mass spectroscopy;
THF is tetrahydrofuran; DCM is dichloromethane;
Com Av is commercially available; and
SM is starting material.
Example 1
Chroman-4-yl-(2-piperidin- -l-ylethyl)amine
4-Chromanone (0.960 g, 6.48 x 10'3 mole) and l-(2-aminoethyl)piperidine (5.163 g, 4.03 x 10"2 mole) were combined in toluene (20 mL) and cooled to 0 °C (ice/water/sodium chloride). The mixture was treated with titanium tetrachloride solution (1.0 M in toluene, 3.2 mL, 3.20 x 10"3 mole), maintaining the reaction temperature at <5 °C. Upon complete addition, the cooling bath was removed and the mixture stirred at ambient temperature for 24.5 hours. The solid was removed by vacuum filtration and the filtrate concentrated to a yellow oil. A solution of the oil in methanol (15 mL) was treated with sodium borohydride (0.253 g, 6.69 x 10"3 mole) and stirred at ambient temperature for 30 minutes. The solvent was evaporated and the residue partitioned between water and diethyl ether. The aqueous portion was extracted with additional diethyl ether. The combined extracts were washed (water, brine), dried, and evaporated to a yellow oil which was purified by chromatography, eluting with l%NH4OH:5%MeOH:94%DCM (v/v/v), to give the product as a pale yellow oil (1.15 g, 68%). NMR: 1.27-1.60 (m, 6H), 1.72-1.98 (m, 3H), 2.20-2.45 (m, 6H), 2.57-2.80 (m, 2H), 3.68 (t, IH), 4.07-4.29 (m, 2H), 6.73 (d, IH), 6.84 (t, IH), 7.11 (t, IH), 7.23 (d, IH). m/s: 261. Example 2 Chroman-4-yl-(N-methyl-2-piperidin- 1 -vie thvPamine
4-[2-(Piperidin-l-yl)ethylamino]chroman (Example 1) (0.700 g, 2.69 x 10"3 mole) was dissolved in methanol (16 mL) and treated with formaldehyde (37% aqueous, 5.4 mL, 7.20 x 10"2 mole). After two hours, sodium borohydride (0.975 g, 2.58 x 10"2 mole) was added and the mixture was stirred at ambient temperature for 38 hours. The reaction mixture was evaporated and the residue partitioned between water and diethyl ether. The aqueous portion was extracted with additional diethyl ether. The combined organic portions were washed (water, brine), dried, and evaporated to a yellow oil which was purified by chromatography, eluting with 1% ΝH4OH:5% MeOH:94% CH2C12 (v/v/v), to give the product as a colourless oil (0.175 g, 24%). NMR: 1.23-1.57 (m, 6H), 1.80-2.03 (m, 2H), 2.10-2.60 (m, 11H), 3.92- 4.15 (m, 2H), 4.23-4.36 (m, IH), 6.70 (d, IH), 6.85 (t, IH), 7.05 (t, IH), 7.44 (d, IH). m/s: 274.
Example 3
("S)-Chroman-4-yl- \2-( 1 ,3 -dihydroisoindol-2-yl)e thyl] amine (a) A suspension of N-(t-butoxycarbonyl)glycine (2.44 g, 1.39 x 10"2 mole) and 1 -hydroxybenzotriaole (1.80 g, 1.33 x 10"2 mole) in DCM (50 mL) was treated with l-[3- dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (3.13 g, 1.63 x 10"2 mole) and triethylamine (2.4 mL, 1.72 x 10"2 mole), respectively. Immediately, a solution of (S)-4- aminochroman (2.00 g, 1.34 x 10"2 mole) in DCM (30 mL) was added. After stirring at ambient temperature for 19 hours, the reaction mixture was partitioned between water and DCM. The aqueous portion was extracted with additional DCM. The combined organic portions were washed (water, brine), dried, and evaporated to an oil (4.17 g, 100%). Η ΝMR (DMSO): 1.39 (s, 9H), 1.80-2.08 (m, 2H), 3.44-3.61 (m, 2H), 4.11-4.26 (m, 2H), 4.94-5.05 (m, IH), 6.77 (d, IH), 6.81-7.00 (m, 2H), 7.08-7.20 (m, 2H), 8.24 (d, IH). m s: 307. (b) The oil from step (a) (4.17 g, 1.36 x 10"2 mole) in THF (70 mL) was treated with concentrated hydrochloric acid (2 mL) and heated at 60 °C for two hours. Additional concentrated hydrochloric acid (2 mL) was added and heating continued at 60 °C for two hours. The reaction mixture was partitioned between IN sodium hydroxide solution and DCM. The aqueous portion was extracted with additional DCM. The combined organic portions were washed (water, brine), dried, and evaporated to a white solid. The solid was dissolved in DCM and purified by chromatography, eluting with 10% 2.0 M ammonia in methanol:90% DCM (v/v), to give the product as a white solid (2.50 g, 89%). Η ΝMR (DMSO): 1.82-2.20 (m, 4H), 3.13 (s, 2H), 4.09-4.27 (m, 2H), 4.95-5.06 (m, IH), 6.77 (d, IH), 6.82-6.92 (m, IH), 7.07-7.22 (m, 2H), 8.17 (d, IH). (c) A suspension of the white solid from step (b) (2.50 g, 1.21 x 10"2 mole) and sodium carbonate (3.86 g, 3.64 x 10"2 mole) in THF (62 mL) was treated with α,α'-dibromo- o-xylene (3.19 g, 1.21 x 10"2 mole) followed by refluxing for six hours. The reaction mixture was partitioned between water and DCM. The aqueous portion was extracted with additional DCM. The combined organic portions were washed (water, brine), dried, and evaporated to a white solid. The solid was dissolved in DCM/methanol and purified by chromatography, eluting with 5% 2.0M ammonia in methanol:95% DCM (v/v), to give the product as a white solid (3.51 g, 94%). 'H ΝMR (DMSO): 1.92-2.08 (m, 2H), 3.42 (s, 2H), 4.00 (s, 4H), 4.16- 4.25 (m, 2H), 5.01-5.13 (m, IH), 6.76 (d, IH), 6.83-6.94 (m, IH), 7.08-7.28 (m, 6H), 8.31 (d, IH). m/s: 309.
(d) A suspension of the white solid from step (c) (3.51 g, 1.14 x 10"2 mole) in
THF (115 mL) was treated with lithium aluminum hydride (1.76 g, 4.64 x 10"2 mole) and refluxed for two hours. The reaction mixture was quenched with sodium sulfate decahydrate until effervescence ceased. Additional THF and diethyl ether were added to aid stirring. The reaction mixture was filtered through diatomaceous earth and the filtrate evaporated to pink oil which was purified by chromatography, eluting with 5% 2.0M ammonia in methanol:95% DCM (v/v), to give the product as a tan oil (2.49 g, 74%). Η NMR (DMSO): 1.83-2.30 (m, 3H), 2.67-2.91 (m, 4H), 3.69-3.78 (m, IH), 3.87 (s, 4H), 4.08-4.32 (m, 2H), 6.73 (d, IH), 6.77-6.89 (m, IH), 7.06-7.33 (m, 6H). m/s: 295. Example 4 .S)-Chroman-4-yl-r2-(1.3-dihvdroisoindol-2-yl)ethyl1methylamine
The tan oil from step (d) of Example 3 (1.33 g, 4.52 x 10"3 mole) and triethylamine (1.5 mL, 1.08 x 10"2 mole) were combined in THF (35 mL) and treated with ethyl chloroformate (0.475 mL, 4.97 x 10"3 mole) at ambient temperature. The mixture was stirred for one hour. The reaction mixture was evaporated and the residue was partitioned between water and ethyl acetate. The aqueous portion was extracted with additional ethyl acetate. The combined organic portions were washed (water, brine), dried, and evaporated to a brown oil which was purified by chromatography, eluting with 2:1 ethyl acetate/ hexane (v/v), to give the carbamate as a tan oil (1.49 g, 90%). A solution of the oil in THF (30 mL) was treated with lithium aluminum hydride (0.627 g, 1.65 x 10"2 mole) and refluxed for two hours. The reaction mixture was quenched with sodium sulfate decahydrate until effervescence ceased. Additional THF and diethyl ether were added to aid stirring. The reaction mixture was filtered through diatomaceous earth and the filtrate was evaporated to a purple oil which was purified by chromatography, eluting with 5% 2.0 M ammonia in methanol: 95% DCM (v/v), to give te title compound as a tan oil (1.03 g, 82%). 'H NMR (DMSO): 1.84-2.02 (m, 2H), 2.24 (s, 3H), 2.53-2.66 (m, 2H), 2.71-2.92 (m, 2H), 3.83 (s, 4H), 3.95-4.14 (m, 2H), 4.26-4.36 (m, IH), 6.72 (d, IH), 6.80-6.90 (m, IH), 7.03-7.26 (m, 5H), 7.47 (d, IH). m/s: 309. Examples 5-10
Using an analogous procedure to that described in Example 3(d), the following compounds were prepared.
Figure imgf000028_0001
Figure imgf000028_0002
S Enantiomer
NMR (DMSO) results: Example 5: (S)-N-benzyl-N-chroman-4-yl-N,N-dimethylethane-l,2-diamine, 1.80-1.97 (m,
2H), 2.10 (s, 3H), 2.16 (s, 3H), 2.42-2.59 (m, 4H), 3.46 (s, 2H), 3.91-4.1 1 (m, 2H), 4.23-4.34
(m, IH), 6.67-6.73 (m, IH), 6.80-6.87 (m, IH), 7.02-7.13 (m, IH), 7.19-7.35 (m, 5H), 7.40-
7.45 (m, IH).
Example 6: (S)-chroman-4-yl-[2-(3,4-dihydro-lH-isoquinolin-2-yl)ethyl]methylamine, 1.82- 2.01 (m, 2Η), 2.23 (s, 3H), 2.52-2.83 (m, 8H), 3.54 (s, 2H), 3.93-4.12 (m, 2H), 4.25-4.35 (m,
IH), 6.71 (d, IH), 6.80-6.90 (m, IH), 6.95-7.14 (m, 5H), 7.46 (d, IH).
Example 7: (S)-chroman-4-ylmethyl-(2-pyrrolidin-l-ylethyl)amine, 1.56-1.68 (m, 4H), 1.80-
2.00 (m, 2H), 2.19 (s, 3H), 2.31-2.60 (m, 8H), 3.91-4.11 (m, 2H), 4.23-4.35 (s, IH), 6.68 (d,
IH), 6.80-6.91 (m, IH), 7.02-7.15 (m, IH), 7.44 (d, IH). Example 8: (S)-(2-azeρan-l-ylethyl)chroman-4-ylamine, 1.46-1.63 (m, 8H), 1.83-2.00 (m,
3H), 2.48-2.79 (m, 8H), 3.63-3.72 (m, IH), 4.07-4.28 (m, 2H), 6.73 (d, IH), 6.79-6.89 (m,
IH), 7.06-7.16 (m, IH), 7.22 (d, IH). Example 9: (S)-N-benzyl-N-chroman-4-yl-N-methylethane-l,2-diamine, 1.84-1.94 (m, 3H), 2.13 (s, 3H), 2.42-2.55 (m, 2H), 2.63-2.85 (m, 2H), 3.40-3.56 (m, 2H), 3.63-3.72 (m, IH), 4.07-4.30 (m, 2H), 6.73 (d, IH), 6.80-6.87 (m, IH), 7.06-7.17 (m, IH), 7.19-7.37 (m, 6H). Example 10: (S)-chroman-4-yl-[2-(3,4-dihydro-lH-isoquinolin-2-yl)ethyl]amine, 1.81-2.12 (m, 3Η), 2.53-2.92 (m, 8H), 3.57 (s, 2H), 3.68-3.78 (m, IH), 4.07-4.29 (m, 2H), 6.72 (d, IH), 6.77-6.85 (m, IH), 7.00-7.17 (m, 5H), 7.24 (d, IH). Example 11 N-chroman-4-yl-NN.N-trimethylpropane-1.3-diamine
4-Chlorochroman (Method A) (0.430 g, 2.30 x 10"3 mole) and Ν,Ν,Ν'-trimethyl-l,3- propanediamine (0.710 g, 6.11 x 10"3 mole) were combined in acetonitrile (25 mL) and heated at 50 °C for 22 hours. The reaction mixture was evaporated and partitioned between 1M sodium hydroxide and diethyl ether. The aqueous portion was extracted with additional diethyl ether. The combined organic portion were washed (water, brine), dried, and evaporated to a yellow oil which was purified by chromatography, eluting with 1% NH4OH: 10% MeOH:89% DCM (v/v/v), to give the product as a colourless oil (0.314 g, 55%). NMR: 1.47-1.65 (m, 2H), 1.82-1.96 (m, 2H), 2.08 (s, 6H), 2.13 (s, 3H), 2.13-2.49 (m, 4H), 3.94 (t, IH), 4.00-4.13 (m, IH), 4.23-4.44 (m, IH), 6.68 (d, IH), 6.83 (t, IH), 7.05 (t, IH), 7.40 (d, IH). Examples 12-20 Using an analogous procedure to that described in Examples 1 or 2, the following compounds were prepared.
Figure imgf000030_0001
Figure imgf000030_0002
NMR results: Example 12: N'-chroman-4-yl-N-methyl-N-phenylpropane-l,3-diamine, 1.58-1.75 (m, 2H), 1.80-2.00 (m, 3H), 2.45-2.77 (m, 2H), 2.86 (s, 3H), 3.27-3.50 (m, 2H), 3.65 (s, IH), 4.07-4.30 (m, 2H), 6.57 (t, IH), 6.64-6.77 (m, 3H), 6.83 (t, IH), 7.05-7.20 (m, 3H), 7.26-7.33 (m, IH). Example 13: N'-chroman-4-yl-N,N-dimethylethane-l,2-diamine, 1.70-2.00 (m, 3H), 2.14 (s, 6H), 2.33 (t, 2H), 2.55-2.78 (m, 2H), 3.68 (t, IH), 4.06-4.30 (m, 2H), 6.67-6.90 (m, 2H), 7.04- 7.27 (m, 2H).
Example 14: chroman-4-yl-(2-mo holin-4-ylethyl)amine, 1.75-1.95 (m, 3H), 2.27-2.47 (m, 6H), 2.60-2.81 (m, 2H), 3.56 (t, 4H), 3.69 (t, IH), 4.07-4.30 (m, 2H), 6.73 (d, IH), 6.84 (t, lH), 7.11 (t, IH), 7.25 (d, IH). Example 15: chroman-4-yl-(3-morpholin-4-ylpropyl)amine, 1.47-1.68 (m, 2H), 1.82-2.00 (m, 3H), 2.23-2.43 (m, 6H), 2.50-2.76 (m, 2H), 3.54 (t, 4H), 3.66 (t, IH), 4.06-4.30 (m, 2H), 6.72 (d, IH), 6.83 (t, IH), 7.10 (t, IH), 7.27 (d, IH).
Example 16: N-benzyl-N-chroman-4-ylethane-l,2-diamine, 1.83-1.91 (m, 2H), 1.94-2.20 (m, 2H), 2.52-2.90 (m, 4H), 3.61-3.73 (m, 3H), 4.06-4.30 (m, 2H), 6.72 (d, IH), 6.83 (t, IH), 7.10 (t, lH), 7.17-7.40 (m, 6H).
Example 17: chroman-4-yl-(3-piperidin-l-ylpropyl)amine, 1.23-1.67 (m, 8H), 1.80-2.02 (m, 3H), 2.17-2.40 (m, 6H), 2.50-2.73 (m, 2H), 3.65 (t, IH), 4.07-4.32 (m, 2H), 6.71 (d, IH), 7.09 (t, IH), 7.26 (d, IH). Example 18: chroman-4-yl-(3-pyrrolidin-l-ylpropyl)amine, 1.51-2.00 (m, 10H), 2.30-2.80 (m, 7H), 3.62-3.72 (m, IH), 4.07-4.32 (m, 2H), 6.71 (d, IH), 6.83 (t, IH), 7.10 (t, IH), 7.26 (d, IH).
Example 19: chroman-4-yl-(2-pyrrolidin-l-ylethyl)amine, 1.60-1.77 (m, 4H), 1.80-2.00 (m, 3H), 2.34-2.57 (m, 6H), 2.60-2.82 (m, 2H), 3.69 (t, IH), 4.07-4.31 (m, 2H), 6.72 (d, IH), 6.84 (t, IH), 7.11 (t, IH), 7.24 (d, IH).
Example 20: N-chroman-4-yl-N,N-dimethylethane-l,2-diamine, 1.82-2.00 (m, 2H), 2.10 (s, 6H), 2.16 (s, 3H), 2.23-2.56 (m, 4H), 3.90-4.12 (m, 2H), 4.24-4.37 (m, IH), 6.68 (d, IH), 6.83 (t, IH), 7.08 (t, IH), 7.43 (d, IH). Example 21 Chroman-4-yl-(N-methyl-2-piperidin- 1 -ylethvDamine bismaleate salt
A solution of chroman-4-yl-(N-methyl-2-piperidin-l-ylethyl)amine (Example 2) (0.170 g, 6.19 x 10"4 mole) in diethyl ether (20 mL) was treated with a solution of maleic acid (0.177 g, 1.52 x 10"3 mole) in diethyl ether (20 mL). The salt form immediately precipitated, adhering to the sides of the flask as a gum. After solidification upon standing overnight, the material was scraped from the sides of the flask, broken up, and collected by vacuum filtration. The solid was vacuum dried at 50 °C for 24 hours to give the salt as a white solid (0.277 g, 88%). ΝMR: 1.47-1.60 (m, 2H), 1.66-1.84 (m, 4H), 1.91-2.02 (m, 2H), 2.18 (s, 3H), 2.65-2.90 (m, 2H), 3.05-3.34 (m, 6H), 4.00-4.13 (m, 2H), 4.25-4.35 (m, IH), 6.14 (s, 4H), 6.75 (d, IH), 6.89 (t, IH), 7.13 (t, IH), 7.46 (d, IH). m/s: 275. Example 22
4-r3-(N.N-Dimethylamino)propyi N-methyl)amino1chroman dihvdrochloride 4-[3-(N,N-Dimethylamino)propyl(N-methyl)amino]chroman (0.314 g, 1.26 x 10"3 mole) was dissolved in diethyl ether and treated with an excess of ethereal hydrochloric acid solution. The resulting solid was collected by vacuum filtration under a cloud of nitrogen and vacuum dried at ambient temperature for 20 hours to give the salt as a white solid (0.287 g, 71%). ΝMR: 2.08-2.48 (m, 4H), 2.62-3.01 (m, 10H), 3.08-3.40 (m, 3H), 4.11-4.20 (m, IH), 4.32-4.48 (m, IH), 4.75-4.88 (m, 0.5H), 4.92-5.05 (m, 0.5H), 6.90 (d, IH), 7.00 (t, IH), 7.25- 7.39 (m, IH), 7.94-8.08 (m, IH), 10.51-10.80 (m, IH), 10.92-11.23 (m, IH). m/s: 249. Examples 23-25
Using the procedure of Example 21, salts of the Examples were prepared. The following salts are provided by way of illustration.
Figure imgf000032_0001
Bismaleate
Figure imgf000032_0002
ΝMR results:
Example 23: 2.00-2.20 (m, 2H), 3.02-3.24 (m, 5H), 4.09-4.33 (m, 6H), 6.09 (s, 4H), 6.83 (d, IH), 6.94 (t, IH), 7.24 (t, IH), 7.35-7.58 (m, 6H).
Example 24: 1.80-2.30 (m, 8H), 2.89-3.60 (m, 9H, H2O), 4.27 (t, 2H), 4.42 (s, IH), 6.04 (s,
4H), 6.89 (d, IH), 6.99 (t, IH), 7.31 (t, IH), 7.42 (d, IH).
Example 25: 1.85-2.02 (m, 7H), 2.16 (s, 3H), 2.65-2.87 (m, 2H), 3.15-3.43 (m, 5H, H2O),
4.00-4.13 (m, 2H), 4.25-4.37 (m, IH), 6.15 (s, 4H), 6.74 (d, IH), 6.90 (t, IH), 7.13 (t, IH), 7.56 (d, IH).
Example 26
(S)-2- Benzylmethylamino)-Ν-chroman-4-ylacetamide
The white solid from Method C (see below) (1.01 g, 4.48 x 10"3 mole) and N- benzylmethylamine (1.46 g, 1.20 x 10"2 mole) were combined in acetonitrile (29 mL) and refluxed for two hours. The reaction mixture was partitioned between water and ethyl acetate. The aqueous portion was extracted with additional ethyl acetate. The combined extracts were washed (water, brine), dried, and evaporated to yield a residue which was purified by chromatography, eluting with 3% 2.0 M ammonia in methanol: 97% DCM (v/v), to give the title compound as an off-white solid (1.25 g, 90%). Η NMR (DMSO): 1.88-2.08 (m, 2H), 2.20 (s, 3H), 3.05 (s, 2H), 3.59 (s, 2H), 4.13-4.25 (m, 2H), 5.00-5.11 (m, IH), 6.78 (d, IH), 6.82-6.91 (m, IH), 7.07-7.37 (m, 7H), 8.18 (d, IH). m s: 311. Examples 27-31
Using an analogous procedure to that described in Example 26, the following compounds were prepared.
Figure imgf000033_0001
Figure imgf000033_0002
1 S Enantiomer SM - Starting Material, MB - Method B, MC - Method C NMR (DMSO) results: Example 27: (-S)-2-(benzylmethylamino)-N-chroman-4-yl-N-methylacetamide, 1.81-2.29 (m, 5H), 2.46 (s, 1.3H), 2.70 (s, 1.7H), 3.23-3.43 (m, 2H), 3.46-3.72 (m, 2H), 4.00-4.38 (m, 2H), 5.35-5.44 (m, 0.4H), 5.76-5.86 (m, 0.6H), 6.74-6.96 (m, 3H), 7.08-7.40 (m, 6H). Example 28: (S)-N-chroman-4-yl-2-(3 ,4-dihydro- 1 H-isoquinolin-2-yl)-N-methylacetamide, 1.84-2.20 (m, 2Η), 2.59-2.97 (m, 6H), 3.26-3.80 (m, 5H), 4.07-4.37 (m, 2H), 5.51-5.61 (m, 0.5H), 5.80-5.89 (m, 0.5H), 6.73-7.20 (m, 8H).
Example 29: (S)-N-chroman-4-yl-N-methyl-2-pyrrolidin-l-ylacetamide, 1.61-1.78 (m, 4H), 1.82-2.20 (m, 2H), 2.40-2.64 (m, 5.2H), 2.70 (s, 1.8H), 3.27-3.48 (m, 2H), 4.08-4.37 (m, 2H), 5.43-5.53 (m, 0.4H), 5.74-5.84 (m, 0.6H), 6.75-6.98 (m, 3H), 7.08-7.19 (m, IH). Example 30: (5)-2-azepan-l-yl-N-chroman-4-ylacetamide, 1.43-1.65 (m, 8H), 1.87-2.11 (m, 2H), 2.57-2.70 (m, 4H), 3.12 (s, 2H), 4.1 1-4.26 (m, 2H), 4.97-5.09 (m, IH), 6.77 (d, IH), 6.80-6.93 (m, IH), 7.07-7.20 (m, 2H), 8.00 (d, IH). Example 31 : (S)-N-chroman-4-yl-2-(3 ,4-dihydro- lH-isoquinolin-2-yl)acetamide, 1.90-2.09 (m, 2Η), 2.70-2.93 (m, 4H), 3.13-3.24 (m, 2H), 3.67 (s, 2H), 4.13-4.25 (m, 2H), 5.02-5.13 (m, 1H),6.75 (d, IH), 6.82-6.92 (m, IH), 7.00-7.20 (m, 6H), 8.21 (d, IH). Reference Example 1
By the procedure of Example 1 the following compound was prepared:
Figure imgf000034_0001
ΝMR results: 0.94 (t, 6H), 1.73-2.00 ( m, 3H), 2.30-2.80 (m, 8H), 3.68 (t, IH), 4.05-4.33 (m,
2H), 6.73 (d, IH), 6.84 (t, IH), 7.10 (t, IH), 7.23 (d, IH); m s: 249.
Preparation of Starting Materials
The starting materials for the Examples above are either commercially available or are readily prepared by standard methods from known materials. For example the following reactions are illustrations but not limitations of the preparation of the starting materials used in the above reactions.
Method A
4-Chlorochroman 4-Chromanol (0.578 g, 3.85 x 10"3 mole) was treated with thionyl chloride (2.0 mL,
2.74 x 10"2 mole) at ambient temperature. After stirring for 48 hours, the reaction mixture was evaporated. The residue was partially purified by chromatography, eluting with 9:1 hexane:ethyl acetate (v/v) to give the title compound as a tan oil (0.430 g, 66%). Method B fS)-4-|"N-Methyl-2-chloroacetamidolthiochroman
(S)-N-Methyl-4-aminochroman (3.33 g, 2.04 x 102 mole) and 2,6-lutidine (3.6 mL, 3.09 x 10"2 mole) were combined in DCM (45 mL) and cooled to 0 °C (ice/water/sodium chloride). Chloroacetyl chloride (2.0 mL, 2.51 x 10"2 mole) was added dropwise, maintaining the reaction temperature at <10 °C. Upon complete addition, the mixture was stirred cold for one hour. The reaction mixture was partitioned between IN aqueous hydrochloric acid and DCM. The organic portion was washed with additional IN aqueous hydrochloric acid. The combined aqueous portions were extracted with DCM. The combined organic portions were washed (saturated aqueous sodium bicarbonate, water, brine), dried, and evaporated to a yellow oil which was purified by chromatography, eluting with 1 : 1 hexane/ethyl acetate (v/v), to give a yellow oil (4.84 g, 99%). Η ΝMR (DMSO): 1.85-2.20 (m, 2H), 2.46-2.55 (m, IH), 2.69 (s, 2H), 4.13-4.39 (m, 2H), 4.43-4.64 (m, 2H), 5.23-5.33 (m, 0.3H), 5.72-5.83 (m, 0.7H), 6.76-7.04 (m, 3H), 7.10-7.22(m, IH). m/s: 240. Method C
(--0-4-[2-Chloroacetamido]thiochroman
(S)-4-Aminochroman (3.42 g, 2.29 x 10"2 mole) and 2,6-lutidine (4.0 mL, 3.43 x 10"2 mole) were combined in DCM (48 mL) and cooled to 0 °C (ice/water/sodium chloride). Chloroacetyl chloride (2.0 mL, 2.51 x 10"2 mole) was added dropwise, maintaining the reaction temperature at <5 °C. Upon complete addition, the mixture was stirred cold for one hour. The reaction mixture was partitioned between 1 Ν aqueous hydrochloric acid and DCM. The organic portion was washed with additional IN aqueous hydrochloric acid. The combined aqueous portions were extracted with DCM. The combined organic portions were washed (saturated aqueous sodium bicarbonate, water, brine), dried, and evaporated to a solid. The solid was triturated (hexane), collected, and dried to give a white solid (4.86 g, 94%). Η ΝMR (DMSO): 1.82-2.12 (m, 2H), 4.02-4.27 (m, 4H), 4.93-5.04 (m, IH), 6.79 (d, IH), 6.84- 6.95 (m, IH), 7.09-7.23 (m, 2H), 8.74 (d, IH). Example 32
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 me/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

CLAIMS:
1. A method of treating neurological disorders comprising administration of a therapeutically-effective amount of any compound according to formula (I):
Figure imgf000037_0001
wherein:
R1 is hydrogen, C,.6alkyl, C2_6alkenyl or C2-6alkynyl;
R2 and R3 are independently selected from hydrogen, C,-6alkyl, C2.6alkenyl, C2. 6alkynyl, aryl, a carbon linked heteroaryl, a carbon-linked heterocycle, C3.12cycloalkyl and C3- I2cycloalkyl fused to a benzene ring, wherein said C,_6alkyl, C2.6alkenyl and C2.6alkynyl are optionally substituted with one or more groups selected from halo, nitro, hydroxy, C,.6alkoxy, cyano, amino, trifluoromethyl, trifluoromethoxy, carboxy, carbamoyl, mercapto, sulphamoyl, mesyl, N-C,.6alkylamino, N,N-(C,.6alkyl)2amino, C,.6alkoxycarbonyl, N-C,.6alkylcarbamoyl, N,N-(C,.6alkyl)2carbamoyl, aryl, a carbon linked heteroaryl, a carbon-linked heterocycle, C3. 12cycloalkyl and C3.12cycloalkyl fused to a benzene ring; and wherein any aryl, heteroaryl, heterocycle, C3.12cycloalkyl and C3.12cycloalkyl fused to a benzene ring may be optionally substituted on a ring carbon with one or more groups selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C,.6alkyl, C2.6alkenyl, C2.6alkynyl, C,.6alkoxy, C,.6alkanoyl, C,.6alkanoyloxy, N- (C,_6alkyl)amino, N,N-(C,.6alkyl)2amino, C,.6alkanoylamino, N-(C,.6alkyl)carbamoyl, N,N-(C,. 6alkyl)2carbamoyl, C,.6alkylS(O)a wherein a is 0, 1 or 2, C,.6alkoxycarbonyl, N-(C,_ 6alkyl)sulphamoyl, N.N-(C,.6alkyl)2sulphamoyl and phenylC,.6alkyl; and a heterocycle or a heteroaryl ring containing an -ΝH- group may be optionally substituted on this nitrogen with C,.6alkyl, C2.6alkenyl, C2.6alkynyl, C,.6alkanoyl, C,.6alkylsulphonyl or phenylC,.6alkyl; or R2 and R3 and the nitrogen atom to which they are attached in combination form a heterocyclic or heteroaryl ring and wherein said heterocyclic or heteroaryl ring is optionally substituted on a ring carbon with one or more groups selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C,.6alkyl, C2.6alkenyl, C2.6alkynyl, C,.6alkoxy, C,.6alkanoyl, C,.6alkanoyloxy, N- (C,.6alkyl)amino, N,N-(C,.6alkyl)2amino, C,.6alkanoylamino, N-(Cι.6alkyl)carbamoyl, N,N-(C,. 6alkyl)2carbamoyl, C,.6alkylS(O)a wherein a is 0, 1 or 2, C,.6alkoxycarbonyl, N-(C,.
6alkyl)sulphamoyl, N,N-(C,.6alkyl)2sulphamoyl or phenylC,.6alkyl; and a heterocyclic or a heteroaryl ring containing an -ΝH- group is optionally substituted on this nitrogen with C,. 6alkyl, C2.6alkenyl, C2-6alkynyl, C,.6alkanoyl or C,.6alkylsulphonyl;
R4 at each occurrence is selected from halo, hydroxy, C,-6alkyl, C,.6alkoxy, haloC,. 6alkyl, cyano, nitro or C2.6alkenyl;
R5 is C,.6alkyl; n is 1 or 2; r is 0, 1, 2, 3 or 4, wherein at each occurrence the value of R4 may be the same or different; and s is 0, 1, 2 or 3 wherein at each occurrence the value of R5 may be the same or different; or a pharmaceutically-acceptable salt or an in vzvo-hydrolysable ester, amide or carbamate thereof.
2. The method according to Claim 1 , for treating stroke, head trauma, transient cerebral ischaemic attack, and chronic neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, diabetic neuropathy, amyotrophic lateral sclerosis, multiple sclerosis and AIDS-related dementia.
3. The method according to Claim 1, for treating neurological disorders treatable by inhibition of the the [3H]-emopamil binding site.
4. A pharmaceutical composition comprising any compound according to formula (I), or a in vzvo-hydrolysable ester, amide or carbamate thereof, together with a pharmaceutically- acceptable carrier, wherein, in a compound of formula (I):
Figure imgf000039_0001
R1 is hydrogen, C,.6alkyl, C2.6alkenyl or C2.6alkynyl;
R2 and R3 are independently selected from hydrogen, C,.6alkyl, C2.6alkenyl, C2. 6alkynyl, aryl, a carbon linked heteroaryl, a carbon-linked heterocycle, C3.12cycloalkyl and C3. 12cycloalkyl fused to a benzene ring, wherein said C,.6alkyl, C2.6alkenyl and C2.6alkynyl are optionally substituted with one or more groups selected from halo, nitro, hydroxy, C,.6alkoxy, cyano, amino, trifluoromethyl, trifluoromethoxy, carboxy, carbamoyl, mercapto, sulphamoyl, mesyl, N-C,.6alkylamino, N,N-(C,.6alkyl)2amino, C,.6alkoxycarbonyl, N-C,.6alkylcarbamoyl, N,N-(C,.6alkyl)2carbamoyl, aryl, a carbon linked heteroaryl, a carbon-linked heterocycle, C3. 12cycloalkyl and C3.12cycloalkyl fused to a benzene ring; and wherein any aryl, heteroaryl, heterocycle, C3.12cycloalkyl and C3.12cycloalkyl fused to a benzene ring may be optionally substituted on a ring carbon with one or more groups selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C,.6alkyl, C2-6alkenyl, C2.6alkynyl, C,.6alkoxy, C,.6alkanoyl, C,.6alkanoyloxy, N- (C,-6alkyl)amino, N,N-(C,.6alkyl)2amino, Cι_6alkanoylamino, N-(C,.6alkyl)carbamoyl, N,N-(C,. 6alkyl)2carbamoyl, C,.6alkylS(O)a wherein a is 0, 1 or 2, C,.6alkoxycarbonyl, N-(C,. 6alkyl)sulphamoyl, N,N-(C,.6alkyl)2sulphamoyl and phenylC,.6alkyl; and a heterocycle or a heteroaryl ring containing an -ΝH- group may be optionally substituted on this nitrogen with C,-6alkyl, C2-6alkenyl, C2.6alkynyl, C,.6alkanoyl, C,.6alkylsulphonyl or phenylC,.6alkyl; or R2 and R3 and the nitrogen atom to which they are attached in combination form a heterocyclic or heteroaryl ring and wherein said heterocyclic or heteroaryl ring is optionally substituted on a ring carbon with one or more groups selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C,.6alkyl, C2.6alkenyl, C2.6alkynyl, C,.6alkoxy, C,-6alkanoyl, Cι.6alkanoyloxy, N- (C,-6alkyl)amino, N.N- C^alkyl^amino, C^alkanoylamino, N-(C,.6alkyl)carbamoyl, N,N-(C,. 6alkyl)2carbamoyl, C,.6alkylS(O)a wherein a is 0, 1 or 2, C,.6alkoxycarbonyl, N-(C,. 6alkyl)sulphamoyl, N,N-(C].6alkyl)2sulphamoyl or phenylC,.6alkyl; and a heterocyclic or a heteroaryl ring containing an -ΝH- group is optionally substituted on this nitrogen with C,. 6alkyl, C2.6alkenyl, C2.6alkynyl, C,.6alkanoyl or C,.6alkylsulphonyl;
R4 at each occurrence is selected from halo, hydroxy, C,.6alkyl, C,.6alkoxy, haloC,. 6alkyl, cyano, nitro or C2.6alkenyl;
R5 is C,.6alkyl; n is 1 or 2; r is 0, 1, 2, 3 or 4, wherein at each occurrence the value of R4 may be the same or different; and s is 0, 1, 2 or 3 wherein at each occurrence the value of R5 may be the same or different; or a pharmaceutically-acceptable salt thereof.
5. A pharmaceutical composition according to Claim 4, comprising any compound in accord with formula (I), wherein:
R1 is hydrogen or C,.6alkyl;
R2 and R3 are independently selected from hydrogen, aryl and C,.6alkyl optionally substituted with aryl; or R2 and R3 and the nitrogen atom to which they are attached in combination form a heterocyclic ring; r is O; s is 0; n is 1 or 2.
6. A pharmaceutical composition according to Claim 6, comprising any compound in accord with formula (I), wherein: R1 is hydrogen or methyl;
R2 and R3 are independently selected from methyl, ethyl or benzyl, or R2 and R3 and the nitrogen atom to which they are attached in combination form a ring selected from pyrrolidin-1-yl, piperidin-1-yl and morpholino.
7. A pharmaceutical composition according to Claim 6, comprising any compound in accord with formula (I), wherein:
R2 and R3 are independently selected from methyl or benzyl, or R2 and R3 and the nitrogen atom to which they are attached in combination form a ring selected from pyrrolidin- 1 -yl and piperidin- 1 -yl.
8. Any compound according to formula (I):
Figure imgf000041_0001
wherein:
R1 is hydrogen, C,.6alkyl, C2.6alkenyl or C2.6alkynyl;
R2 and R3 are independently selected from hydrogen, C,.6alkyl, C2.6alkenyl, C2_ 6alkynyl, aryl, a carbon linked heteroaryl, a carbon-linked heterocycle, C3.12cycloalkyl and C3_ I2cycloalkyl fused to a benzene ring, wherein said C,.6alkyl, C2.6alkenyl and C2.6alkynyl are optionally substituted with one or more groups selected from halo, nitro, hydroxy, C,.6alkoxy, cyano, amino, trifluoromethyl, trifluoromethoxy, carboxy, carbamoyl, mercapto, sulphamoyl, mesyl, N-C,.6alkylamino, N,N-(C,.6alkyl)2amino, C,.6alkoxycarbonyl, N-C,.6alkylcarbamoyl, N,N-(C,.6alkyl)2carbamoyl, aryl, a carbon linked heteroaryl, a carbon-linked heterocycle, C3. l2cycloalkyl and C3.12cycloalkyl fused to a benzene ring; and wherein any aryl, heteroaryl, heterocycle, C3.]2cycloalkyl and C3.12cycloalkyl fused to a benzene ring may be optionally substituted on a ring carbon with one or more groups selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C,.6alkyl, C2.6alkenyl, C2.6alkynyl, C,.6alkoxy, C,.6alkanoyl, C,-6alkanoyloxy, N- (C,-6alkyl)amino, N^N^C^a-kyl^-u no, C,.6alkanoylamino, N-(C,.6alkyl)carbamoyl, N,N-(C,_ 6alkyl)2carbamoyl, C,.6alkylS(O)a wherein a is 0, 1 or 2, C,.6alkoxycarbonyl, N-(C,.
6alkyl)sulphamoyl, N,N-(C,.6alkyl)2sulphamoyl and phenylC,-6alkyl; and a heterocycle or a heteroaryl ring containing an -NH- group may be optionally substituted on this nitrogen with C,_6alkyl, C2-6alkenyl, C2.6alkynyl, C,.6alkanoyl, C]-6alkylsulphonyl or phenylC,.6alkyl; or R2 and R3 and the nitrogen atom to which they are attached in combination form a heterocyclic or heteroaryl ring and wherein said heterocyclic or heteroaryl ring is optionally substituted on a ring carbon with one or more groups selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C,.6alkyl, C2.6alkenyl, C2.6alkynyl, C,.6alkoxy, C,.6alkanoyl, C,.6alkanoyloxy, N- (C,.6alkyl)amino, N-N-(C,-6alkyl)2amino, C,.6alkanoylamino, N-(C,.6alkyl)carbamoyl, N.N-(C,_ 6alkyl)2carbamoyl, C,.6alkylS(O)a wherein a is 0, 1 or 2, C,.6alkoxycarbonyl, N-(C,. 6alkyl)sulphamoyl, N,N-(C,.6alkyl)2sulphamoyl or phenylC,.6alkyl; and a heterocyclic or a heteroaryl ring containing an -ΝH- group is optionally substituted on this nitrogen with C,. 6alkyl, C2.6alkenyl, C2.5alkynyl, C,.6alkanoyl or Cj.6alkylsulphonyl;
R4 at each occurrence is selected from halo, hydroxy, C,.6alkyl, C,.6alkoxy, haloC,. 6alkyl, cyano, nitro or C2.6alkenyl; R5 is C,.6alkyl; n is 1 or 2; r is 0, 1, 2, 3 or 4, wherein at each occurrence the value of R4 may be the same or different; and s is 0, 1, 2 or 3 wherein at each occurrence the value of R5 may be the same or different; or a pharmaceutically-acceptable salt or an in vzvo-hydrolysable ester, amide or carbamate thereof; with a proviso wherein in such compounds: if r is 1, R4 is a 6-linked cyano moiety, s is 2 and both R5 moieties are 2-linked methyl, n is 1, and R' and R2 are both H, then R3 is not phenyl or benzyl; if r and s are both 0, R1 is H and n is 2, then R1 and R2 are not both ethyl or not both H, or if r and s are both 0, R1 is H and n is 1, then R1 and R2 are not both ethyl.
9. A compound according to Claim 8, wherein: R1 is hydrogen or C,.6alkyl;
R2 and R3 are independently selected from hydrogen, aryl and C,.6alkyl optionally substituted with aryl; or R2 and R3 and the nitrogen atom to which they are attached in combination form a heterocyclic ring; r is 0; s is 0; n is 1 or 2; or a pharmaceutically-acceptable salt or an in vzvo-hydrolysable ester, amide or carbamate thereof.
10. A compound according to Claim 9, wherein: R1 is hydrogen or methyl;
R2 and R3 are independently selected from methyl, ethyl or benzyl, or R2 and R3 and the nitrogen atom to which they are attached in combination form a ring selected from pyrrolidin-1-yl, piperidin-1-yl and morpholino; or a pharmaceutically-acceptable salt or an in vzvo-hydrolysable ester, amide or carbamate thereof.
11 A compound according to Claim 10, wherein:
R2 and R3 are independently selected from methyl or benzyl, or R2 and R3 and the nitrogen atom to which they are attached in combination form a ring selected from pyrrolidin-1-yl and piperidin-1-yl; or a pharmaceutically-acceptable salt or and in vzvo-hydrolysable ester, amide or carbamate thereof.
12. A compound according to Claim 8, selected from: chroman-4-yl-(2-piperidin- 1 -ylethyl)amine; chroman-4-yl-(N-methyl-2-piperidin- 1 -ylethyl)amine;
(S)-chroman-4-yl-[2-(l,3-dihydroisoindol-2-yl)ethyl]amine;
(S)-chroman-4-yl-[2-(l,3-dihydroisoindol-2-yl)ethyl]methylamine
(S)-N-benzyl-N-chroman-4-yl-N,N-dimethyle thane- 1 ,2-diamine; (-S)-chroman-4-yl-[2-(3,4-dihydro-lH-isoquinolin-2-yl)ethyl]methylamine;
(S)-chroman-4-ylmethyl-(2-pyrrolidin- 1 -ylethyl)amine; (S)-(2-azepan- 1 -ylethyl)chroman-4-ylamine;
(S)-N-benzyl-N-chroman-4-yl-N-methylethane- 1 ,2-diamine;
(S)-chroman-4-yl-[2-(3,4-dihydro-lH-isoquinolin-2-yl)ethyl]amine;
N-chroman-4-yl-N, N' N -trimethylpropane- 1 ,3 -diamine; N'-chroman-4-yl-N-methyl-N-phenylpropane- 1 ,3-diamine;
N'-chroman-4-yl-N, N-dimethylethane- 1 ,2-diamine; chroman-4-yl-(2-mo holin-4-ylethyl)amine; chroman-4-yl-(3-moφholin-4-ylpropyl)amine;
N-benzyl-N-chroman-4-ylethane- 1 ,2-diamine; chroman-4-yl-(3-piperidin-l -ylpropyl)amine; chroman-4-yl-(3-pyrrolidin-l-ylpropyl)amine; chroman-4-yl-(2-pyrrolidin- 1 -ylethyl)amine;
N-chroman-4-yl-N,N-dimethylethane- 1 ,2-diamine;
(S)-2-(benzylmethylamino)-N-chroman-4-ylacetamide; (S)-2-(benzylmethylamino)-N-chroman-4-yl-N-methylacetamide;
(S)-N-chroman-4-yl-2-(3,4-dihydro-lH-isoquinolin-2-yl)-N-methylacetamide;
(S)-N-chroman-4-yl-N-methyl-2-pyrrolidin- 1 -ylacetamide;
(S)-2-azepan-l -yl-N-chroman-4-ylacetamide, and
(S)-N-chroman-4-yl-2-(3,4-dihydro-lH-isoquinolin-2-yl)acetamide.
13. A method of making a compound of formula (I) according to Claim 8, wherein R1 ,
R2, R3, R\ R5, s, r and n unless otherwise defined are as defined in Claim 8, said method comprising: a) reacting a ketone of formula (II):
Figure imgf000044_0001
(II) with an amine of formula (III):
Figure imgf000045_0001
(in); wherein Rb and Rc are R2 and R3 respectively, unless the value of R2 and/or R3 is hydrogen, in which case the appropriate Rb and/or Rc is a suitable amino protecting group such as those defined below; or b) reacting an amine of formula (IV):
Figure imgf000045_0002
(IV) with an aldehyde of formula (V):
Figure imgf000045_0003
(V) wherein Rb and Rc are as defined above; or c) reacting an aldehyde of formula (VI):
Figure imgf000045_0004
with an amine of formula: R2
I HNS R3
(VII) wherein Ra is R1 unless the value of R1 is hydrogen, in which case Ra is a suitable amino protecting group such as those defined below; or d) if R1 is C,.6alkyl, reacting a compound of formula (VIII):
Figure imgf000046_0001
wherein R and Rc are as defined above, with a compound of formula (IX);
O
K^H (IX) wherein K is hydrogen or C,.5alkyl; or e) reacting a compound of formula (X):
Figure imgf000046_0002
(X) wherein L is a suitable displaceable group, with an amine of formula (III); or f) reacting an amine of formula (IV) with a compound of formula (XI):
Figure imgf000046_0003
(XI) wherein L is a suitable displaceable group and Rb and Rc are as defined above; or g) reacting a compound of formula (XII):
Figure imgf000047_0001
(XII) wherein L is a suitable displaceable group, with an amine of formula (VII); or h) if R1 is not hydrogen, reacting a compound of formula (VIII) with a compound of formula (XIII):
R'-L
(XIII) wherein L is a suitable displaceable group; or i) reducing a compound of formula (XIV):
Figure imgf000047_0002
or j) reducing a compound of formula (XV):
Figure imgf000048_0001
or k) if R1 is not hydrogen, reducing a compound of formula (XVI):
Figure imgf000048_0002
where: for preparing a compound wherein R is methyl, G is a suitable displaceable group; or for preparing a compound wherein R1 is C2.6alkyl, G is C,.5alkyl; and thereafter if necessary: converting a compound of the formula (I) into another compound of the formula (I); removing any protecting groups; or forming a pharmaceutically-acceptable salt or in vzvo-hydrolysable ester, amide or carbamate.
PCT/GB2000/002304 1999-06-17 2000-06-14 Chroman derivatives against neurological disorders WO2000078742A1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU54141/00A AU5414100A (en) 1999-06-17 2000-06-14 Chroman derivatives against neurological disorders
JP2001504908A JP2003502415A (en) 1999-06-17 2000-06-14 Chromane derivatives for neurological disorders
EP00938917A EP1192146A1 (en) 1999-06-17 2000-06-14 Chroman derivatives resisting neurological disorders

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9914025.3A GB9914025D0 (en) 1999-06-17 1999-06-17 Chemical compounds
GB9914025.3 1999-06-17

Publications (1)

Publication Number Publication Date
WO2000078742A1 true WO2000078742A1 (en) 2000-12-28

Family

ID=10855475

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2000/002304 WO2000078742A1 (en) 1999-06-17 2000-06-14 Chroman derivatives against neurological disorders

Country Status (5)

Country Link
EP (1) EP1192146A1 (en)
JP (1) JP2003502415A (en)
AU (1) AU5414100A (en)
GB (1) GB9914025D0 (en)
WO (1) WO2000078742A1 (en)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001068609A1 (en) * 2000-03-14 2001-09-20 Actelion Pharmaceuticals Ltd. 1,2,3,4-tetrahydroisoquinoline derivatives
US7763638B2 (en) 2004-03-01 2010-07-27 Actelion Pharmaceuticals Ltd. Substituted 1,2,3,4-tetrahydroisoquinoline derivatives
WO2018023070A1 (en) * 2016-07-29 2018-02-01 Sunovion Pharmaceuticals, Inc. Compounds and compositions and uses thereof
US10196403B2 (en) 2016-07-29 2019-02-05 Sunovion Pharmaceuticals Inc. Compounds and compositions and uses thereof
US10780074B2 (en) 2017-08-02 2020-09-22 Sunovion Pharmaceuticals Inc. Compounds and uses thereof
US11136304B2 (en) 2019-03-14 2021-10-05 Sunovion Pharmaceuticals Inc. Salts of a heterocyclic compound and crystalline forms, processes for preparing, therapeutic uses, and pharmaceutical compositions thereof

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3067399B2 (en) * 1992-07-03 2000-07-17 株式会社日立製作所 Semiconductor cooling device

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0359537A1 (en) * 1988-09-16 1990-03-21 Beecham Group Plc Benzopyran derivatives with antihypertensive activity
FR2670780A1 (en) * 1990-12-20 1992-06-26 Synthelabo 4-(Acylamino)benzopyran derivatives, their preparation and their application in therapeutics
FR2687401A1 (en) * 1992-02-18 1993-08-20 Meram Lab 1,4-DIALKYLPIPERAZINE DERIVATIVES, OBTAINING METHODS AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME
EP0587180A2 (en) * 1992-09-11 1994-03-16 E.R. SQUIBB &amp; SONS, INC. Aryl urea (Thiourea) and cyanoguanidine derivatives
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
WO1999038863A1 (en) * 1998-01-29 1999-08-05 Astrazeneca Uk Limited 1,4-diazacycloheptane derivatives for the treatment of neurological disorders
WO2000040574A1 (en) * 1999-01-05 2000-07-13 Astrazeneca Ab 1,4-diazacycloheptane compounds, process for their preparation, and their use as medicaments

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0359537A1 (en) * 1988-09-16 1990-03-21 Beecham Group Plc Benzopyran derivatives with antihypertensive activity
FR2670780A1 (en) * 1990-12-20 1992-06-26 Synthelabo 4-(Acylamino)benzopyran derivatives, their preparation and their application in therapeutics
FR2687401A1 (en) * 1992-02-18 1993-08-20 Meram Lab 1,4-DIALKYLPIPERAZINE DERIVATIVES, OBTAINING METHODS AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME
EP0587180A2 (en) * 1992-09-11 1994-03-16 E.R. SQUIBB &amp; SONS, INC. Aryl urea (Thiourea) and cyanoguanidine derivatives
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
WO1999038863A1 (en) * 1998-01-29 1999-08-05 Astrazeneca Uk Limited 1,4-diazacycloheptane derivatives for the treatment of neurological disorders
WO2000040574A1 (en) * 1999-01-05 2000-07-13 Astrazeneca Ab 1,4-diazacycloheptane compounds, process for their preparation, and their use as medicaments

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 58, no. 13, 24 June 1963, Columbus, Ohio, US; abstract no. 13896g, ZAGOREVSKII V.A. ET AL: "Pyran series, its analogs and related compounds. I. 4-aminochroman derivatives" XP002152684 *
DING C.Z.: "Synthesis of 4-(N-alkyl-N- heteroaryl)amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile derivatives via an unusual 1,4-oxygen to nitrogen heteroaryl migration", TETRAHEDRON LETTERS., vol. 37, no. 26, 24 June 1996 (1996-06-24), ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM., NL, pages 4447 - 4450, XP002152683, ISSN: 0040-4039 *
EVANS J.M.: "Synthesis and antihypertensive activity of substituted trans-4-amino-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ols", JOURNAL OF MEDICINAL CHEMISTRY., vol. 26, no. 11, November 1983 (1983-11-01), AMERICAN CHEMICAL SOCIETY. WASHINGTON., US, pages 1582 - 1589, XP002152682, ISSN: 0022-2623 *
ZH. OBSHCH. KHIM., vol. 32, 1962, pages 3930 - 3934 *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001068609A1 (en) * 2000-03-14 2001-09-20 Actelion Pharmaceuticals Ltd. 1,2,3,4-tetrahydroisoquinoline derivatives
US6703392B2 (en) 2000-03-14 2004-03-09 Actelion Pharmaceuticals Ltd. 1,2,3,4-tetrahydroisoquinoline derivatives
US7763638B2 (en) 2004-03-01 2010-07-27 Actelion Pharmaceuticals Ltd. Substituted 1,2,3,4-tetrahydroisoquinoline derivatives
WO2018023070A1 (en) * 2016-07-29 2018-02-01 Sunovion Pharmaceuticals, Inc. Compounds and compositions and uses thereof
US10196403B2 (en) 2016-07-29 2019-02-05 Sunovion Pharmaceuticals Inc. Compounds and compositions and uses thereof
CN110087687A (en) * 2016-07-29 2019-08-02 赛诺维信制药公司 Compound, composition and application thereof
US10927124B2 (en) 2016-07-29 2021-02-23 Sunovion Pharmaceuticals Inc. Compounds and compositions and uses thereof
US11077090B2 (en) 2016-07-29 2021-08-03 Sunovion Pharmaceuticals Inc. Compounds and compositions and uses thereof
US11958862B2 (en) 2016-07-29 2024-04-16 Sumitomo Pharma America, Inc. Compounds and compositions and uses thereof
US10780074B2 (en) 2017-08-02 2020-09-22 Sunovion Pharmaceuticals Inc. Compounds and uses thereof
US11491133B2 (en) 2017-08-02 2022-11-08 Sunovion Pharmaceuticals Inc. Heteroaryl-isochroman compounds and uses thereof
US11136304B2 (en) 2019-03-14 2021-10-05 Sunovion Pharmaceuticals Inc. Salts of a heterocyclic compound and crystalline forms, processes for preparing, therapeutic uses, and pharmaceutical compositions thereof

Also Published As

Publication number Publication date
AU5414100A (en) 2001-01-09
EP1192146A1 (en) 2002-04-03
JP2003502415A (en) 2003-01-21
GB9914025D0 (en) 1999-08-18

Similar Documents

Publication Publication Date Title
TW380138B (en) Piperidine derivatives which are selective antagonists of the human NK3 receptor and their use as medicinal products
JP3534765B2 (en) Novel 4-piperidinyl-substituted lactams as neurokinin 2 receptor antagonists for the treatment of asthma
IE831730L (en) Quinoline derivatives
CS240954B2 (en) Preparation method of 1,2-dihydropyridines
CZ282919B6 (en) Novel n-alkylene piperidine derivatives, process of their preparation, intermediate for their preparation and pharmaceutical compositions containing such derivatives
CA2255727A1 (en) Pharmaceutical for treating of neurological and neuropsychiatric disorders
WO2000078742A1 (en) Chroman derivatives against neurological disorders
US6417183B1 (en) 1,4-diazacycloheptane derivatives
WO2000035882A1 (en) 1,2,3,4-tetrahydronaphthalenes and their pharmaceutical use
JP2022551156A (en) Homopiperazinyl and homopiperidinylquinazolin-4(3H)-one derivatives with diverse activities against pain
EP1192148A1 (en) Thiochroman derivatives resisting neurological disorders
SK13462001A3 (en) Novel morpholine derivatives, method for the production thereof and pharmaceutical preparations containing said derivatives
EP1192141A1 (en) 1,4-diazacycloheptane derivatives as neuroprotective agents
WO2000078718A1 (en) 4-aminopiperidine derivatives of tetrahydronaphthalene, chromans and thiochromans
EP1198463A2 (en) Compounds for use in treatment of neurological disorders
US6407093B1 (en) 1,4-Diazacycloheptane derivatives for the treatment of neurological disorders
EP1140863A1 (en) 1,4-diazacycloheptane derivatives useful in the treatment of neurological disorders
EP1140891A1 (en) 1,4-diazacycloheptane compounds, process for their preparation, and their use as medicaments
EP1140880A1 (en) Homopiperazine derivatives as selective emopamil inhibitors
WO2002051793A1 (en) Sterol isomerase inhibitors
MXPA00006078A (en) 1,4-diazacycloheptane derivatives

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY CA CH CN CR CU CZ DE DK DM DZ 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 MZ 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 document number: 2001 504908

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 2000938917

Country of ref document: EP

Ref document number: 10018901

Country of ref document: US

WWP Wipo information: published in national office

Ref document number: 2000938917

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: 2000938917

Country of ref document: EP

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载