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WO2000078718A1 - Derives 4-aminopiperidine de tetrahydronaphtalene, chromans et thiochromans - Google Patents

Derives 4-aminopiperidine de tetrahydronaphtalene, chromans et thiochromans Download PDF

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Publication number
WO2000078718A1
WO2000078718A1 PCT/GB2000/002306 GB0002306W WO0078718A1 WO 2000078718 A1 WO2000078718 A1 WO 2000078718A1 GB 0002306 W GB0002306 W GB 0002306W WO 0078718 A1 WO0078718 A1 WO 0078718A1
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Prior art keywords
formula
compound
piperidine
naphthalenyl
tetrahydro
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Inventor
Edward John Warawa
Charles David Mclaren
Richard Elliot Simon-Bierenbaum
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AstraZeneca UK Ltd
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AstraZeneca UK Ltd
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Priority to EP00938919A priority Critical patent/EP1204641A1/fr
Priority to JP2001504885A priority patent/JP2003502404A/ja
Priority to AU54142/00A priority patent/AU5414200A/en
Publication of WO2000078718A1 publication Critical patent/WO2000078718A1/fr
Anticipated expiration legal-status Critical
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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
    • C07D405/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to chemical compounds, in particular 1 ,2,3,4- tetrahydronaphthalenes, chromans and thiochromans, to processes for their preparation and to chemical intermediates useful in such processes.
  • the present invention further relates to
  • 1,2,3,4-tetrahydronaphthalenes 1,2,3,4-tetrahydronaphthalenes, chromans and thiochromans, 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 ATDS-related dementia.
  • the compounds useful in the present invention are believed to act by binding with the [ 3 H]-emopamil binding site.
  • 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
  • [ 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 NMD A receptor (N-Methyl-D-aspartate) and/or the sigma-1 binding site. Summary of the Invention
  • the present invention comprises a class of compounds that show selective action at the [ H]-emopamil binding site and that are neuroprotective without acting directly at either VSCC or NMDA receptors, and which exhibit fewer associated side effects such as hypotension seen with emopamil or behavioural manifestations seen with ifenprodil.
  • R 1 and R 2 are independently selected from hydrogen, optionally substituted C ⁇ -6alkyl, optionally substituted C -6 alkenyl, optionally substituted C 3 .6alkynyl wherein said optional substituents are chosen from one or more groups selected from halo, nitro, hydroxy, Cj. 6 alkoxy, cyano, amino, trifluoromethyl, trifluoromethoxy, carboxy, carbamoyl, mercapto, sulphamoyl, mesyl, N-C ⁇ -6 alkylamino, N,N-(C ⁇ .6alkyl)2amino, C ⁇ . alkoxycarbonyl, N-Cj. 6 alkylcarbamoyl or N,N-(C ⁇ -6alkyl) 2 carbamoyl, or R or R 2 is a group of the formula:
  • B is aryl, a carbon linked heteroaryl, a carbon-linked heterocycle, C 3- ⁇ 2 cycloalkyl or C 3 - ⁇ 2 cycloalkyl fused to a benzene ring; q is 0, 1, 2, 3, 4, 5 or 6; and wherein said 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, Ci- ⁇ alkyl, C 2-6 alkenyl, C2-6 lkynyl, 6 alkanoyl, Ci-ealkanoyloxy, N-(C ⁇ - 6 alkyl)amino, N,N-(C ⁇ alkyl) 2 amino, Ci- ⁇ alkanoylamino, N- (C ⁇ .6alkyl)carb
  • R 3 is halo, hydroxy, cyano, nitro or C 2-6 alkenyl;
  • R 4 is d- ⁇ alkyl;
  • X is -CH 2 -, -O- or -S-; r is 0, 1, 2, 3 or 4, wherein the values of R 3 may be the same or different; and s is 0, 1, 2 or 3 wherein the values of R 4 may be the same or different; or a pharmaceutically-acceptable salt or an in v/ ' vo-hydrolysable ester, amide or carbamate thereof.
  • the invention comprises a method for using compounds of Formula (I) for the treatment of neurological disorders such as stroke, head trauma, transient cerebral ischaemic attack, and chronic neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, diabetic neuropathy, amyotrophic lateral sclerosis, multiple sclerosis and ALDS-related dementia
  • neurological disorders such as stroke, head trauma, transient cerebral ischaemic attack, and chronic neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, diabetic neuropathy, amyotrophic lateral sclerosis, multiple sclerosis and ALDS-related dementia
  • the invention comprises methods for making compounds of formula
  • the invention comprises pharmaceutical compositions comprising compounds of formula (I) together excipients, diluents or stabilisers, as further disclosed herein.
  • pharmaceutical compositions comprising compounds of formula (I) together excipients, diluents or stabilisers, as further disclosed herein.
  • alkyl includes both straight and branched chain alkyl groups but references to individual alkyl groups such as “propyl” are specific for the straight chain version only.
  • alkenyl alkynyl
  • phenylC ⁇ - 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- 5-14 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, oxazolyi, isoxazolyl, pyridyl, pyridyl- -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- 5-14 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 Ci- ⁇ alkyl include methyl, ethyl, isopropyl and t- butyl; include benzyl, phenyl ethyl and phenylpropyl; examples of Ci- ⁇ alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, n- and t- butoxycarbonyl; examples include methoxy, ethoxy and propoxy; examples of C ⁇ .
  • 6 alkanoylamino include formamido, acetamido and propionylamino;
  • examples of C ⁇ -6alkylS(O) a where a is 0, 1 or 2 include methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl and ethylsulphonyl;
  • examples of Ci- ⁇ alkylsulphonyl include mesyl and ethylsulphonyl;
  • examples of Cj- ⁇ alkanoyl include propionyl and acetyl;
  • examples of Ci- ⁇ alkanoyloxy include propionyloxy and acetyloxy;
  • examples of N-C ⁇ -6 alkylamino include N-methylamino and N-ethylamino;
  • examples ofN,N-(C ⁇ -6 alkyl) 2 amino include N,N-dimethylamino, N,N-diethy
  • examples ofN-(C 1-6 alkyl)carbamoyl include N-methylcarbamoyl and N-ethylcarbamoyl
  • examples of N,N-(Ci. 6 alkyl) 2 carbamoyl include N,N-dimethylcarbamoyl and N-methyl-N- ethylcarbamoyl.
  • R 1 and R 2 are independently selected from hydrogen and optionally substituted C ⁇ aH yl or R 1 or R 2 is a group of the formula (IA) as defined hereinabove wherein B is aryl and q is 1 ; or R 1 and R 2 together with the nitrogen atom to which they are attached form a heterocyclic ring.
  • R 1 and R 2 are independently selected from hydrogen, optionally substituted Ci-salkyl and benzyl; or R 1 and R 2 together with the nitrogen atom to which they are attached form a heterocyclic ring.
  • R 1 and R 2 are independently selected from hydrogen, methyl, n-propyl, ISO- propyl, iso-amyl and benzyl, or R 1 and R 2 together with the nitrogen atom to which they are attached form pipe ⁇ dine ring
  • r is 0
  • s is 0
  • X is CH 2
  • X is S
  • R 1 and R 2 are independently selected from hydrogen and optionally substituted Cj. 6 alkyl or R 1 or R 2 is a group of the formula (IA) as defined hereinabove wherein B is aryl and q
  • R 1 and R 2 together with the nitrogen atom to which they are attached form a heterocyclic ring, r is O, s is 0, and
  • X is CH 2 , S or O, or a pharmaceutically-acceptable salt or an in v/vo-hydrolysable ester, amide or carbamate thereof
  • R 1 and R 2 are independently selected from hydrogen, optionally substituted Ci-salkyl and benzyl, or R 1 and R 2 together with the nitrogen atom to which they are attached form a heterocyclic ring, r is O, s is 0, and X is CH 2 , S or O, or a pharmaceutically-acceptable salt or an in v/vo-hydrolysable ester, amide or carbamate thereof
  • a compound of formula (I) wherein
  • R and R 2 are independently selected from hydrogen, methyl, n-propyl, iso-propyl, ISO- amyl and benzyl, or R and R 2 together with the nitrogen atom to which they are attached form pipe ⁇ dine ring, r is O, s is 0, and
  • X is CH 2 , S or O, or a pharmaceutically-acceptable salt or an in v/vo-hydrolysable ester, amide or carbamate thereof
  • Preferred compounds of the invention are those of Examples
  • a preferred aspect of the invention relates to any one of the Examples
  • Preferred aspects of the invention relate to a compound of formula (I) as hereinbefore defined or a pharmaceutically-acceptable salt thereof
  • Suitable pharmaceutically-acceptable salts include acid addition salts such as methanesulphonate, fumarate, hydrochlo ⁇ de, 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-methylpipe ⁇ dine, N-ethylpipe ⁇ dine, 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 1-position of the 1,2,3,4- tetrahydronaphthalene ring and the 4-posit ⁇ on of the
  • the invention further relates to all tautomeric forms of the compounds of formula (I). It is also to be understood that certain compounds of the formula (I) can exist in solvated as well as unsolvated forms such as, for example, hydrated forms It is to be understood that the invention encompasses all such solvated and unsolvated forms
  • v/vo-hydrolysable esters, amides and carbamates are compounds that hydrolyse in the human body to produce the parent compound Such esters, amides and carbamates can be identified by administering, for example intravenously to a test ammal, the compound under test and subsequently examining the test animal's body fluids Suitable in v/vo-hydrolysable amides and carbamates include N-carbomethoxy and N-acetyl
  • An in v/vo-hydrolysable ester of a compound of the formula (I) containing carboxy or hydroxy group is, for example, a pharmaceutically-acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol
  • Suitable pharmaceutically-acceptable esters for carboxy include Ci- ⁇ alkoxymethyi esters for example methoxymethyl, Ci 6 alkanoyloxymethyl esters for example pivaloyloxymethyl, phtha dyl esters, C 3 8 cycloalkoxy-carbonyloxyC ⁇ 6 lkyl esters for example 1 - cyclohexylcarbonyloxyethyl, l,3-d ⁇ oxolen-2-onylmethyl esters for example 5-methyl-l,3- d ⁇ oxolen-2-onylmethyl, and C ⁇ -6 alkoxycarbonyloxyethyl esters for example 1 - methoxycarbonyloxyethyl and may be formed at any carboxy group in the compounds of this invention
  • An /// v/vo-hydrolysable ester of a compound of the formula (I) containing a hydroxy group includes inorganic esters such as phosphate esters and ⁇ -acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group
  • ⁇ -acyloxyalkyl ethers include acetoxymethoxy and 2,2- dimethylpropionyloxymethoxy
  • a selection of in v/vo-hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N-(dialkylam ⁇ noethyl)-A - alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxy
  • Another aspect of the present invention provides a process for preparing a compound of formula (I) or a pharmaceutically-acceptable salt or an in v/vo-hydrolysable ester, amide or carbamate thereof which process (wherein R 1 , R 2 , R 3 , R 4 , X, r and s are, unless otherwise specified, as defined in formula (I)) comprises of a) reacting a compound of formula (II)
  • R d -L (VII) wherein L is a leaving group and i) R c is R 1 except hydrogen or R c is an amino protecting group and R ⁇ is R except hydrogen; or ii) R c is R 2 except hydrogen or R c is an amino protecting group and R d is R except hydrogen; d) reacting a compound of formula (VIII):
  • R c is R except hydrogen and R e is optionally substituted C ⁇ -5 alkyl or a group of formula (IA) as defined above wherein q is 0-5; or ii) R c is R 2 except hydrogen and R e is optionally substituted C ⁇ -5 alkyl or a group of formula (IA) as defined above wherein q is 0-5; or g) for compounds of formula (I) wherein one of R 1 and R is optionally substituted C ⁇ . 6 alkyl or a group of formula (IA) as defined above wherein q>0; by reducing a compound of formula (XI):
  • L is a leaving group, suitable values for L are for example, a halogeno or sulphonyloxy group, for example a chloro, bromo, methanesulphonyloxy or toluene-4-sulphonyloxy group
  • 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 an organic base such as Hunig's base or excess amine
  • an inert solvent for example tetrahydrofuran, dimethyl acetamide or toluene and at a temperature in the range of 50-120 °C, preferably at or near reflux
  • a reducing agent such as hydrogen and a hydrogenation catalyst (for example palladium on carbon), or zinc and hydrochloric acid, or sodium cyanoborohydride, or sodium triacetoxyborohydride, or sodium borohydride, iron pentacarbonyl and alcoholic potassium hydroxide, or borane and pyridine or formic acid.
  • a suitable solvent such as an alcohol, for example methanol or ethanol, and at a temperature in the range of 0-50 °C, preferably at or near room temperature.
  • Compounds of formula (XI) are reduced under standard reduction conditions for reducing an amide to an amine.
  • a reducing agent such as borane, sodium borohydride or lithium aluminium hydride
  • an inert solvent such as toluene or tetrahydrofiiran
  • 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 trifluoro acetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate).
  • a suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.
  • a suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl.
  • the deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • a suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • a base such as sodium hydroxide
  • a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • the protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art.
  • a compound of the formula (I) or a pharmaceutically-acceptable salt or in v/vo-hydrolysable ester, amide or carbamate thereof for the therapeutic treatment (including prophylactic treatment) of mammals including humans, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
  • 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 lsotonic 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
  • a pharmaceutical composition which comprises a compound of the formula (I) as defined hereinbefore or a pharmaceutically-acceptable salt or an in v/vo-hydrolysable ester, amide or carbamate thereof, in association with a pharmaceutically-acceptable excipient or carrier
  • a compound of the formula (I) or a pharmaceutically-acceptable salt or an in v/vo-hydrolysable ester, amide or carbamate thereof as defined hereinbefore for use in a method of treatment of the human or animal body by therapy
  • a further feature of the present invention is a compound of formula (I) and pharmaceutically-acceptable salts or an in v/vo-hydrolysable ester, amide or carbamate thereof, for use as a medicament
  • this is a compound of formula (I) or a pharmaceutically-acceptable salt or an in v/vo-hydrolysable ester, amide or carbamate thereof, for use as a medicament to inhibit the [ 3 H]-emopamil binding site in a warm-blooded animal such as a human being
  • a compound of the formula (I) or a pharmaceutically-acceptable salt or an in v/vo-hydrolysable ester, amide or carbamate thereof, in the manufacture of a medicament for use in the inhibition of the [ 3 H]-emopamil binding site in a warm-blooded animal such as a human being.
  • a method of inhibiting of the [ 3 H]-emopamil binding site in a warm-blooded animal, such as a human being, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I) or a pharmaceutically-acceptable salt or an in v/vo-hydrolysable ester, amide or carbamate thereof, as defined hereinbefore.
  • Assay buffer 10 mM Tris-HCl, 0.1 mM phenylmethylsulphonyl 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 ICso below 300nM in this test were of interest.
  • PEI polyethylenimine
  • 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. (-)-[ 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 3 H-D888 (Amersham) rat cortical membranes: 6 mg/ml original wet weight compounds: 0.3-100 ⁇ M Total volume: 1000 ⁇ l
  • 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. When they have regained the righting reflex and are beginning to walk around, they are again dosed with the test compound and returned to their home cages. This occurs approximately five minutes after the end of surgery.
  • gerbils Twenty-four hours post ischaemia gerbils are tested for spontaneous locomotor activity, using a Photobeam Activity System from San Diego Instruments. They are individually placed in Plexiglas chambers measuring 27.5 cm x 27.5 cm x 15 cm deep. The chambers are surrounded by photocells, and every time a beam is broken one count is recorded. Each gerbil is tested for two hours, and cumulative counts are recorded at 30, 60, 90, and 120 minutes. Mean counts are recorded for each group and drug groups are compared to control with an ANOVA and Bonferroni post test. After each gerbil is tested it is returned to its home cage. At this time gerbils are also observed for any changes from normal behaviour.
  • the MCA trunk was ligated immediately above the rhinal fissure with 10-0 suture. Complete interruption of blood flow was confirmed under an operating microscope. Both common carotid arteries were then occluded using nontraumatic aneurysm clips. After a predetermined duration of ischaemia (45 min), blood flow was restored in all three arteries. Twenty-four hours post occlusion, rats were killed under ketamine anaesthesia by intracardiac perfusion with 200 ml of 0.9% 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
  • TLC's were monitored on silica gel plates: Silica Gel GHLF (Analtech), 250 microns, plates (2.5 x 10 cm). The detection methods used were UV light, iodine, and chloroplatinate.
  • Kugelrohr distillation was using apparatus supplied by Aldrich Chemical Co; it is bulb- to-bulb short path distillation; the air bath temperature at which the material distills is denoted as the boiling point;
  • DMSO dimethylsulphoxide
  • CDC1 3 is deuterated chloroform
  • THF is tetrahydrofiiran
  • DCM is dichloromethane
  • MeOH is methanol
  • DMAC is dimethyl acetamide.
  • N-ethyl-N-methyl-4-oxo-piperidinium iodide (8.53 g, 31.7 mmol) was reacted with 4-amino-3,4-dihydro-2- -benzothiopyran (3.5 g, 21.2 mmol) to give the title compound (4.53 g).
  • a compound of formula (I) is dissolved in an isotonic sterile solution (5 mg/ml).

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Abstract

L'invention concerne des 1,2,3,4-tétrahydronaphtalènes, des chromans et des thiochromans de formule (I) dans laquelle r, s et X sont tels que définis dans la description, et R?1, R2, R3 et R4¿ sont divers substituants étant également tels que définis dans la description. L'invention concerne en outre des compositions pharmaceutiques renfermant lesdits composés et des procédés d'utilisation de ces derniers dans le traitement thérapeutique de troubles neurologiques.
PCT/GB2000/002306 1999-06-17 2000-06-14 Derives 4-aminopiperidine de tetrahydronaphtalene, chromans et thiochromans Ceased WO2000078718A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP00938919A EP1204641A1 (fr) 1999-06-17 2000-06-14 Derives 4-aminopiperidine de tetrahydronaphtalene, chromans et thiochromans
JP2001504885A JP2003502404A (ja) 1999-06-17 2000-06-14 テトラヒドロナフタレン、クロマンおよびチオクロマンの４−アミノピペリジン誘導体
AU54142/00A AU5414200A (en) 1999-06-17 2000-06-14 4-aminopiperidine derivatives of tetrahydronaphthalene, chromans and thiochromans

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GB9914024.6 1999-06-17
GBGB9914024.6A GB9914024D0 (en) 1999-06-17 1999-06-17 Chemical compounds

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WO2000078718A1 true WO2000078718A1 (fr) 2000-12-28

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108456183A (zh) * 2018-03-09 2018-08-28 上海工程技术大学 Gedatolisib的制备方法及中间体

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KR100899061B1 (ko) * 2004-12-21 2009-05-25 에프. 호프만-라 로슈 아게 테트랄린 및 인단 유도체 및 이의 용도

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2468601A1 (fr) * 1979-10-29 1981-05-08 Maruko Pharmaceutical Co Nouveaux derives de flavanne utiles notamment comme anticonvulsivants
EP0350805A1 (fr) * 1988-07-12 1990-01-17 Beiersdorf-Lilly GmbH Dérivés benzopyraniques, procédé pour leur préparation et leur application, aussi bien que les préparations les contenant
WO1993016057A1 (fr) * 1992-02-18 1993-08-19 Les Laboratoires Meram Derives de la 1,4-dialkylpiperazine, procedes d'obtention et compositions pharmaceutiques les contenant
WO1997031887A1 (fr) * 1996-03-01 1997-09-04 Zeneca Limited Derives de l'aminotetraline, compositions contenant ces derives et methodes pour les utiliser
WO1998000412A1 (fr) * 1996-07-01 1998-01-08 Schering Corporation Antagonistes muscariniques
EP0856514A1 (fr) * 1997-01-30 1998-08-05 F. Hoffmann-La Roche Ag Dérivés de la 1,3,8-triazaspiro[4,5]decan-4-one substitues en position 8
WO2000035882A1 (fr) * 1998-12-15 2000-06-22 Astrazeneca Ab 1,2,3,4-tetrahydronaphtalenes et leur utilisation pharmaceutique

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2468601A1 (fr) * 1979-10-29 1981-05-08 Maruko Pharmaceutical Co Nouveaux derives de flavanne utiles notamment comme anticonvulsivants
EP0350805A1 (fr) * 1988-07-12 1990-01-17 Beiersdorf-Lilly GmbH Dérivés benzopyraniques, procédé pour leur préparation et leur application, aussi bien que les préparations les contenant
WO1993016057A1 (fr) * 1992-02-18 1993-08-19 Les Laboratoires Meram Derives de la 1,4-dialkylpiperazine, procedes d'obtention et compositions pharmaceutiques les contenant
WO1997031887A1 (fr) * 1996-03-01 1997-09-04 Zeneca Limited Derives de l'aminotetraline, compositions contenant ces derives et methodes pour les utiliser
WO1998000412A1 (fr) * 1996-07-01 1998-01-08 Schering Corporation Antagonistes muscariniques
EP0856514A1 (fr) * 1997-01-30 1998-08-05 F. Hoffmann-La Roche Ag Dérivés de la 1,3,8-triazaspiro[4,5]decan-4-one substitues en position 8
WO2000035882A1 (fr) * 1998-12-15 2000-06-22 Astrazeneca Ab 1,2,3,4-tetrahydronaphtalenes et leur utilisation pharmaceutique

Non-Patent Citations (1)

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Title
EVANS J M ET AL: "SYNTHESIS AND ANTIHYPERTENSIVE ACTIVITY OF 6,7-DISUBSTITUTED TRANS-4-AMINO-3,4-DIHYDRO-2,2-DIMETHYL-2H-1-BENZOPYRAN-3-OLS", JOURNAL OF MEDICINAL CHEMISTRY,US,AMERICAN CHEMICAL SOCIETY. WASHINGTON, vol. 27, no. 9, 1984, pages 1127 - 1131, XP002048426, ISSN: 0022-2623 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108456183A (zh) * 2018-03-09 2018-08-28 上海工程技术大学 Gedatolisib的制备方法及中间体

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AU5414200A (en) 2001-01-09

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