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WO2000078742A1 - Derives du chromane utilises contre les troubles neurologiques - Google Patents

Derives du chromane utilises contre les troubles neurologiques Download PDF

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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
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Prior art keywords
alkyl
formula
chroman
amino
carbamoyl
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English (en)
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Deborah Weng Chun Chen
Janet Marie Forst
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AstraZeneca UK Ltd
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AstraZeneca UK Ltd
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Priority to JP2001504908A priority Critical patent/JP2003502415A/ja
Priority to AU54141/00A priority patent/AU5414100A/en
Priority to EP00938917A priority patent/EP1192146A1/fr
Publication of WO2000078742A1 publication Critical patent/WO2000078742A1/fr
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    • 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).

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Abstract

L'invention concerne des composés de formule (I) dans laquelle n, r et s sont tels que définis dans la description et R?1, R2, R3, R4 et R5¿ représentent divers substituants étant également tels que définis dans la description. L'invention concerne en outre des procédés d'utilisation desdits composés dans le traitement de troubles neurologiques, ainsi que des compositions pharmaceutiques renfermant les composés.
PCT/GB2000/002304 1999-06-17 2000-06-14 Derives du chromane utilises contre les troubles neurologiques Ceased WO2000078742A1 (fr)

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WO2001068609A1 (fr) * 2000-03-14 2001-09-20 Actelion Pharmaceuticals Ltd. Derives de 1,2,3,4-tetrahydroisoquinoline
US7763638B2 (en) 2004-03-01 2010-07-27 Actelion Pharmaceuticals Ltd. Substituted 1,2,3,4-tetrahydroisoquinoline derivatives
WO2018023070A1 (fr) * 2016-07-29 2018-02-01 Sunovion Pharmaceuticals, Inc. Composés et compositions, et utilisations associées
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

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JP3067399B2 (ja) * 1992-07-03 2000-07-17 株式会社日立製作所 半導体冷却装置

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001068609A1 (fr) * 2000-03-14 2001-09-20 Actelion Pharmaceuticals Ltd. Derives de 1,2,3,4-tetrahydroisoquinoline
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 (fr) * 2016-07-29 2018-02-01 Sunovion Pharmaceuticals, Inc. Composés et compositions, et utilisations associées
US10196403B2 (en) 2016-07-29 2019-02-05 Sunovion Pharmaceuticals Inc. Compounds and compositions and uses thereof
CN110087687A (zh) * 2016-07-29 2019-08-02 赛诺维信制药公司 化合物、组合物及其用途
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

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