EP1140852A1 - 1,2,3,4-tetrahydronaphtalenes et leur utilisation pharmaceutique - Google Patents

1,2,3,4-tetrahydronaphtalenes et leur utilisation pharmaceutique

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EP1140852A1
EP1140852A1 EP99959569A EP99959569A EP1140852A1 EP 1140852 A1 EP1140852 A1 EP 1140852A1 EP 99959569 A EP99959569 A EP 99959569A EP 99959569 A EP99959569 A EP 99959569A EP 1140852 A1 EP1140852 A1 EP 1140852A1
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alkyl
formula
hydrogen
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Deborah Weng Chun Chen
Janet Marie Forst
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AstraZeneca AB
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AstraZeneca AB
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P3/00—Drugs for disorders of the metabolism
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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    • 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
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/33—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C211/39—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton
    • C07C211/41—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton containing condensed ring systems
    • C07C211/42—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton containing condensed ring systems with six-membered aromatic rings being part of the condensed ring systems
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    • 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
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/58—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/14—All rings being cycloaliphatic
    • C07C2602/26—All rings being cycloaliphatic the ring system containing ten carbon atoms
    • C07C2602/28—Hydrogenated naphthalenes

Definitions

  • the present invention relates to chemical compounds, in particular 1,2,3,4-tetrahydronaphthalenes, to processes for their preparation and to chemical intermediates useful in such processes.
  • the present invention further relates to 1,2,3,4-tetrahydronaphthalenes, to pharmaceutical compositions containing them and to their use in methods of therapeutic treatment of animals including man, in particular in the treatment of neurological disorders. Background
  • Neurological disorders include stroke, head trauma, transient cerebral ischaemic attack, and chronic neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, diabetic neuropathy, amyotrophic lateral sclerosis, multiple sclerosis and AIDS-related dementia.
  • Emopamil has classically been thought of as a neuroprotective agent whose efficacy is most likely derived from actions at either voltage-sensitive calcium channels (VSCC) or 5-HT receptors.
  • VSCC voltage-sensitive calcium channels
  • 5-HT receptors 5-HT 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 NMDA receptor (N-Methyl-D-aspartate) and/or the sigma-1 binding site. It is thought that compounds that interact with either the VSCC or the ⁇ MDA receptor, are responsible for the side effects usually seen with emopamil, such as hypotension, or those seen with ifenprodil, such as behavioural manifestations. Summary of The Invention
  • the present invention provides compounds of formula I:
  • R 1 is selected from hydrogen, C ⁇ _ 6 alkyl, C . 6 alkenyl, C 2 .6alkynyl and phenylC 2 . 6 alkyl;
  • R 2 and R 3 are independently selected from hydrogen, C ⁇ _ alkyl, phenylsulphonyl, 1- (1,2,3,4-tetrahydronaphthyl), a group of the formula IA: (CH, 2 ) P «
  • A is halo, nitro, hydroxy, C 1- alkoxy, cyano, a ino, trifluoromethyl, trifluoromethoxy, carboxy, carbamoyl, mercapto, sulphamoyl, mesyl, N-Ci_ 6 alkylamino, N,N- (C ⁇ .
  • aryl, heteroaryl or heterocyclyl may be optionally substituted on a ring carbon with one or more M groups where M at each occurrence is independently selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C 1-6 alkyl, C 2 .
  • a heterocyclyl or a heteroaryl ring having an - ⁇ H- group may be optionally substituted on this nitrogen with C ⁇ . 6 alkyl, C 2- alkenyl, C 2 . 6 alkynyl, C ⁇ _ 6 alkanoyl, C ⁇ _ 6 alkylsulphonyl or phenylC ⁇ _ 6 alkyl, or
  • R 2 and R 3 together with the nitrogen atom to which they are attached form a heterocyclyl or heteroaryl ring, where said heterocyclyl or heteroaryl ring may have an - ⁇ H- group that may be substituted on the nitrogen with C ⁇ _ 6 alkyl, C 2 . 6 alkenyl, C 2 .
  • heterocyclyl or heteroaryl ring may have an -O- group
  • said heterocyclyl or heteroaryl ring may be optionally substituted with an ortho-fused aryl moiety
  • any aforesaid heterocyclyl, heteroaryl ring or aryl moiety may be optionally substituted on a ring carbon with one or more R 9 groups selected from M as heretofore defined, r is 4 and R 4 at each occurrence is independently selected from hydrogen, halo, hydroxy, C ⁇ - 6 alkyl, C ⁇ .
  • Particular compounds according to formula I provided by the present invention are compounds having the formula XVII:
  • R is selected from hydrogen, C 2 . 6 alkenyl, C 2 _ 6 alkynyl and phenylC 2 _ 6 alkyl;
  • R 8 is selected from hydrogen and C ⁇ - 6 alkyl;
  • r is 4 and R 4 at each occurrence is independently selected from hydrogen, halo, hydroxy, Cj- 6 alkyl, Cj_ 6 alkoxy, hydroxyC ⁇ _ 6 alkyl, cyano, nitro and C 2 .
  • alkenyl; s is 7 and R 5 at each occurrence is independently selected from hydrogen and C ⁇ _ 6 alkyl, and n is 1 or 2; or a pharmaceutically-acceptable salt or an in v vo-hydrolysable ester, amide or carbamate thereof.
  • R is selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and phenylC 2- alkyl, and r is 4 and R at each occurrence is independently selected from hydrogen, halo, hydroxy, C ⁇ -6 alkyl, C ⁇ . 6 alkoxy, hydroxyC ⁇ .6alkyl, haloC 1-6 alkyl, cyano, nitro and C 2-6 alkenyl; s is 7 and R 5 at each occurrence is independently selected from hydrogen and C ⁇ -6 alkyl, and n is 1 or 2; or a pharmaceutically-acceptable salt or an in v/vo-hydrolysable ester, amide or carbamate thereof.
  • Still other particular compounds according to formula I provided by the present invention are compounds having the formula XIX:
  • R is selected from hydrogen, C ⁇ _6alkyl, C 2-6 alkenyl, C 2 . alkynyl and phenylC 2 . 6 alkyl, and v is 4 and R 9 is independently selected at each occurrence from hydrogen, halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C ⁇ .
  • R 1 is selected from hydrogen, C 2 . 6 alkenyl, C 2 . 6 alkynyl and phenylC 2 - alkyl; r is 4 and R 4 at each occurrence is independently selected from hydrogen, halo, hydroxy, C ⁇ . . 6 alkyl, C ⁇ _ 6 alkoxy, hydroxy C 1-6 alkyl, haloC ⁇ - 6 alkyl, cyano, nitro and C 2 . alkenyl; s is 7 and R 5 at each occurrence is independently selected from hydrogen and Cj- ⁇ alkyl, m is an integer selected from the range 1 to 5;
  • R 10 is selected from hydrogen and Cj_ 6 alkyl, and n is 1 or 2; or a pharmaceutically-acceptable salt or an in v/vo-hydrolysable ester, amide or carbamate thereof.
  • R 1 is selected from hydrogen, C ⁇ - alkyl, C 2-6 alkenyl, C 2-6 alkynyl and phenylC 2-6 alkyl;
  • R 2 and R 3 are independently selected from hydrogen, C ⁇ _ 6 alkyl, phenylsulphonyl, 1- (1,2,3,4-tetrahydronaphthyl), a group of the formula IA: (CH 2 ) p — A IA where A is halo, nitro, hydroxy, C ⁇ -6 alkoxy, cyano, amino, trifluoromethyl, trifluoromethoxy, carboxy, carbamoyl, mercapto, sulphamoyl, mesyl, N-C ⁇ - 6 alkylamino, N,N- (Ci.
  • R 6 and R 7 are independently selected from hydrogen and C 1-3 alkyl, and B is aryl, a carbon linked heteroaryl, a carbon-linked heterocyclyl, C 3- ⁇ 2 cycloalkyl or
  • R 2 and R 3 together with the nitrogen atom to which they are attached form a heterocyclyl or heteroaryl ring, wherein said heterocyclyl or heteroaryl ring may be optionally substituted on a ring carbon with one or more groups selected from M as heretofore defined, said heterocyclyl or a heteroaryl ring may have an - ⁇ H- group that may be substituted on the nitrogen with d.
  • 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Ci- ⁇ alkanoyl, C 1-6 alkylsulphonyl, or said heterocyclyl or a heteroaryl ring may be optionally substituted with an ortho-fused aryl moiety;
  • r is 4 and R 4 at each occurrence is independently selected from hydrogen, halo, hydroxy, C ⁇ -6 alkyl, C ⁇ . 6 alkoxy, hydroxyC ⁇ -6 alkyl, haloC ⁇ -6 alkyl, cyano, nitro and C 2 . 6 alkenyl;
  • s is 7 and R 5 at each occurrence is independently selected from hydrogen and C
  • R 1 is selected from hydrogen, Cj. alkyl, C 2 _ 6 alkenyl, C 2 . 6 alkynyl and phenylC 2 _ 6 alkyl; r is 4 and R 4 at each occurrence is independently selected from hydrogen, halo, hydroxy, C ⁇ _ 6 alkyl, hydroxyC ⁇ _ 6 alkyl, haloC ⁇ _ 6 alkyl, cyano, nitro and C 2 _ 6 alkenyl; s is 7 and R 5 at each occurrence is independently selected from hydrogen and
  • m is an integer selected from the range 1 to 5;
  • R 7 is selected from hydrogen and C ⁇ . 6 alkyl, and n is 1 or 2; or a pharmaceutically-acceptable salt or an in v/vo-hydrolysable ester, amide or carbamate thereof.
  • R 1 is selected from hydrogen, d_ alkyl, C 2 . 6 alkenyl, C -6 alkynyl and phenylC 2-6 alkyl; v is 4 and R 9 is independently selected at each occurrence from hydrogen, halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, d -6 alkyl, C 2 .
  • alkyl as in for example C 1- 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 as in for example C 1- alkyl
  • alkynyl includes 2-phenylethyl, 2-phenylpropyl and 3-phenylpropyl.
  • halo means fluoro, chloro, bromo and iodo.
  • aryl means an unsaturated carbon ring. Particularly aryl is phenyl, naphthyl or biphenyl. More particularly aryl is phenyl.
  • heteroaryl or “heteroaryl ring” means, unless otherwise further specified, monocyclic-, bicyclic- or tricyclic- 5-14 membered rings that are 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 “heterocyclyl ring” means, unless otherwise further specified, a mono- or bicyclic- 5-14 membered ring, that is totally saturated, with up to five ring heteroatoms selected from nitrogen, oxygen and sulphur wherein a -CH 2 - group can optionally be replaced by a -C(O)-.
  • heterocyclyls include morpholinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, homopiperidinyl, homopiperazinyl and quinuclidinyl.
  • examples of Cj_ 6 alkyl include Cj. alkyl moieties such as methyl, ethyl, isopropyl and t-butyl;
  • examples of phenylCj- ⁇ alkyl include phenylC ⁇ - alkyl moieties such as benzyl,
  • examples of phenylC 2-6 alkyl include phenylC 2- alkyl moieties such as phenylethyl and phenylpropyl;
  • examples of C ⁇ _ 6 alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, n- and t-butoxycarbonyl;
  • examples of d ⁇ alkoxy include methoxy, ethoxy and propoxy; examples of C ⁇ .
  • alkanoylamino include formamido, acetamido and propionylamino
  • examples of C ⁇ _ 6 alkylSO a where a is 0, 1 or 2 include methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl and ethyl sulphonyl
  • examples of C ⁇ _ 6 alkylsulphonyl include mesyl and ethylsulphonyl
  • examples of C ⁇ -6 alkanoyl include propionyl and acetyl
  • examples of N-C 1-6 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 examples of
  • l2 cycloalkyl include cyclopropyl and cyclohexyl; examples of C 3- ⁇ 2 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- alkynyl include ethynyl, 1-propynyl and 2-propynyl; examples of haloC 2- alkyl include 2-chloroethyl and 2-bromopropyl; examples of N-(C 1- alkyl)sulphamoyl include N-methylsulphamoyl and N-ethylsulphamoyl; examples of N,N-
  • (d-6alkyl) 2 sulphamoyl include N,N-dimethylsulphamoyl and N-methyl-N-ethylsulphamoyl; examples of N-(C ⁇ _ alkyl)carbamoyl include N-methylcarbamoyl and N-ethylcarbamoyl; examples of N,N-(C ⁇ - alkyl) 2 carbamoyl include N,N-dimethylcarbamoyl and N-methyl-N- ethylcarbamoyl; examples of include propionyloxy, acetyloxy and formyloxy.
  • R is hydrogen, C ⁇ -6 alkyl or phenylC 2 . 6 alkyl. More particularly R 1 is hydrogen, C ⁇ _ 4 alkyl or phenylC 2 . 4 alkyl. Particularly R 1 is hydrogen, methyl or ethyl.
  • R 1 is hydrogen or methyl.
  • R 1 is methyl
  • R " and R are independently selected from hydrogen, C ⁇ _ 6 alkyl or a group of the formulae I A or IB:
  • R ⁇ and R 3 together with the nitrogen atom to which they are attached 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, Cj- 6 alkoxy, C ⁇ .
  • R and R are independently selected from hydrogen, C ⁇ _ 6 alkyl, or a group of the formula (IB) as depicted above wherein B is aryl, a carbon-linked heterocyclyl, where a heterocyclyl containing an - ⁇ H- group may be optionally substituted on the nitrogen with phenylC ⁇ _ 6 alkyl, or C 3 _ ⁇ 2 cycloalkyl fused to a benzene ring.
  • R and R together with the nitrogen atom to which they are attached form a heterocyclyl or heteroaryl ring wherein said heterocyclyl ring may be optionally substituted on a ring carbon with one or more groups selected from C ⁇ _ 6 alkyl and a heterocyclyl ring containing an - ⁇ H- group may be optionally substituted on this nitrogen with C ⁇ . 6 alkyl.
  • R 2 and R 3 are independently selected from methyl, ethyl, isopropyl, phenyl, benzyl or phenylethyl, or R and R together with the nitrogen atom to which they are attached form a pyrrolidin-1-yl, 2-methylpiperidin-l-yl, piperidin-1-yl, 4-methylpiperazin-l-yl, homopiperidin-1-yl or l,2,3,4-tetrahydroisoquinol-2-yl ring.
  • R 2 and R 3 are independently selected from methyl, ethyl, isopropyl, benzyl or phenylethyl, or R 2 and R 3 together with the nitrogen atom to which they are attached form a 2-methylpiperidin-l-yl, piperidin-1-yl, homopiperidin-1-yl or l,2,3,4-tetrahydroisoquinol-2-yl ring.
  • R 2 and R 3 are ethyl or R 2 and R 3 together with the nitrogen to which they are attached form a piperidin-1-yl or l,2,3,4-tetrahydroisoquinol-2-yl ring.
  • R at each occurrence is selected from hydrogen, hydroxyCj- 6 alkyl, C 2-6 alkenyl, halo or C ⁇ -6 alkyl. More particularly R 4 at each occurrence is selected from hydrogen, halo or C ⁇ _ 4 alkyl. Particularly R 4 at each occurrence is selected from hydrogen, bromo, 2-hydroxy-2-propyl, 2-propenyl, tert-butyl or methyl.
  • Still more particularly compounds of the invention are selected from compounds of formulae XXX, XXXI and XXXII,
  • R 5 moieties are selected from hydrogen and C ⁇ . alkyl. More particularly R 5 moieties are selected from hydrogen, methyl and ethyl. Most particularly R 5 moieties are selected from hydrogen and methyl. Particularly all R 5 moieties are hydrogen.
  • n is an integer selected from 1 or 2.
  • R 1 is hydrogen, C ⁇ - alkyl or phenylC 2 . 6 alkyl;
  • R 2 and R 3 are independently selected from hydrogen, C 1-6 alkyl, or R 2 or R 3 is a group of the formula IB as described herein wherein B is phenyl, a carbon-linked heterocyclyl, where a heterocyclyl containing an -NH- group may be optionally substituted on this nitrogen with phenylC ⁇ -6 alkyl, or C 3 _ ⁇ cycloalkyl fused to a benzene ring and q is an integer selected from the range 0 to 6, or
  • R 2 and R 3 together with the nitrogen atom to which they are attached form a heterocyclyl or heteroaryl ring, wherein said heterocyclyl or heteroaryl ring optionally contains one further heteroatom selected from oxygen or nitrogen and wherein said heterocyclyl ring may be optionally substituted on a ring carbon with one or more groups selected from C ⁇ _ alkyl and a heterocyclyl ring containing an -NH- group may be optionally substituted on this nitrogen with Ci- alkyl;
  • R 4 is hydrogen, halo, Cj_ 6 alkyl, hydroxyC ⁇ - 6 alkyl or C 2 _ 6 alkenyl where each R 4 may be the same or different and at least one R 4 moiety is hydrogen;
  • R 5 is hydrogen or Cj_ 4 alkyl where each R 5 may be the same or different and at least one R 5 moiety is hydrogen; or a pharmaceutically-acceptable salt or an in v/vo-hydrolysable ester, amide or carbamate thereof.
  • R 1 is hydrogen, Cj. alkyl or pheny!C 2-4 alkyl
  • R 2 and R 3 are independently selected from methyl, ethyl, isopropyl, phenyl, benzyl or phenylethyl, or
  • R 2 and R 3 together with the nitrogen atom to which they are attached form a pyrrolidin-1-yl, 2-methylpiperidin-l-yl, piperidin-1-yl, 4-methylpiperazin-l-yl, homopiperidin-1-yl or l,2,3,4-tetrahydroisoquinol-2-yl ring;
  • R 4 is hydrogen, halo or d- alkyl where each R 4 may be the same or different and at least two R 4 moieties are hydrogen;
  • R 5 is hydrogen, methyl or ethyl where each R 5 may be the same or different and at least two R 5 moieties are hydrogen, and n is 1, or a pharmaceutically-acceptable salt or an in v/vo-hydrolysable ester, amide or carbamate thereof.
  • R 1 is hydrogen, methyl or ethyl
  • one of R 2 and R 3 is methyl and the other is phenyl, benzyl or phenylethyl, or one of R 2 and R 3 is hydrogen and the other is isopropyl, benzyl, 1,2,3,4-tetrahydronapth-l-yl or N-(phenylethyl)piperidin-4-yl, or R 2 and R 3 are the same group and are selected from methyl, ethyl and isopropyl, or
  • R 2 and R 3 together with the nitrogen atom to which they are attached form a pyrrolidinl-yl, 2-methylpiperidin-l-yl, piperidin-1-yl, 4-methylpiperazin-l-yl, mo ⁇ holino, homopiperidin-1-yl or l,2,3,4-tetrahydroisoquinol-2-yl ring; one R 4 moiety is bromo, or two R 4 moieties are methyl and other R 4 moieties are hydrogen; and
  • R 5 is always hydrogen, and n is 1, or a pharmaceutically-acceptable salt or and in v/vo-hydrolysable ester, amide or carbamate thereof.
  • R 1 is hydrogen or methyl; one of R 2 and R 3 is methyl and the other is benzyl or phenylethyl, or
  • R 2 and R 3 are the same group and are selected from ethyl or isopropyl, or R 2 and R 3 together with the nitrogen atom to which they are attached form a
  • R 1 is methyl
  • R 2 and R 3 are both ethyl, or R 2 and R 3 together with the nitrogen to which they are attached form a piperidin-1-yl or l,2,3,4-tetrahydroisoquinol-2-yl ring; the R 4 is always hydrogen, or R 4 at the 6- position is bromo, or R 4 at the 5 and 8 positions is methyl; and R 5 is hydrogen, and n is 1 or a pharmaceutically-acceptable salt or and in v/vo-hydrolysable ester, amide or carbamate thereof.
  • Suitable pharmaceutically-acceptable salts include acid-addition salts such as methanesulphonate, fumarate, hydrochloride, hydrobromide, citrate, maleate, phosphate and sulphate.
  • 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, mo ⁇ holine, N-methylpiperidine, N-ethylpiperidine, procaine, dibenzylamine and N,N-dibenzylethylamine, or amino acids, for example lysine.
  • a compound of the invention may have 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.
  • esters As used herein, in v/vo-hydrolysable esters, amides and carbamates are compounds that hydrolyse in the human body to produce the parent compound. Such esters, amides and carbamates can be identified by administering, for example intravenously to a test animal, the compound under test and subsequently examining the test animal's body fluids. Suitable in v/vo-hydrolysable amides and carbamates include N-carbomethoxy and N-acetyl.
  • An in v/vo-hydrolysable ester of a compound of the formula I containing carboxy or hydroxy group is, for example, a pharmaceutically-acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol.
  • Suitable pharmaceutically-acceptable esters for carboxy include C). 6 alkoxymethyl esters, for example me thoxy methyl; C]. 6 alkanoyloxymethyl esters for example pivaloyloxymethyl; phthalidyl esters; C 3-8 cycloalkoxy-carbonyloxyC ⁇ - 6 alkyl esters, for example 1-cyclohexylcarbonyloxyethyl; l,3-dioxolen-2-onylmethyl esters, for example 5-methyl-l,3-dioxolen-2-onylmethyl; and Cj- 6 alkoxycarbonyloxyethyl esters, for example 1-methoxycarbonyloxyethyl and may be formed at any carboxy group of a compound of the present invention.
  • An in v/vo-hydrolysable ester of a compound of the formula I containing a hydroxy group includes inorganic esters such as phosphate esters and ⁇ -acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester yield the parent hydroxy group.
  • inorganic esters such as phosphate esters and ⁇ -acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester yield the parent hydroxy group.
  • ⁇ -acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy.
  • a selection of in v/vo-hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N- (dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl.
  • Another aspect of the present invention provides a process for preparing compounds of formula I wherein R 1 , R 2 , R 3 , R 4 , R 5 and n, are, unless otherwise specified, as defined in formula I which process comprises: a) reacting a ketone of formula II:
  • R of a compound of formula I when R of a compound of formula I is hydrogen R a is suitable amino protecting group such as those defined below; or when R of a compound of formula I is not hydrogen R a is R 1 ; or d) if R 1 is Cj- alkyl or phenylC 2 . 6 alkyl, reacting a compound of formula VIII:
  • suitable values for L are a halogeno or sulphonyloxy group, for example: chloro, bromo, methanesulphonyloxy or toluene-4-sulphonyloxy; for k), suitable values for G are C ⁇ _ 6 alkoxy, for example methoxy or ethoxy; and thereafter if necessary: i) converting a compound of the formula I into another compound of the formula I; ii) removing any protecting groups; or iii) forming a pharmaceutically-acceptable salt or in v/vo-hydrolysable ester, amide or carbamate.
  • Ketones or aldehydes may be reacted with amines under standard reductive amination conditions.
  • a reducing agent such as hydrogen and a hydrogenation catalyst (for example palladium on carbon), or zinc and hydrochloric acid, or sodium cyanoborohydride, or sodium triacetoxyborohydride, or sodium borohydride, iron pentacarbonyl and alcoholic potassium hydroxide, or borane and pyridine or formic acid.
  • the reaction is preferably carried out in the presence of a suitable solvent such as an alcohol, for example methanol or ethanol, and at a temperature in the range of 0-50 °C, preferably at or near room temperature.
  • 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.
  • 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 before or 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.
  • 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.
  • 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 or prophylactic treatment of mammals including humans, such a compound would normally be 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 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 AIDS-related dementia.
  • compositions may be administered, 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.
  • compositions of this invention may also contain, or be simultaneously or sequentially co-administered with, one or more pharmacological agents of value in treating one or more disease conditions as described herein.
  • Pharmaceutical compositions comprising compounds of this invention will normally be administered to humans so that, for example, a daily dose of 0.05 to 75 mg/kg body weight (and preferably of 0.1 to 30 mg/kg body weight) is received. This daily dose may be given in divided doses as necessary, the precise amount of the compound received and the route of administration depending on the weight, age and sex of the patient being treated and on the particular disease condition being treated according to principles known in the art.
  • unit dosage forms will contain about 1 mg to 500 mg of a compound of this invention.
  • a pharmaceutical composition which comprises a compound of the formula I as defined hereinbefore or a pharmaceutically-acceptable salt or an in v/vo-hydrolysable ester, amide or carbamate thereof, in association with a pharmaceutically-acceptable excipient or carrier.
  • a further feature of the present invention is a compound of formula I and pharmaceutically-acceptable salts or an in v/vo-hydrolysable ester, amide or carbamate thereof, for use as a medicament.
  • a compound of the present invention suitable for use as a medicament is a compound of formula I: i wherein:
  • R 1 is hydrogen, C h alky!, C 2-6 alkenyl, C 2 . 6 alkynyl or phenylC 2 . 6 alkyl; R 2 and R 3 are independently selected from hydrogen, C ⁇ _ 6 alkyl, phenylsulphonyl, 1-
  • A is halo, nitro, hydroxy, C]_ 6 alkoxy, cyano, amino, trifluoromethyl, trifluoromethoxy, carboxy, carbamoyl, mercapto, sulphamoyl, mesyl, N-C ⁇ . 6 alkylamino, N,N- (C ⁇ . 6 alkyl) 2 amino, d_ alkoxycarbonyl, N-C ⁇ - alkylcarbamoyl or N,N-(C ⁇ . 6 alkyl) 2 carbamoyl and p is 2 to 6, or
  • R 2 or R 3 is a group of the formula IB: (CR 6 R 7 )— B
  • R 6 and R 7 are independently selected from hydrogen and Cj -3 alkyl
  • B is aryl, a carbon linked heteroaryl, a carbon-linked heterocyclyl, C 3 _ ⁇ 2 cycloalkyl or C 3- ⁇ 2 cycloalkyl fused to a benzene ring
  • q is an integer selected from the range 0 to 6
  • said aryl, heteroaryl or heterocyclyl may be optionally substituted on a ring carbon with one or more M groups where M at each occurrence is independently selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C ⁇ .
  • R and R together with the nitrogen atom to which they are attached form a heterocyclyl or heteroaryl ring, wherein said heterocyclyl or heteroaryl ring may be optionally substituted on a ring carbon with one or more groups selected from M as heretofore defined, said heterocyclyl or a heteroaryl ring may have an -NH- group that may be substituted on the nitrogen with C ⁇ _ 6 alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C ⁇ -6 alkanoyl, C ⁇ . 6 alkylsulphonyl, or said heterocyclyl or a heteroaryl ring may be optionally substituted with an ortho-fused aryl moiety; R 4 at each occurrence is independently selected from hydrogen, halo, hydroxy,
  • R 5 at each occurrence is independently selected from hydrogen and Cj. alkyl; n is 1 or 2; or a pharmaceutically-acceptable salt or an in v/vo-hydrolysable ester, amide or carbamate thereof.
  • Compounds of formula I are useful in medicaments that 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 selectively 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 formulae I, XVII, XVIII, XIX or XX or a pharmaceutically-acceptable salt or an in v/vo-hydrolysable ester, amide or carbamate thereof, as defined hereinbefore.
  • binding affinities (IC 50 ) for 75 representative compounds of the invention to the [ 3 H]-emopamil binding site ranged from 7 nM to 261 nM.
  • binding affinities (IC 50 ) for 52 representative compounds of the invention from the aforementioned group of 75 to the H-D-888 binding site ranged from 1091 nM to 58,415 nM. 10
  • the assays were perfomed as follows:
  • Binding at the [ 3 H] -emopamil binding site was determined by a modification of the method described by Zech et al. (Zech , C, Staudinger R., M ⁇ hlbacher, J. and Glossmann, H. Novel sites for phenylalkylamines: characterisation of a sodium-sensitive drug receptor with (- 15 )- 3 H-emopamil. E r. J. Pharm., (1991), 208, 1 19-130). Guinea-pig liver membrane preparation:
  • Assay buffer 10 mM Tris-HCl, 0.1 mM phenylmethylsulfonyl fluoride (PMSF), 0.2% 30 bovine serum albumin (BSA), pH 7.4 at 4 °C.
  • PMSF phenylmethylsulfonyl fluoride
  • BSA bovine serum albumin
  • Radioligand 0.96 nM (-)- 3 H-emopamil (Amersham).
  • Guinea pig liver membranes 40mg/mL original wet weight.
  • 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.
  • PEI polyethylenimine
  • 3 H-D-888 binding was determined by a modification of Reynolds et al. (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. (1986) 237: no.3, 731-738).
  • 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.
  • membrane buffer 5 mM Hepes, 0.2% BSA, pH 7.4
  • Rat cortical membranes 6 mg/mL original wet weight
  • 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% polyethylenimine (PEI) and washed three times with 5 mL of wash buffer containing 20 mM Hepes, 20 mM MgCl , 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.
  • mice Male Mongolian gerbils (Charles River) weighing 60-70 grams are used in these experiments. They are housed in individual cages with food (Purina Rodent Chow) and water available ad libitum. The animal room is maintained at 23 ⁇ 2 °C, and is on an automatic 12 hour light cycle.
  • the gerbils are brought to the surgical suite and dosed intraperitoneally with the test agent or vehicle, forty-five minutes prior to surgery. Drugs are administered at a volume of 5 mL/kg (intraperitoneal). Vehicle is generally saline, with sodium phosphate added to adjust the pH, if needed. Forty-five minutes after dosing the gerbils are anaesthetised with halothane (3.3%) which is delivered along with oxygen (1.5 1/M) through a face mask. After the gerbils are anaesthetised, halothane is continued at a maintenance level of 1.5-2 % along with oxygen. The ventral surface of the neck is shaved and cleaned with alcohol.
  • Surgical procedures are carried out on a thermostat-controlled heating pad set to 37 °C.
  • An incision is made in the neck, the carotid arteries are dissected away from the surrounding tissue, and isolated with a 5 cm length of Silastic tubing.
  • both arteries have been isolated they are clamped with microaneurysm clips (Roboz Instruments).
  • the arteries are visually inspected to determine that the blood flow has been stopped. After 5 minutes the clips are gently removed from the arteries and blood flow begins again.
  • a sham control group is treated identically but is not subjected to carotid artery occlusion.
  • the incisions are closed with suture and the gerbils removed from the anaesthesia masks and placed on another heating pad to recover from the anaesthesia.
  • Sprague-Dawley CD (Charles River) rats 250g-300g were used. Anaesthesia was induced with 5% halothane, reducing to 3% then 1.5%, with approximately 30% N 2 O and 20 65% O 2 .
  • the left femoral vein was cannulated with cannula filled with 0.4 ml of 100 i.u./ml heparin prior to use and the cannula exteriorised through the tail. A tail cuff was fitted. Test substance or saline was infused (blinded) at 3.3 ml/kg/hr, halothane was reduced to 1%, then after 5-10 min, surgery was performed as described below.
  • the right carotid surgically exposed and ligated. An incision was made above the left 25 eye and scalp muscle retracted, and a 3mm trochar hole was made above the zygomatic arch.
  • the middle cerebral artery was exposed using bone nibblers and the dura removed. The main branch of the middle cerebral artery was occluded below the bifurcation by cauterisation using a Surgicare Hi-Temp Fine-Tip device Model 8500. Typically 2-4 branches were also cauterised.
  • the left carotid was then clipped, the time recorded and the muscle and skin were sutured. The rats were moved to another anaesthetic station.
  • N 2 O was withdrawn and animals were maintained on 1% halothane, 40% air, 60% O 2 for 1 hour without monitoring of the pO 2 and pCO 2 .
  • the right carotid clip was then removed and the incision sutured. Animals were removed from anaesthesia and allowed to recover.
  • 'Temgesic' 0.012ml (0.03 mg/ml) s.c. was administered under the direction of a veterinary surgeon as soon as the animals became mobile and exhibited normal gait and cage exploration. Animals were then moved to a lit holding room. Sample preparation
  • 2% halothane were placed in a stereotactic head frame with ear bars and tooth bars and maintained at 38 °C.
  • the stereotactic device was placed within a 63mm birdcage coil in a 4.7 T magnet. ECG was monitored.
  • Segmentation was performed using the region-growing algorithms within 'Tosca' v2.5 (IBM) segmentation software.
  • the endpoint was volume in voxels. This was converted to volume in ml with the aid of a standard calibration factor.
  • DMSO dimethylsulphoxide
  • ⁇ MP is N-methylpyrrolidone
  • Example 1 N'.N'-Diisopropyl-N ⁇ -tetrahydro-l-naphthalenyll-l ⁇ -ethanediamine.
  • -Tetralone 0.37g, 5.72xl0 "3 mole
  • 2-(diisopropylamino)ethylamine 5.165g, 3.58xl0 "2 mole
  • the mixture was treated with titanium tetrachloride solution (l.OM in toluene, 3.0 mL, 3.0xl0 "3 mole), maintaining the reaction temperature at ⁇ 5 °C.
  • l-[2-(Diisopropylamino)ethylamino]-l,2,3,4-tetrahydronaphthalene (Example 1) (0.319g, l.l ⁇ xlO '3 mole) was dissolved in methanol (7 mL) and the solution was treated with formaldehyde (37% aqueous, 3.0 mL, 4.00x10 " mole).
  • Example 62 N'-2-Cvanobenzyl-N -methyl-N -methyl-N -IY 1.SV 1 ,2.3.4-tetrahydronaphthalen- 1 - yllethane- 1 ,2-diamine.
  • l-[2-(Methylamino)ethylamino]-l,2,3,4-tetrahydronaphthalene (Example 122) (0.704g, 3.22xl0 "3 mole) and potassium carbonate (0.477g, 3.23x10 3 mole) were combined in acetonitrile (20 mL) according to the foregoing scheme.
  • Example 74 l-r2-(N-Phenethylpiperidin-4-ylamino)ethylamino1-l,2,3,4-tetrahydronaphthalene.
  • 1 -[2-(N-Phenethylpiperidin-4-ylamino)acetamido]- 1 ,2,3,4-tetrahydronaphthalene (Example 118) (0.584g, 1.49xl0 "3 mole) was dissolved in tetrahydrofuran (10 mL) and treated with 1.0 M borane-tetrahydrofuran (13.0 mL, 1.30x10 2 mole) at ambient temperature.
  • 6-Isopropenyl-N-methyl-N-(2-piperidinoethyl)- 1 ,2,3,4-tetrahydro- 1-naphthalenamine 6-Isopropenyl-N-methyl-N-(2-piperidinoethyl)- 1 ,2,3,4-tetrahydro- 1-naphthalenamine was made by adding titanium(IN) chloride (l.OM in methylene chloride, 267 ⁇ L, 0.267 mmol) to a solution of a compound of Example 80 (88 mg, 0.267 mmol) in 5.3 mL of methylene chloride at -30 to -40 °C. A light brown suspension was obtained. After 10 min, dimethylzinc (2.0 M in toluene, 133.5 ⁇ L, 0.267 mmol) was added.
  • titanium(IN) chloride l.OM in methylene chloride, 267 ⁇ L, 0.267 mmol
  • 6-(7ert-butyl)-N-methyl-N-(2-piperidinoethyl)- 1 ,2,3,4-tetrahydro- 1-naphthalenamine 6-(7ert-butyl)-N-methyl-N-(2-piperidinoethyl)- 1 ,2,3,4-tetrahydro- 1 -naphthalenamine was made by adding dimethylzinc (2.0M in toluene, 133.5 ⁇ L, 0.267 mmol) to a solution of titanium(IV) chloride (l.OM in methylene chloride, 267 ⁇ L, 0.267 mmol) in 0.6 mL of methylene chloride at -30 °C, and stirring the resulting orange suspension for 30 min.
  • dimethylzinc 2.0M in toluene, 133.5 ⁇ L, 0.267 mmol
  • titanium(IV) chloride l.OM in methylene chloride, 267 ⁇ L, 0.267 mmol
  • N' ,N -dimethyl-N'-r( IS)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyll- 1 ,2-ethanediamine A suspension of N-(t-butoxycarbonyl)glycine (2.26g, 1.29xl0 "2 mole) and 1- hydroxybenzotriazole (1.77g, 1.31xl0 "2 mole) in DCM (40 mL) was treated with l-[3- (dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (2.86 g, 1.49xl0 "2 mole).
  • the coupling agent was washed in with DCM (lOmL), then triethylamine (2.1 mL, 1.51xlO "2 mole) was added. Immediately, a solution of (S)-l-methylamino-l,2,3,4- tetrahydronaphthalene (Smith, R.A.; White, R.L.; Krantz, A., J. Med. Chem., (1988), 31, 1558-66) (1.95g, 1.21xl0 "2 mole) in DCM (50 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.
  • N-Methyl-2-rmethyl(phenylsulfonyl)amino1-N-r( IS)- 1 ,2.3,4-tetrahydro- 1 - naphthalenyllacetamide A suspension of N-phenylsulfonylsarcosine (1.00, 4.35x10 "3 mole) and 1- hydroxybenzotriazole (0.63 g, 4.69xl0 "3 mole) in DCM (15 mL) was treated with l-[3- (dimethylamino)propyl]-3-ethyl carbodiimide hydrochloride (1.03 g, 5.38xl0 "3 mole).
  • Example 124 l-r2-(N-Phenethylpiperidin-4-ylamino)acetamido1-l,2,3,4-tetrahydronaphthalene.
  • l-(2-aminoacetamido)-l,2,3,4-tetrahydronaphthalene (Czech. Patent Application No. CS 71-7151) (0.355g, 1.74xl0 "3 mole) and N-phenethyl-4-piperidone (0.361g, 1.77xl0 "3 mole) were combined in dichloromethane (5 mL) and treated with glacial acetic acid (0.100 mL, 1.75xl0 "3 mole).
  • Example 125 l-r3-(4-methylpiperazin-l- y l ) propyl ( N-acet y l ) aminol-l,2,3,4-tetrahvdronaphthalene.
  • l-[3-(4-methylpiperazin-l-yl)propylamino]-l,2,3,4-tetrahydronaphthalene (Example 130) (0.292g, 1.02xl0 "3 mole) and triethylamine (0.500 mL, 3.59xl0 "3 mole) were combined in dichloromethane (8 mL) and treated with acetyl chloride (0.185 mL, 2.60xl0 "3 mole).
  • N-Methyl-3-piperidino-N-r(lS)-l,2,3,4-tetrahydro-l-naphthalenvnpropanamide N-Methyl-3-piperidino-N-[(lS)-l,2,3,4-tetrahydro-l-naphthalenyl]propanamide was made by adding a solution of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (2.85 g, 14.9 mmol) and triethylamine (2.1 mL, 14.9 mmol) in 50 mL of dichloromethane to a solution of 1-piperidinepropionic acid (2.14 g, 13.6 mmol) and 1-hydroxybenzotriazole hydrate (1.84 g, 13.6 mmol) in 50 mL of dichloromethane.
  • Example 135 N-Methyl-3-piperidino-N-r(lR)-l,2,3,4-tetrahydro-l-naphthalenynpropanamide.
  • N-Methyl-3-piperidino-N-[( 1R)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyljpropanamide was made by the method of Example 134.
  • ⁇ ⁇ MR 300 MHz, CDC1 3 ): 1.45 (m, 2H), 1.61 (m, 4H), 1.72-2.11 (m, 4H), 2.46 (m, 4H), 2.55-2.90 (m, 7H), 3.66 (m, IH), 5.07 (m, IH), 5.94 (m, IH), 6.99-7.20 (m, 3H), 7.32 (m, IH).
  • m/s (M+l) + 301.
  • 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 dérivés de 1,2,3,4-tétrahydronaphtalène correspondant à la formule (I) dans laquelle R1 est choisi dans le groupe constitué par alkyle C¿1-6?, alcényle C2-6, alcynyle C2-6 et phényl-alkyle C2-6, et R?2, R3, R4 et R5¿ possèdent les notations données dans la description. L'invention concerne également des procédés de fabrication de ces dérivés ainsi que des compositions les contenant. Les composés correspondant à la formule (I) sont utiles sur le plan pharmacologique.
EP99959569A 1998-12-15 1999-12-10 1,2,3,4-tetrahydronaphtalenes et leur utilisation pharmaceutique Withdrawn EP1140852A1 (fr)

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GB9827467 1998-12-15
GBGB9827467.3A GB9827467D0 (en) 1998-12-15 1998-12-15 Chemical compounds
PCT/GB1999/004167 WO2000035882A1 (fr) 1998-12-15 1999-12-10 1,2,3,4-tetrahydronaphtalenes et leur utilisation pharmaceutique

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GB9914024D0 (en) * 1999-06-17 1999-08-18 Zeneca Ltd Chemical compounds
MXPA02008797A (es) 2000-03-14 2005-09-08 Actelion Pharmaceuticals Ltd Derivados de 1,2,3,4-tetrahidroisoquinolina.
CA2557163C (fr) 2004-03-01 2011-08-16 Actelion Pharmaceuticals Ltd Derives de 1,2,3,4-tetrahydroisoquinoleine substitues
ES2603262T3 (es) 2012-07-20 2017-02-24 Bayer Pharma Aktiengesellschaft Ácidos aminoindano-carboxílicos y aminotetralin-carboxílicos sustituidos y su uso
SG10201700454PA (en) 2012-07-20 2017-03-30 Bayer Pharma AG Novel 5-aminotetrahydroquinoline-2-carboxylic acids and use thereof

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BR9909994A (pt) * 1998-04-29 2000-12-26 Smithkline Beecharm P L C Quinolinas usadas como inibidores de mrs e bactericidas

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