WO2000035882A1 - 1,2,3,4-tetrahydronaphthalenes and their pharmaceutical use - Google Patents
1,2,3,4-tetrahydronaphthalenes and their pharmaceutical use Download PDFInfo
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- WO2000035882A1 WO2000035882A1 PCT/GB1999/004167 GB9904167W WO0035882A1 WO 2000035882 A1 WO2000035882 A1 WO 2000035882A1 GB 9904167 W GB9904167 W GB 9904167W WO 0035882 A1 WO0035882 A1 WO 0035882A1
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- 0 CC(C)N(CC(C)(C)CC(C)(C)C1=CC=C(C)*)C(C)(C)CC(C)(C)C1=CC Chemical compound CC(C)N(CC(C)(C)CC(C)(C)C1=CC=C(C)*)C(C)(C)CC(C)(C)C1=CC 0.000 description 4
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- 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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- 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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- C07D213/02—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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- 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
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- 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
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- 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
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- 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
1,2,3,4-Tetrahydronapthalene derivatives of formula (I) wherein R1 is selected from hydrogen, C¿1-6?alkyl, C2-6alkenyl, C2-6alkynyl and phenylC2-6alkyl and R?2, R3, R4 and R5¿ are as defined in the specification are described, together with processes for their manufacture and compositions containing them. Compounds of formula (I) are pharmacologically useful.
Description
1 , 2 , 3 , 4-TETRAHYDRONAPHTHALENES AND THEIR PHARA ACEUTICAL USE
Field of The Invention
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, to which the present invention relates, include stroke, head trauma, transient cerebral ischaemic attack, and chronic neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, diabetic neuropathy, amyotrophic lateral sclerosis, multiple sclerosis and AIDS-related dementia. Emopamil has classically been thought of as a neuroprotective agent whose efficacy is most likely derived from actions at either voltage-sensitive calcium channels (VSCC) or 5-HT receptors. An apparent paradox to this logic is that verapamil, although chemically and pharmacologically very similar to emopamil, is not neuroprotective. While the lack of neuroprotective efficacy by verapamil was initially explained by lack of CNS penetration, recent studies suggest other factors may be involved (Keith et al., Br. J. Pharmacol. 1 13: 379-384, 1994).
[3H]-Emopamil binding defines a unique high affinity site that is not related to VSCC, is found in the brain, but is most prevalent in the liver (Moebius et al., Mol. Pharmacol. 43: 139-148, 1993). Moebius et al. have termed this the "anti-ischaemic" binding site on the basis of high affinity displacement by several chemically disparate neuroprotective agents. In liver, the [3H]-emopamil binding site is localised to the endoplasmic reticulum.
Neuroprotective compounds are known, for example emopamil and ifenprodil, that exhibit high affinity for the [3H]-emopamil binding site. However these are not selective inhibitors and exhibit activity either at neuronal VSCC, the polyamine site of the NMDA receptor (N-Methyl-D-aspartate) and/or the sigma-1 binding site. It is thought that compounds that interact with either the VSCC or the ΝMDA receptor, are responsible for the side effects
usually seen with emopamil, such as hypotension, or those seen with ifenprodil, such as behavioural manifestations. Summary of The Invention
We have now found a class of compounds that selectively bind at the [3H] -emopamil binding site.
The present invention provides compounds of formula I:
wherein: R1 is selected from hydrogen, Cι_6alkyl, C .6alkenyl, C2.6alkynyl and phenylC2.6alkyl;
R2 and R3 are independently selected from hydrogen, Cι_ alkyl, phenylsulphonyl, 1- (1,2,3,4-tetrahydronaphthyl), a group of the formula IA: (CH, 2)P «
IA wherein A is halo, nitro, hydroxy, C1- alkoxy, cyano, a ino, trifluoromethyl, trifluoromethoxy, carboxy, carbamoyl, mercapto, sulphamoyl, mesyl, N-Ci_6alkylamino, N,N- (Cι.6alkyl)2amino, C1-6alkoxycarbonyl, N-Cι-6alkylcarbamoyl or N,N-(Cι-6alkyl)2carbamoyl, and p is an integer selected from the range 2 to 6, and a group of the formula IB:
IB wherein R6 and R7 are independently selected from hydrogen and Cι-3alkyl, and B is aryl, a carbon linked heteroaryl, a carbon-linked heterocyclyl, C3.12cycloalkyl or C3-ι2cycloalkyl fused to a benzene ring; q is an integer selected from the range 0 to 6; and wherein 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, C1-6alkyl, C2.6alkenyl, C2-6alkynyl, Cι-6alkoxy, Cι-6alkanoyl, Cι-6alkanoyloxy, N-
(Cι- alkyl)amino, N,N-(Cι-6alkyl)2amino, Cι_6alkanoylamino, N-(Cι-6alkyl)carbamoyl, N.N- (Cι-6alkyl)2carbamoyl, Cι-6alkylSOa where a is an integer selected from 0, 1 or 2, Cι-6alkoxycarbonyl, N-(Cι_6alkyl)sulphamoyl, N,N-(Cι_6alkyl)2sulphamoyl and phenylCι. alkyl; and a heterocyclyl or a heteroaryl ring having an -ΝH- group may be optionally substituted on this nitrogen with Cι.6alkyl, C2- alkenyl, C2.6alkynyl, Cι_6alkanoyl, Cι_6alkylsulphonyl or phenylCι_6alkyl, or
R2 and R3 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 -ΝH- group that may be substituted on the nitrogen with Cι_6alkyl, C2.6alkenyl, C2.6alkynyl, Cι-6alkanoyl or Cι_6alkylsulphonyl, said heterocyclyl or heteroaryl ring may have an -O- group, said heterocyclyl or heteroaryl ring may be optionally substituted with an ortho-fused aryl moiety, and wherein any aforesaid heterocyclyl, heteroaryl ring or aryl moiety may be optionally substituted on a ring carbon with one or more R9 groups selected from M as heretofore defined, r is 4 and R4 at each occurrence is independently selected from hydrogen, halo, hydroxy, Cι-6alkyl, Cι.6alkoxy, hydroxyCι- alkyl, haloCι-6alkyl, cyano, nitro and C2-6alkenyl; s is 7 and R5 at each occurrence is independently selected from hydrogen and Cι-6alkyl, and n is 1 or 2; or a pharmaceutically-acceptable salt or an in vzvø-hydrolysable ester, amide or carbamate thereof; provided that said compound of formula I is not Ν,N-diethyl-N'-( 1,2,3 ,4-tetrahydro-l - naphthalenyl)- 1 ,2-ethanediamine, N-propyl-N'-( 1 ,2,3,4-tetrahydro-5-methoxy- 1 - naphthalenyl)- 1 ,2-ethanediamine, N-propyl-N'-( 1 ,2,3,4-tetrahydro-7-methoxy- 1 - naphthalenyl)- 1 ,2-ethanediamine, N-propyl-N'-( 1 ,2,3,4-tetrahydro-8-methoxy- 1 - naphthalenyl)- 1 ,2-ethanediamine or N-propyl-N'-( 1 ,2,3,4-tetrahydro-5,8-dimethoxy- 1 - naphthalenyl)- 1 ,2-ethanediamine.
Particular compounds according to formula I provided by the present invention are compounds having the formula XVII:
XVII wherein:
R is selected from hydrogen,
C2.6alkenyl, C2_6alkynyl and phenylC2_6alkyl; R8 is selected from hydrogen and Cι-6alkyl; r is 4 and R4 at each occurrence is independently selected from hydrogen, halo, hydroxy, Cj-6alkyl, Cj_6alkoxy, hydroxyCι_6alkyl,
cyano, nitro and C2. alkenyl; s is 7 and R5 at each occurrence is independently selected from hydrogen and Cι_6alkyl, and n is 1 or 2; or a pharmaceutically-acceptable salt or an in v vo-hydrolysable ester, amide or carbamate thereof.
Other particular compounds according to formula I provided by the present invention are compounds having the formula XVIII:
XVIII wherein:
R is selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl and phenylC2- alkyl, and r is 4 and R at each occurrence is independently selected from hydrogen, halo, hydroxy, Cι-6alkyl, Cι.6alkoxy, hydroxyCι.6alkyl, haloC1-6alkyl, cyano, nitro and C2-6alkenyl; s is 7 and R5 at each occurrence is independently selected from hydrogen and Cι-6alkyl, 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:
XIX wherein:
R is selected from hydrogen, Cι_6alkyl, C2-6alkenyl, C2. alkynyl and phenylC2.6alkyl, and v is 4 and R9 is independently selected at each occurrence from hydrogen, halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl,
C2.6alkenyl, C2.6alkynyl, Cι. alkoxy, Cι-6alkanoyl, Cι_6alkanoyloxy, N- (Cι_6alkyl)amino, N,N-(Cι_6alkyl)2amino, Cι.6alkanoylamino, N-(Cι.. alkyl)carbamoyl, N,N- (Cι_6alkyl)2carbamoyl, Cι-6alkylSOa where a is an integer selected from 0, 1 or 2, Cι-6alkoxycarbonyl, N-(C1-6alkyl)sulphamoyl, N,N-(Cι.6alkyl)2sulphamoyl and phenylCι-6alkyl; r is 4 and R4 at each occurrence is independently selected from hydrogen, halo, hydroxy,
hydroxyCι-6alkyl, haloCι- alkyl, cyano, nitro and C2-6alkenyl; s is 7 and R5 at each occurrence is independently selected from hydrogen and
Cι-6alkyl, and n is 1 or 2, t is 0, 1 or 2, and u is 0 or 1; or a pharmaceutically-acceptable salt or an in v/vo-hydrolysable ester, amide or carbamate thereof. Yet other particular compounds according to formula I provided by the present invention are compounds having the formula XX:
XX wherein:
R1 is selected from hydrogen,
C2.6alkenyl, C2.6alkynyl and phenylC2- alkyl; r is 4 and R4 at each occurrence is independently selected from hydrogen, halo, hydroxy, Cι..6alkyl, Cι_6alkoxy, hydroxy C1-6alkyl, haloCι-6alkyl, cyano, nitro and C2. alkenyl; s is 7 and R5 at each occurrence is independently selected from hydrogen and Cj-βalkyl, m is an integer selected from the range 1 to 5;
R10 is selected from hydrogen and Cj_6alkyl, and n is 1 or 2; or a pharmaceutically-acceptable salt or an in v/vo-hydrolysable ester, amide or carbamate thereof.
Intermediates of compounds according to formula I are provided by the present invention. Such compounds have the formula XXIX:
XXIX wherein:
R1 is selected from hydrogen, Cι- alkyl, C2-6alkenyl, C2-6alkynyl and phenylC2-6alkyl; R2 and R3 are independently selected from hydrogen, Cι_6alkyl, phenylsulphonyl, 1- (1,2,3,4-tetrahydronaphthyl), a group of the formula IA: (CH2)p— A
IA where A is halo, nitro, hydroxy, Cι-6alkoxy, cyano, amino, trifluoromethyl, trifluoromethoxy, carboxy, carbamoyl, mercapto, sulphamoyl, mesyl, N-Cι-6alkylamino, N,N- (Ci.6alkyl)2amino, Cι-6alkoxycarbonyl, N-Cι.6alkylcarbamoyl or N,N-(Cι_6alkyl)2carbamoyl, and p is an integer selected from the range 2 to 6, and a group of the formula IB: (CR6R7)q— B
where R6 and R7 are independently selected from hydrogen and C1-3alkyl, and B is aryl, a carbon linked heteroaryl, a carbon-linked heterocyclyl, C3-ι2cycloalkyl or
C3_ι2cycloalkyl fused to a benzene ring; q is an integer selected from the range 0 to 6; and wherein 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, Cj- alkyl, C2.6alkenyl, C2.6alkynyl, d^alkoxy, d..6alkanoyl, Cι-6alkanoyloxy, N-(Ci_6alkyl)amino, N,N-(Cι-6alkyl)2amino, Cι„ alkanoylamino, N- (Cι_6alkyl)carbamoyl, N,N-(Cι-6alkyl)2carbamoyl, d-6alkylSOa where a is an integer selected from 0, 1 or 2, Cι_6alkoxycarbonyl, N-(Cι_6alkyl)sulphamoyl, N,N-(d_6alkyl)2sulphamoyl and phenylCι-6alkyl; and a heterocyclyl or a heteroaryl ring having an -ΝH- group may be optionally substituted on this nitrogen with Cj.6alkyl, C2- alkenyl, C2.6alkynyl, Cι_6alkanoyl, Cι.6alkylsulphonyl or phenylCι-6alkyl, or
R2 and R3 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 -ΝH- group that may be substituted on the nitrogen with d.6alkyl, C2-6alkenyl, C2-6alkynyl, Ci-βalkanoyl, C1-6alkylsulphonyl, or said heterocyclyl or a heteroaryl ring may be optionally substituted with an ortho-fused aryl moiety; r is 4 and R4 at each occurrence is independently selected from hydrogen, halo, hydroxy, Cι-6alkyl, Cι.6alkoxy, hydroxyCι-6alkyl, haloCι-6alkyl, cyano, nitro and C2.6alkenyl; s is 7 and R5 at each occurrence is independently selected from hydrogen and C|. alkyl, and
n is 1 or 2.
Other intermediates of compounds according to formula I provided by the present invention have the formula XXI:
R1 is selected from hydrogen, Cj. alkyl, C2_6alkenyl, C2.6alkynyl and phenylC2_6alkyl; r is 4 and R4 at each occurrence is independently selected from hydrogen, halo, hydroxy, Cι_6alkyl,
hydroxyCι_6alkyl, haloCι_6alkyl, cyano, nitro and C2_6alkenyl; s is 7 and R5 at each occurrence is independently selected from hydrogen and
C1-6alkyl, m is an integer selected from the range 1 to 5;
R7 is selected from hydrogen and Cι.6alkyl, and n is 1 or 2; or a pharmaceutically-acceptable salt or an in v/vo-hydrolysable ester, amide or carbamate thereof.
Further intermediates of compounds according to formula I provided by the present invention have the formula XXII:
XXII wherein:
R1 is selected from hydrogen, d_ alkyl, C2.6alkenyl, C -6alkynyl and phenylC2-6alkyl;
v is 4 and R9 is independently selected at each occurrence from hydrogen, halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, d-6alkyl, C2.6alkenyl, C2-6alkynyl, Cι_6alkoxy, Cι_ alkanoyl, d_6alkanoyloxy, N- (Cι-6alkyl)amino, N,N-(Cι_6alkyl)2amino, Cι_6alkanoylamino, N-(Cι-6alkyl)carbamoyl, N,N- (Cι_6alkyl)2carbamoyl, Cι_6alkylSOa where a is an integer selected from 0, 1 or 2, Cι_ alkoxycarbonyl, N-(Cι_6alkyl)sulphamoyl, N,N-(Cι-6alkyl)2sulphamoyl and phenylCι-6alkyl; r is 4 and R4 at each occurrence is independently selected from hydrogen, halo, hydroxy, Cι-6alkyl, Cι-6alkoxy, hydroxyCι„6alkyl, haloCι„6alkyl, cyano, nitro and C2.6alkenyl; s is 7 and R5 at each occurrence is independently selected from hydrogen and
Cι.6alkyl, n is 1 or 2, t is 0, 1 or 2, and u is 0 or 1; or a pharmaceutically-acceptable salt or an in v/vo-hydrolysable ester, amide or carbamate thereof. Detailed description of The Invention As used herein the term "alkyl," as in for example C1- alkyl, includes both straight and branched chain alkyl groups but references to individual alkyl groups such as "propyl" are specific for the straight chain version only. A similar convention applies to "alkenyl", "alkynyl" and other radicals, for example "phenylCι_6alkyl" includes 2-phenylethyl, 2-phenylpropyl and 3-phenylpropyl. As used herein "halo" means fluoro, chloro, bromo and iodo.
As used herein, aryl means an unsaturated carbon ring. Particularly aryl is phenyl, naphthyl or biphenyl. More particularly aryl is phenyl.
As used herein, "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 -CH2- group can optionally be replaced by a -C(O)-, and a ring nitrogen atom may be optionally oxidised to form the N-oxide. Examples of such heteroaryls include thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, pyridyl, pyridyl-N-oxide, oxopyridyl, oxoquinolyl, pyrimidinyl, pyrazinyl, oxopyrazinyl, pyridazinyl, indolinyl, benzofuranyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolinyl, quinazolinyl, xanthenyl, quinoxalinyl, indazolyl, benzofuranyl and cinnolinolyl.
As used herein "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 -CH2- group can optionally be replaced by a -C(O)-. Examples of such heterocyclyls include morpholinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, homopiperidinyl, homopiperazinyl and quinuclidinyl.
As used herein, where optional substituents are selected from "one or more" groups it is to be understood that this encompasses compounds where all substituents are chosen from one of the specified groups and compounds where substituents are chosen from more than one of the specified groups.
As used herein terms such as "0 to 6" means each integral value in the stated range, that is, for 0 to 6 the values 0, 1, 2, 3, 4, 5 and 6, similarly, terms such as "range 0 to 2" means the values 0, 1 and 2.
In the present invention, examples of Cj_6alkyl include Cj. alkyl moieties such as methyl, ethyl, isopropyl and t-butyl; examples of phenylCj-βalkyl include phenylCι- alkyl moieties such as benzyl, examples of phenylC2-6alkyl include phenylC2- alkyl moieties such as phenylethyl and phenylpropyl; examples of Cι_6alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, n- and t-butoxycarbonyl; examples of d^alkoxy include methoxy, ethoxy and propoxy; examples of Cι. alkanoylamino include formamido, acetamido and propionylamino; examples of Cι_6alkylSOa where a is 0, 1 or 2 include
methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl and ethyl sulphonyl; examples of Cι_6alkylsulphonyl include mesyl and ethylsulphonyl; examples of Cι-6alkanoyl include propionyl and acetyl; examples of N-C1-6alkylamino include N-methylamino and N- ethylamino; examples of N,N-(Cι-6alkyl)2amino include N,N-dimethylamino, N,N- diethylamino and N-ethyl-N-methylamino; examples of C3.l2cycloalkyl include cyclopropyl and cyclohexyl; examples of C3-ι2cycloalkyl fused to a benzene ring are 1,2,3,4- tetrahydronaphthyl and 2,3-dihydroindenyl; examples of C2-6alkenyl include vinyl, allyl and 1-propenyl; examples of C2- alkynyl include ethynyl, 1-propynyl and 2-propynyl; examples of haloC2- alkyl include 2-chloroethyl and 2-bromopropyl; examples of N-(C1- alkyl)sulphamoyl include N-methylsulphamoyl and N-ethylsulphamoyl; examples of N,N-
(d-6alkyl)2sulphamoyl include N,N-dimethylsulphamoyl and N-methyl-N-ethylsulphamoyl; examples of N-(Cι_ alkyl)carbamoyl include N-methylcarbamoyl and N-ethylcarbamoyl;
examples of N,N-(Cι- alkyl)2carbamoyl include N,N-dimethylcarbamoyl and N-methyl-N- ethylcarbamoyl; examples of
include propionyloxy, acetyloxy and formyloxy. In a particular compound of the invention, R is hydrogen, Cι-6alkyl or phenylC2.6alkyl. More particularly R1 is hydrogen, Cι_4alkyl or phenylC2.4alkyl. Particularly R1 is hydrogen, methyl or ethyl.
More particularly R1 is hydrogen or methyl.
In a particularly preferred aspect R1 is methyl.
In one aspect of the invention, R" and R are independently selected from hydrogen, Cι_6alkyl or a group of the formulae I A or IB:
-(CH2)p— A (CR6R7) — B "" ^
IA IB as heretofore defined.
In another particular aspect of the invention, R~ and R3 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, Cι.6alkyl, C2-6alkenyl, C2-6alkynyl, Cj-6alkoxy, Cι.6alkanoyl, d_ alkanoyloxy, N- (Cι_6alkyl)amino, N,N-(Cι_6alkyl)2amino, Cι.6alkanoylamino, N-(Cι.6alkyl)carbamoyl, N,N- (Cι_ alkyl)2carbamoyl, Cι-6alkylSOa wherein a is an integer selected from the range 0 to 2, Ci.6alkoxycarbonyl, N-(Cι-6alkyl)sulphamoyl, N,N-(Cι-6alkyl) sulphamoyl or phenylCι-6alkyl.
In a further aspect of the invention, R and R are independently selected from hydrogen, Cι_6alkyl, or a group of the formula (IB) as depicted above wherein B is aryl, a carbon-linked heterocyclyl, where a heterocyclyl containing an -ΝH- group may be optionally substituted on the nitrogen with phenylCι_6alkyl, or C3_ι2cycloalkyl fused to a benzene ring. In another aspect of the invention, 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 Cι_6alkyl and a heterocyclyl ring containing an -ΝH- group may be optionally substituted on this nitrogen with Cι.6alkyl.
In another aspect of the invention, R2 and R3 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.
In a particular aspect of the invention, R2 and R3 are independently selected from methyl, ethyl, isopropyl, benzyl or phenylethyl, or R2 and R3 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.
More particularly R2 and R3 are ethyl or R2 and R3 together with the nitrogen to which they are attached form a piperidin-1-yl or l,2,3,4-tetrahydroisoquinol-2-yl ring.
In particular aspects of the invention, R at each occurrence is selected from hydrogen, hydroxyCj-6alkyl, C2-6alkenyl, halo or Cι-6alkyl. More particularly R4 at each occurrence is selected from hydrogen, halo or Cι_4alkyl. Particularly R4 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,
XXX XXXI XXXII wherein R1, R2, R3 and n are as defined heretofore for compounds of formula I.
In a particular aspect of the invention, R5 moieties are selected from hydrogen and Cι. alkyl. More particularly R5 moieties are selected from hydrogen, methyl and ethyl. Most particularly R5 moieties are selected from hydrogen and methyl. Particularly all R5 moieties are hydrogen.
In particular aspects of the invention n is an integer selected from 1 or 2.
Therefore, in a particular aspect of the invention there is provided a compound of formula I as depicted above wherein: R1 is hydrogen, Cι- alkyl or phenylC2.6alkyl;
R2 and R3 are independently selected from hydrogen, C1-6alkyl, or R2 or R3 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 phenylCι-6alkyl, or C3_ι cycloalkyl fused to a benzene ring and q is an integer selected from the range 0 to 6, or
R2 and R3 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 Cι_ alkyl and a heterocyclyl ring containing an -NH- group may be optionally substituted on this nitrogen with Ci- alkyl; R4 is hydrogen, halo, Cj_6alkyl, hydroxyCι-6alkyl or C2_6alkenyl where each R4 may be the same or different and at least one R4 moiety is hydrogen;
R5 is hydrogen or Cj_4alkyl where each R5 may be the same or different and at least one R5 moiety is hydrogen; or a pharmaceutically-acceptable salt or an in v/vo-hydrolysable ester, amide or carbamate thereof.
In a more particular aspect of the invention there is provided a compound of the formula I as depicted above wherein:
R1 is hydrogen, Cj. alkyl or pheny!C2-4alkyl;
R2 and R3 are independently selected from methyl, ethyl, isopropyl, phenyl, benzyl or phenylethyl, or
R2 and R3 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;
R4 is hydrogen, halo or d- alkyl where each R4 may be the same or different and at least two R4 moieties are hydrogen;
R5 is hydrogen, methyl or ethyl where each R5 may be the same or different and at least two R5 moieties are hydrogen, and n is 1, or a pharmaceutically-acceptable salt or an in v/vo-hydrolysable ester, amide or carbamate thereof.
In a particular aspect of the invention there is provided a compound of formula I as depicted above wherein:
R1 is hydrogen, methyl or ethyl; one of R2 and R3 is methyl and the other is phenyl, benzyl or phenylethyl, or one of R2 and R3 is hydrogen and the other is isopropyl, benzyl, 1,2,3,4-tetrahydronapth-l-yl or N-(phenylethyl)piperidin-4-yl, or R2 and R3 are the same group and are selected from methyl, ethyl and isopropyl, or
R2 and R3 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, moφholino, homopiperidin-1-yl or l,2,3,4-tetrahydroisoquinol-2-yl ring; one R4 moiety is bromo, or two R4 moieties are methyl and other R4 moieties are hydrogen; and
R5 is always hydrogen, and n is 1, or a pharmaceutically-acceptable salt or and in v/vo-hydrolysable ester, amide or carbamate thereof. In a still more particular aspect of the invention there is provided a compound of formula I as depicted above wherein:
R1 is hydrogen or methyl; one of R2 and R3 is methyl and the other is benzyl or phenylethyl, or
R2 and R3 are the same group and are selected from ethyl or isopropyl, or R2 and R3 together with the nitrogen atom to which they are attached form a
2-methylpiperidin-l-yl, piperidin-1-yl, homopiperidin-1-yl, pyrrolidin-1-yl or a l,2,3,4-tetrahydroisoquinol-2-yl ring; the R4 is always hydrogen, or R4 at the 6- position is bromo, or R4 at the 5 and 8 positions is methyl; and R5 is hydrogen, and n is 1, or a pharmaceutically-acceptable salt or and in v/vo-hydrolysable ester, amide or carbamate thereof.
In a yet more particular aspect of the invention there is provided a compound of formula I as depicted above wherein:
R1 is methyl;
R2 and R3 are both ethyl, or
R2 and R3 together with the nitrogen to which they are attached form a piperidin-1-yl or l,2,3,4-tetrahydroisoquinol-2-yl ring; the R4 is always hydrogen, or R4 at the 6- position is bromo, or R4 at the 5 and 8 positions is methyl; and R5 is hydrogen, and n is 1 or a pharmaceutically-acceptable salt or and in v/vo-hydrolysable ester, amide or carbamate thereof.
Particular compounds of the invention are those of the examples herein. Suitable pharmaceutically-acceptable salts include acid-addition salts such as methanesulphonate, fumarate, hydrochloride, hydrobromide, citrate, maleate, phosphate and sulphate. In another aspect suitable salts are base salts such as an alkali metal salt, for example sodium, an alkaline earth metal salt, for example calcium or magnesium, an organic amine salt, for example triethylamine, moφholine, 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.
Compounds of formula I possess a chiral centre at the 1 -position of the 1,2,3,4-tetrahydronaphthalene ring. Certain compounds of formula I may also have other chiral centres, for example certain of the values of R1, R2, R3, R4, R5 and certain of the optional substituents may possess chiral centres. It is to be understood that the invention encompasses all such optical isomers and diastereoisomers of compounds of formula I that act at the [3H] -emopamil binding site. The invention further relates to all tautomeric forms of the compounds of formula I.
It is also to be understood that certain compounds of the formula I can exist in unsolvated as well as solvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated and unsolvated forms.
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).6alkoxymethyl esters, for example me thoxy methyl; C].6alkanoyloxymethyl esters for example pivaloyloxymethyl; phthalidyl esters; C3-8cycloalkoxy-carbonyloxyCι-6alkyl esters, for example 1-cyclohexylcarbonyloxyethyl; l,3-dioxolen-2-onylmethyl esters, for example 5-methyl-l,3-dioxolen-2-onylmethyl; and Cj-6alkoxycarbonyloxyethyl 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 α-acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester yield the parent hydroxy group. Examples of α-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 R1, R2, R3, R4, R5 and n, are, unless otherwise specified, as defined in formula I which process comprises: a) reacting a ketone of formula II:
HI; wherein: when R2 or R3 of a compound of formula I is hydrogen Rb and Rc are suitable amino protecting groups such as those defined below; or when R2 or R3 of a compound of formula I is not hydrogen Rb and Rc are R2 and R3 respectively; or b) reacting an amine of formula IV:
IV with an aldehyde of formula V:
V wherein R and Rc are as defined above; or c) reacting an aldehyde of formula VI:
VI with an amine of formula:
Rb
HN
Rc
VII
wherein: when R of a compound of formula I is hydrogen Ra is suitable amino protecting group such as those defined below; or when R of a compound of formula I is not hydrogen Ra is R1; or d) if R1 is Cj- alkyl or phenylC2.6alkyl, reacting a compound of formula VIII:
IX wherein J is hydrogen, Cj.salkyl, or phenylCι_5alkyl; or e) reacting a compound of formula X:
X wherein L is a suitable displaceable group, with an amine of formula III; or f) reacting an amine of formula IV with a compound of formula XI:
XI wherein L is a suitable displaceable group and Rb and Rc are as defined above; or g) reacting a compound of formula XII:
XII wherein L is a suitable displaceable group, with an amine of formula VII; or h) if R is not hydrogen, reacting a compound of formula VIII with a compound of formula XIII:
R'-L xm wherein L is a suitable displaceable group; or i) reducing a compound of formula XIV:
XIV or j) reducing a compound of formula XV:
XV or k) reducing a compound of formula XVI:
XVI wherein: for e), f), g) and h) 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 Cι_6alkoxy, 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.
Specific reaction conditions for reactions a), b), c) and d) are as follows: Ketones or aldehydes may be reacted with amines under standard reductive amination conditions. For example in the presence of a reducing agent such as hydrogen and a hydrogenation catalyst (for example palladium on carbon), or zinc and hydrochloric acid, or sodium cyanoborohydride, or sodium triacetoxyborohydride, or sodium borohydride, iron pentacarbonyl and alcoholic potassium hydroxide, or borane and pyridine or formic acid. The reaction is 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.
Compounds of formula II, III, IV, V, VII and IX are commercially available compounds, or are described in the literature, or are prepared by standard processes known in the art.
Compounds of formula VI may be prepared according to the following scheme:
VIA VIB VIC
Compounds of formula VIII may be prepared according to the following scheme:
Compounds of formula X, XI and XIII are commercially available compounds, or are described in the literature, or are prepared by standard processes known in the art.
Compounds of formula XII may be prepared according to the following scheme. Sodium borohydride
VIA + 
Methanol. - xπ XIIA
Compounds of formula XIIA are commercially available compounds, or they are known in the literature, or they are prepared by standard processes known in the art. Specific reaction conditions for reactions i), j) and k) are as follows: Compounds of formula XIV, XV and XVI are reduced under standard reduction conditions for reducing an amide to an amine. For example, in the presence of a reducing agent such as borane, sodium borohydride or lithium aluminium hydride, in an inert solvent such as toluene or tetrahydrofuran, and at a temperature in the range of 50-120 °C, preferably at or near reflux.
Compounds of formula XIV may be prepared according to the following scheme:
Certain compounds of formula XIV wherein R1 is not hydrogen bind selectively at the [3H] -emopamil binding site as described in the examples herein.
Compounds of formula XV may be prepared according to the following scheme:
Compounds of formula XVI may be prepared according to the following scheme:
XVIA Compounds of formula XIVA and XVIA are commercially available compounds, or are described in the literature, or are prepared by standard processes known in the art.
When an optically active form of a compound of the formula I is required, it may be obtained, for example, by carrying out one of the aforesaid procedures using an optically active starting material or by resolution of a racemic form of said compound using a conventional procedure.
An example of converting one compound of formula I into another compound of formula I is the conversion of R1, R2 or R3 when they are hydrogen to a different R1, R2, or R3. For example, an alkyl group could be introduced by standard alkylation or reductive amination techniques, such as those described above. It will be appreciated that certain of the various ring substituents in the compounds of the present invention may be introduced by standard aromatic substitution reactions or generated by conventional functional group modifications either 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. The reagents and reaction conditions for such procedures are well known in the chemical art. Particular examples of aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid, the introduction of an acyl group using, for example, an acyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; the introduction of an alkyl group using an alkyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; and the introduction of a halogeno group. Particular examples of modifications include the reduction of a nitro group to an amino group by for example, catalytic hydrogenation with a nickel catalyst or treatment with iron in the presence of hydrochloric acid with heating; oxidation of alkylthio to alkylsulphinyl or alkylsulphonyl.
It will also be appreciated that in some of the reactions mentioned herein it may be necessary/desirable to protect any sensitive groups in the compounds. The instances where protection is necessary or desirable and suitable methods for protection are known to those skilled in the art. Conventional protecting groups may be used in accordance with standard practice (for illustration see T.W. Greene, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991). Thus, if reactants include groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein.
A suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a t-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis
acid for example boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.
A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
The protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art. In order to use a compound of the formula I or a pharmaceutically-acceptable salt or in v/vo-hydrolysable ester, amide or carbamate thereof for the therapeutic treatment 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. Such pharmaceutical compositions may be administered, for example, by oral, topical, parenteral, buccal, nasal, vaginal or rectal administration or by inhalation. For these puφoses the compounds of this invention may be formulated by means known in the art into the form of, for example, tablets, capsules, aqueous
or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, finely divided powders or aerosols for inhalation, and for parenteral use (including intravenous, intramuscular or infusion) sterile aqueous or oily solutions or suspensions or sterile emulsions. A preferred route of administration is intravenously in sterile isotonic solution.
In addition to the compounds of the present invention the pharmaceutical composition of this invention may also contain, or be simultaneously or sequentially co-administered with, one or more pharmacological agents of value in treating one or more disease conditions 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.
Typically unit dosage forms will contain about 1 mg to 500 mg of a compound of this invention.
According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the formula I as defined hereinbefore or a pharmaceutically-acceptable salt or an in v/vo-hydrolysable ester, amide or carbamate thereof, in association with a pharmaceutically-acceptable excipient or carrier.
According to a further aspect of the present invention there is provided a compound of the formula I or a pharmaceutically-acceptable salt or an in v/vo-hydrolysable ester, amide or carbamate thereof, as defined hereinbefore for use in a method of treatment of the human or animal body by therapy.
A further feature of the present invention is a compound of formula I and pharmaceutically-acceptable salts or an in v/vo-hydrolysable ester, amide or carbamate thereof, for use as a medicament.
A compound of the present invention suitable for use as a medicament is a compound of formula I:
i wherein:
R1 is hydrogen, Chalky!, C2-6alkenyl, C2.6alkynyl or phenylC2.6alkyl; R2 and R3 are independently selected from hydrogen, Cι_6alkyl, phenylsulphonyl, 1-
(1,2,3,4-tetrahydronaphthyl) or a group of the formula IA: (CH2)p— A
IA wherein A is halo, nitro, hydroxy, C]_6alkoxy, cyano, amino, trifluoromethyl, trifluoromethoxy, carboxy, carbamoyl, mercapto, sulphamoyl, mesyl, N-Cι.6alkylamino, N,N- (Cι.6alkyl)2amino, d_ alkoxycarbonyl, N-Cι- alkylcarbamoyl or N,N-(Cι.6alkyl)2carbamoyl and p is 2 to 6, or
R2 or R3 is a group of the formula IB: (CR6R7)— B
IB wherein:
R6 and R7 are independently selected from hydrogen and Cj-3alkyl, and B is aryl, a carbon linked heteroaryl, a carbon-linked heterocyclyl, C3_ι2cycloalkyl or C3-ι2cycloalkyl fused to a benzene ring; q is an integer selected from the range 0 to 6; and wherein 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, Cι..6alkyl, C2-6alkenyl, C2.6alkynyl, Cι- alkoxy, Cι-6alkanoyl, C1-6alkanoyloxy, N-(Cι-6alkyl)amino, N,N-(Cι_6alkyl)2amino, Cι.6alkanoylamino, N- (Cι-6alkyl)carbamoyl, N,N-(Cι-6alkyl)2carbamoyl, Cι-6alkylSOa wherein a is 0 to 2, C1-6alkoxycarbonyl, N-(Cι.6alkyl)sulphamoyl, N,N-(Cι_6alkyl)2sulphamoyl and phenylCι- alkyl; and a heterocyclyl or a heteroaryl ring containing an -ΝH- group may be
optionally substituted on this nitrogen with Cι_6alkyl, C2.6alkenyl, C2.6alkynyl, C.ι.6alkanoyl, Cι-6alkylsulphonyl or phenylCι-6alkyl, or
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 Cι_6alkyl, C2.6alkenyl, C2.6alkynyl, Cι-6alkanoyl, Cι.6alkylsulphonyl, or said heterocyclyl or a heteroaryl ring may be optionally substituted with an ortho-fused aryl moiety; R4 at each occurrence is independently selected from hydrogen, halo, hydroxy,
Cι_ alkyl, Cι.6alkoxy, hydroxyCι_6alkyl, haloCι_6alkyl, cyano, nitro and C2.6alkenyl;
R5 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.
Other compounds of the present invention suitable for use as a medicament are compounds according to formula I having formulae XVII, XVIII, XIX or XX as described herein.
Compounds of formula I are useful in medicaments that inhibit the [3H] -emopamil binding site in a warm-blooded animal such as a human being. Thus, according to a further aspect of the invention there is provided the use of a compound of the formula I, or a pharmaceutically-acceptable salt or an in v/vo-hydrolysable ester, amide or carbamate thereof, in the manufacture of a medicament for use in the inhibition of the [3H]-emopamil binding site in a warm-blooded animal such as a human being. Thus, according to a still further aspect of the invention there is provided the use of compounds of formulae XVII, XVEII, XIX or XX or pharmaceutically-acceptable salts or in v/vo-hydrolysable esters, amides or carbamates thereof, in the manufacture of a medicament for use in the inhibition of the [3H]-emopamil binding site in a warm-blooded animal such as a human being.
According to a further feature of the invention there is provided a method of selectively inhibiting of the [3H] -emopamil binding site in a warm-blooded animal, such as a human being, in need of such treatment which comprises administering to said animal an effective amount of a compound of 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.
The following Biological Test Methods, Results and Examples serve to illustrate the present invention. 5 Biological Test Methods
In summary, the binding affinities (IC50) for 75 representative compounds of the invention to the [3H]-emopamil binding site ranged from 7 nM to 261 nM. In contrast, binding affinities (IC50) 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:
H-Emopamil binding to guinea pig liver membranes
Binding at the [3H] -emopamil binding site was determined by a modification of the method described by Zech et al. (Zech , C, Staudinger R., Mϋhlbacher, J. and Glossmann, H. Novel sites for phenylalkylamines: characterisation of a sodium-sensitive drug receptor with (- 15 )-3H-emopamil. E r. J. Pharm., (1991), 208, 1 19-130). Guinea-pig liver membrane preparation:
Male guinea pigs were sacrificed by CO2 asphyxiation with dry ice. The livers were quickly excised and weighed and rinsed in membrane preparation buffer containing 10 mM Hepes, 1 mM Tris base-EDTA, 250 mM sucrose, pH 7.4. The livers were then minced, 20 homogenised in 10 times volume with a motor driven Teflon-glass homogeniser with three strokes on ice. The homogenate was centrifuged at 1000 x g in a SS34 rotor for 5 minutes at 4 °C. The supernatant was filtered through 4 layers of gauze and then centrifuged at 8000 x g for 10 minutes at 4 °C. This resulting supernatant was centrifuged at 40,000 x g for 15 minutes at 4 °C. The resulting pellet was resuspended in assay buffer and centrifuged again at 25 40,000 x g for 15 minutes at 4 °C. This pellet was resuspended in assay buffer (2.5 fold with respect to original wet weight) and homogenised with one stroke with the Teflon-glass homogeniser. Aliquots of 1 mL were stored at -70 °C. Assay Reaction Mixture:
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.
Radioligand: 0.96 nM (-)-3H-emopamil (Amersham).
Guinea pig liver membranes: 40mg/mL original wet weight.
Compounds: 1-300 nM.
Total volume: 500 μL.
This mixture was incubated for 60 minutes at 37 °C. The incubation was terminated by filtering with a Brandel Cell Harvester over Whatman GF/C filters that had been soaked for at least 120 minutes in 0.3% polyethylenimine (PEI) and washed three times with 5 mL of wash buffer containing 10 mM Tris-HCl, 10 mM MgCl2, 0.2% BSA, pH 7.4 at 25 °C. Specific binding was defined with 10 μM emopamil.
Results:
Seventy five compounds according to formula I bound to the 3H-emopamil binding site of guinea pig liver membranes with IC5o's in the range from 7 nM to 261 nM. In general, compounds of the present invention bound to the [3H] -emopamil binding site with an IC5 below 300nM in this test. The following results were obtained for selected compounds binding to the 3H-Emopamil binding site of guinea pig liver membranes.
H-D-888 binding to rat hrain cortical membranes
3H-D-888 binding was determined by a modification of Reynolds et al. (Reynolds ,
I.J., Snowman, A.M. and Synder, S.H. (-)-[3H] Desmethoxyverapamil labels multiple calcium channel modular receptors in brain and skeletal muscle membranes: differentiation by temperature and dihydropyridines. J. Pharmacol. Exp. Ther. (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.
Assay Reaction Mixture:
Assay buffer: 50 mM Hepes, 0.2% BSA, pH 7.4 Radioligand: lηM 3H-D888 (Amersham)
Rat cortical membranes: 6 mg/mL original wet weight
Compounds: 0.3-100 μM
Total volume: 1000 μL
This mixture was incubated for 60 minutes at 25 °C. The assay was terminated by filtering with a Brandel Cell Harvester over Whatman GF/C filters that had been soaked for at least 120 minutes in 0.3% 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 μM methoxyverapamil (D-600). This assay was used to determine in vitro selectivity of compounds vs. L-type voltage sensitive calcium channels, i.e. high affinity for the 3H-D888 binding site would show a lack of selectivity.
Results:
Fifty-nine compounds according to formula I bound to the 3H-D-888 binding site of rat brain cortical membranes with IC5o's in the range from 1091 nM to 58,415 nM. In general, compounds of the present invention bound to the 3H-D-888 binding site with an IC50 above 3000 nM in this test. The following results were obtained for selected compounds binding to the H-D-888 binding site of rat brain cortical membranes.
Gerbil Global Model of Cerebral Ischaemia
Male Mongolian gerbils (Charles River) weighing 60-70 grams are used in these experiments. They are housed in individual cages with food (Purina Rodent Chow) and water available ad libitum. The animal room is maintained at 23 ± 2 °C, and is on an automatic 12 hour light cycle.
The gerbils are brought to the surgical suite and dosed intraperitoneally with the test agent or vehicle, forty-five minutes prior to surgery. Drugs are administered at a volume of 5 mL/kg (intraperitoneal). Vehicle is generally saline, with sodium phosphate added to adjust the pH, if needed. Forty-five minutes after dosing the gerbils are anaesthetised with halothane (3.3%) which is delivered along with oxygen (1.5 1/M) through a face mask. After the gerbils are anaesthetised, halothane is continued at a maintenance level of 1.5-2 % along with oxygen. The ventral surface of the neck is shaved and cleaned with alcohol. Surgical procedures are carried out on a thermostat-controlled heating pad set to 37 °C. An incision is made in the neck, the carotid arteries are dissected away from the surrounding tissue, and isolated with a 5 cm length of Silastic tubing. When both arteries have been isolated they are clamped with microaneurysm clips (Roboz Instruments). The arteries are visually inspected to determine that the blood flow has been stopped. After 5 minutes the clips are gently removed from the arteries and blood flow begins again. A sham control group is treated identically but is not subjected to carotid artery occlusion. The incisions are closed with suture and the gerbils
removed from the anaesthesia masks and placed on another heating pad to recover from the anaesthesia. When they have regained the righting reflex and are beginning to walk around, they are again dosed with the test compound and returned to their home cages. This occurs approximately five minutes after the end of surgery. 5 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,
10 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.
Results:
15 The following results were obtained for selected compounds tested for efficacy in the foregoing assay.
Transient focal ischaemia in rats
The method was performed substantially as described by Lin et al. (Lin, T-N., He, 0 Y.Y., Wu, G., Khan, M. And Hsu, C.Y. Effect of brain edema on infarct volume in a focal model cerebral ischaemia model in rats. Stroke, (1993), 24, 117-121). This model is generally considered to be relevant to the clinical situation. Male Long-Evans rats 250-350 g were used.
Surgery to establish a focal ischaemia was conducted under anaesthesia induced with 100 mg/kg ketamine and 5 mg/kg i.m. xylazine. Rectal temperature was monitored and maintained at 37.0 + 0.5 °C. The right middle cerebral artery (MCA) was exposed using microsurgical techniques. The MCA trunk was ligated immediately above the rhinal fissure with 10-0
5 suture. Complete interruption of blood flow was confirmed under an operating microscope. Both common carotid arteries were then occluded using nontraumatic aneurysm clips. After a predetermined duration of ischaemia (45 min), blood flow was restored in all three arteries. Twenty-four hours post occlusion, rats were killed under ketamine anesthesia by intracardiac perfusion with 200 mL of 0.9% NaCl. The brain was removed and processed with 2%
10 triphenyltetrazolium chloride to identify and quantitate the infarcted brain region. Compounds were administered by intravenous infusion for 4 hours. Results:
The following results were obtained for selected compounds tested in the foregoing assay.
15
Permanent focal ischaemia in rats Animal preparation
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% N2O and 20 65% O2. 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. N2O was withdrawn and animals were maintained on 1% halothane, 40% air, 60% O2 for 1 hour without monitoring of the pO2 and pCO2. 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
Samples were prepared in saline adjusted to give a clear solution pH 6-6.5 MRI After 23-25 hours animals were anaesthetised using 3% halothane and maintained at
2% halothane. They 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. Following siting scans, tuning and shimming, a multislice T2-weighted MRI data set was acquired using a Varian INOVA console using the following parameters: Non-fat-suppressed spin-echo; TE= 60msec; TR= 2100 msec; slice thickness= 1 mm; Field of view= 50x50mm; Matrix 256x256. Segmentation
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. Statistical analysis
A sequential design was used. The study was powered to have a 5% false positive and 5% false negative probability, assuming the true neuroprotection is at least 40%, in a onesided homoscedastic t-test in log space, assuming CoV (saline) =40% and CoV (treated) =40%. The critical values in the sequential design were:
Critical N (i.e. at least N treated and at | 6 | 9 I 12 15
Results:
The following results were obtained for selected compounds tested in the foregoing assay.
Examples
The Examples which follow are intended to illustrate but not limit the invention. In the Examples, unless otherwise stated:- (i) concentrations were carried out by rotary evaporation in vacuo;
(ii) operations were carried out at ambient temperature, that is in the range 18-26 °C and under a nitrogen atmosphere;
(iii) column chromatography (by the flash procedure) was performed on Merck Kieselgel silica (Art. 9385); (iv) yields are given for illustration only and are not necessarily the maximum attainable;
(v) the structure of the end-products of the formula I were generally confirmed by NMR and mass spectral techniques; proton magnetic resonance spectra were determined in DMSO-d6 unless otherwise stated using a Varian Gemini 2000 spectrometer operating at a field strength of 300 MHz; chemical shifts are reported in parts per million downfield from tetramethylsilane as an internal standard (δ scale) and peak multiplicities are shown thus: s, singlet; bs, broad singlet; d, doublet; AB or dd, doublet of doublets; t, triplet; dt, double of triplets; m, multiplet; bm, broad multiplet; fast-atom bombardment (FAB) mass spectral data were obtained using a Platform spectrometer (supplied by Micromass) run in electrospray and,
where appropriate, either positive ion data or negative ion data were collected, herein (M+H)+ is quoted;
(vi) intermediates were not generally fully characterised and purity was in general assessed by mass spectral (MS) or NMR analysis; and (vii) in which the following abbreviations (also used hereinabove) may be used:
DMF is N,N-dimethylformamide
DMSO is dimethylsulphoxide
CDC13 is deuterated chloroform m/s is mass spectroscopy THF is tetrahydrofuran
DCM is dichloromethane
ΝMP is N-methylpyrrolidone.
Example 1 N'.N'-Diisopropyl-N^π^^ -tetrahydro-l-naphthalenyll-l^-ethanediamine. -Tetralone (0.837g, 5.72xl0"3 mole) and 2-(diisopropylamino)ethylamine (5.165g, 3.58xl0"2 mole) were combined in toluene (30 mL) and cooled to 0 °C (ice/water/sodium chloride). 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. Upon complete addition, additional toluene (20 mL) was added to improve stirring and the mixture was stirred at ambient temperature for 16 hours. The gel/solid was removed by vacuum filtration and the filtrate was concentrated to a brown residue. A solution of the residue in methanol (30 mL) was treated with sodium borohydride (0.288g, 7.61x10" mole) and the reaction mixture was stirred at ambient temperature for one hour. The solvent was evaporated and the residue partitioned between water and diethyl ether. The aqueous portion was extracted with additional diethyl ether. The combined extracts were washed (water, brine), dried, and evaporated to a brown oil which was purified by chromatography, eluting with 1% ΝH4OH: 5% MeOH: 94% CH2C12 (v/v/v), to give the product as a brown oil (0.8 lOg, 51%). 1H NMR: 0.85-1.02 (m, 12H), 1.56-2.00 (m, 6H), 2.41-2.80 (m, 5H), 2.88-3.02 (m, 2H), 3.63 (t, 1H), 7.00-7.16 (m, 3H),7.26-7.33 (m, 1H); m/s: 275.
Example 2
N'.N'-Diisopropyl-N^methyl-^-l^^ -tetrahydro-l -naphthalenyl- 1 ,2- ethanediamine. l-[2-(Diisopropylamino)ethylamino]-l,2,3,4-tetrahydronaphthalene (Example 1) (0.319g, l.lόxlO'3 mole) was dissolved in methanol (7 mL) and the solution was treated with formaldehyde (37% aqueous, 3.0 mL, 4.00x10" mole). After one hour, sodium borohydride (0.501g, 1.32xl0"2 mole) was added in small portions, and the mixture was stirred for 15 hours at ambient temperature. The reaction mixture was evaporated and partitioned between saturated aqueous ammonium chloride and dichloromethane. The aqueous portion was extracted with additional dichloromethane. The combined extracts were washed (brine), dried, and evaporated to a brown oil. Due to the presence of remaining starting material, the product mixture was resubmitted to the reaction conditions described above. The product was purified by chromatography, eluting with 3.0% 2.0 M ΝH3 in MeOH: 97% CH2C12 (v/v), to give the product as a pale yellow oil (0.212g, 63%). Η NMR: 0.82-0.98 (m, 12H), 1.44-1.68 (m, 2H), 1.84-2.00 (m, 2H), 2.24 (s, 3H), 2.26-2.50 (m, 4H), 2.63-2.76 (m, 2H), 2.80-2.95 (m, 2H), 3.73-3.86 (m, 1H), 6.98-7.17 (m, 3H), 7.56-7.66 (m, 1H); m/s: 289.
Example 3
N1,N'-Diethyl-N -methyl-N2-r( 1R)- 1.2,3.4-tetrahvdro- 1 -naphthalenyll- 1.2- ethanediamine.
(R)-l-[2-(Diethylamino)ethylamino]- 1,2,3 ,4-tetrahydronaphthalene (Example 34) (3.53g, 1.43xl0"2 mole) and triethylamine (4.0 mL, 2.87x10"2 mole) were combined in tetrahydrofuran (135 mL) and treated with ethyl chloroformate (1.5 mL, 1.57x10 " mole) at ambient temperature. The mixture was stirred for 14.5 hours. The reaction mixture was evaporated and partitioned between water and ether. The aqueous portion was extracted with additional ether. The combined organic portions were washed (aqueous sodium bicarbonate, water, brine), dried, and evaporated to yield a yellow oil (4.52g). A solution of the oil in tetrahydrofuran (100 mL) was treated with lithium aluminium hydride (2.16 g, 5.68xl0"2 mole) and refluxed for two hours. The reaction mixture was quenched with sodium sulphate decahydrate until effervescence ceased. Additional tetrahydrofuran was added to aid stirring. The reaction mixture was filtered through diatomaceous earth and filtrate evaporated to a yellow oil which was purified by chromatography, eluting with 3% 2.0M ΝH3 in MeOH:97%
CH2C12 (v/v), to give the product as a pale yellow oil (3.54g). NMR: 0.90 (t, 6H), 1.46-1.68 (m, 2H), 1.83-2.00 (m, 2H), 2.19 (s, 3H), 2.31-2.80 (m, 10H), 3.77-3.87 (m, 1H), 7.00-7.17 (m, 3H), 7.56-7.63 (m, 1H); m s: 261.
5 Example 4
N-Ethyl-N-(3-(4-methylpiperazino)propyl)-l,2,3,4-tetrahvdro-l-naphthalenamine. Borane-methylsulphide complex (1.0 mL, 1.05x10' mole) was added to a solution of l-[3-(4-methylpiperazin-l-yl)propyl(N-acetyl)amino]-l,2,3,4-tetrahydronaphthalene (Example 119) (0.160g, 4.85xl0"4 mole) in tetrahydrofuran (2 mL). The mixture was heated at 70 °C for
10 18 hours. The reaction mixture was quenched with methanol at ambient temperature and heated at 70 °C for one hour, followed by addition of concentrated hydrochloric acid ( 1.0 mL) and heating at 70 °C for 10 minutes. The quenched mixture stirred at ambient temperature for 0.5 hour. The solvent was evaporated, and the residue was partitioned between 1M sodium hydroxide and diethyl ether. The aqueous portion was saturated with solid sodium chloride
15 and extracted with additional diethyl ether. The combined extracts were washed (brine), dried, and evaporated to a yellow oil which was purified by chromatography, eluting with 1% ΝH4OH/5% MeOH: 94% CH2C12 (v/v/v), to give the product as a pale yellow oil (0.105g, 68%). Η NMR: 0.96 (t, 3H), 1.40-1.69 (m, 4H), 1.86-2.03 (m, 2H), 2.12 (s, 3H), 2.13-2.80 (m, 16H), 3.83-3.94 (m, 1H), 6.97-7.16 (m, 3H), 7.61 (d, 1H); m/s: 316. 0
Example 5
N .N -Diethyl-N^methyl-N2-^ IS)- 1 ,2,3,4-tetrahydro- 1 -naphthalenyll- 1.2- ethanediamine.
Potassium carbonate (12.9 g, 46.5 mmol) was added to a solution of 5 (S)-l-methylamino-l,2,3,4-tetrahydronaphthalene (Smith, R.A.; White, R.L.; Krantz, A., J. Med. Chem., (1988), 31, 1558-66) (3.0 g, 18.6 mmol) and 2-diethylaminoethyl chloride hydrochloride (8.0 g, 46.5 mmol) in 186 mL of absolute ethanol and the reaction mixture was heated to reflux for 24 hours. The reaction was then cooled and then filtered through a short pad of diatomaceous earth and solvents were removed in vacuo. Purification by silica gel 0 chromatography (15: 1 dichloromethane:2M ammonia in methanol) followed by Kugelrohr distillation yielded the titled compound (2.21 g, 45%). ΝMR (CDC13): 0.99 (t, 6H), 1.64 (m,
4H), 1.98 (m, 2H), 2.27 (s, 3H), 2.50 (m, 6H), 2.72 (m, 2H), 3.87 (m, 1H), 7.09 (m, 3H), 7.66 (d, 1H); m/s: 261.
Example 6 N-r2-r3.4-dihvdroisoquinolin-2(lH)-yllethvn-N-methyl-N-r(lS)-1.2.3.4- tetrahydronaphthalen- 1 -yllamine.
Borane-methylsulphide complex (33.0 mL, 0.348 mole) was added to a solution of (S)- 1-[2-( 1 ,2,3,4-tetrahydroisoquinolin-2-yl)-N-methylacetamido]- 1 ,2,3,4- tetrahydronaphthalene (Example 88) (5.87g, 1.76xl0"2mole) in TΗF (80 mL). The mixture was heated at 70 °C for 7.5 hours. The reaction mixture was quenched with methanol (100 mL) and heated at 70 °C for 30 minutes, followed by addition of concentrated ΗC1 (5 mL) and heating for 10 minutes. The quenched mixture stirred at ambient temperature for 12.5 hours. The solvent was evaporated, and the residue partitioned between aqueous 1 M ΝaOΗ and ethyl acetate. The aqueous portion was saturated with solid sodium chloride and extracted with additional ethyl acetate. The combined extracts were washed (brine), dried, and evaporated to yield a residue which was purified by chromatography, eluting with 5 % 2.0 M ΝΗ3 in MeOH:95 % CH2C12 (v/v), to give the product as a pale yellow oil (3.99g). Η NMR: 1.50-1.67 (m, 2H), 1.87-2.00 (m, 2H), 2.22 (s, 3H), 2.53-2.83 (m, 10H), 3.50-3.59 (m, 2H), 3.81-3.91 (m, 1H), 6.94-7.17 (m, 7H), 7.57-7.65 (m, 1H). m/s: 321.
Example 7
1 -r2-(N-benzyl-N-ethyl)ethyll-(N-methyl)-amino- 1 ,2,3,4-tetrahydronaphthalene. A solution of a compound according to Example 98 (1.02g, 3.03xl0"3 mole) in THF (25 mL) was treated with lithium aluminum hydride (0.46g, 1.22xl0"3 mole) and refluxed for 3.5 hours. The reaction mixture was quenched with sodium sulfate decahydrate until effervescence ceased. Additional THF and diethyl ether were added to aid stirring. The reaction mixture was filtered through diatomaceous earth and the filtrate evaporated to a yellow oil which was purified by chromatography, eluting with 3% 2.0 M ΝH3 in methanol:97% DCM (v/v), to give the product as a pale yellow oil (0.82 g, 84%). Η NMR: 0.94 (t, 3H), 1.41-1.66 (m, 2H), 1.81-1.98 (m, 2H), 2.13 (s, 3H), 2.35-2.78 (m, 8H), 3.52 (s, 2H), 3.74-3.84 (m, 1H), 6.97-7.13 (m, 3H), 7.17-7.36 (m, 5H), 7.51-7.60 (m, 1H). m/s: 323.
Examples 8-43
Compounds according to formula XXIII shown in tables 1 and 2 were prepared using procedures analogous to those described in Examples 1-7.
Table 1
S Enantiomer
•>
R Enantiomer
3 The preparation of 5-bromo-α-tetralone is described in Hanuise, J., Smolders, R.R., Ing. Chim., (1977), 59, (286), 79-94. # Compound previously described. M* Made by method of Example Number
Table 2
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. 2-Cyanobenzyl bromide (0.629g, 3.21x10 3 mole) was added to the mixture and washed in with additional acetonitrile (22 mL). The mixture was refluxed for two hours, then concentrated under reduced pressure. The residue was partitioned between water and DCM. The aqueous portion was extracted with additional DCM. The combined organic portions were washed (water, brine), dried, and evaporated to a yellow oil which was purified by chromatography, eluting with 3% 2.0M ΝH3 in MeOH:97% DCM (v/v), to give the product as a yellow oil (1.02 g, 95%). Η NMR: 1.45- 1.68 (m, 2H), 1.80-2.00 (m, 2H), 2.14 (s, 6H), 2.40-2.80 (m, 6H), 3.65 (d, 2H), 3.75-3.88 (m, IH), 6.98-7.14 (m, 3H), 7.40-7.49 (m, IH), 7.49-7.60 (m, 2H), 7.60-7.70 (m, IH), 7.78 (d, IH). m/s: 334.
Examples 63-72
The compounds shown in Table 3 were made according to the procedure of Example 62.
Table 3
S Enantiomer
Example 73
1 - ( 2-Piperidin- 1 -ylethvirN-(3-phenylpropyl)lamino } - 1 ,2,3 ,4-tetrahydronaphthalene. l-Bromo-3-phenylpropane (296 μL, 1.93 mmol) was added to a solution of l-(2-piperidin-l-ylethylamino)-l,2,3,4-tetrahydronaphthalene (Example 60) (500 mg, 1.93 mmol) in 3.9 mL of THF, followed by triethylamine (269 μL, 1.93 mmol) and the reaction was heated to reflux. After refluxing overnight, the reaction was still incomplete and an additional 296 μL of l-bromo-3-phenylpropane and 269 μL of triethylamine was added and heating was continued for 4 days. The reaction mixture was cooled and solvents were removed in vacuo to yield an orange liquid. Purification by silica gel chromatography (30: 1 dichloromethane :2M ammonia in methanol) afforded 258 mg of the desired product. Η ΝMR (CDC13): 7.76 (d, IH), 7.32-7.02 (m, 8H), 3.95 (dd, IH), 2.81-2.32 (m, 12H), 2.01 (m, 2H), 1.78 (m, 2H), 2.70-1.26 (m, 10H); m/s: 377.
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, 1.30x102 mole) at ambient temperature. After one hour, xylene (30 mL) was added and the mixture was refluxed for 24 hours. The mixture was cooled to ambient temperature, quenched with 1M hydrochloric acid (30 mL), and stirred for 22 hours. The reaction mixture was partitioned between 1M sodium hydroxide and dichloromethane. The aqueous portion was extracted with additional dichloromethane. The combined organic portions were washed (brine), dried, and evaporated to yellow oil which was purified by chromatography, eluting with 1% ammonium hydroxide: 10% methanol:89% methylene chloride (v/v/v), to give the product as a colourless oil (0.113g). Η ΝMR: 1.11-
1.31 (m, 2H), 1.52-2.06 (m, 10H), 2.24-2.94 (m, 13H), 3.64 (t, IH), 7.00-7.40 (m, 9H); m/s: 378.
Example 75 N-r2-r3,4-dihvdroisoquinolin-2(lH)-vnethyll-N-methyl-N-r( IS)- 1.2.3.4- tetrahydronaphthalen-l-yllamine bismaleate salt.
A solution of N- [2-[3,4-dihydroisoquinolin-2( lH)-yl]ethyl]-N-methyl-N-[( IS)- 1 ,2,3,4- tetrahydronaphthalen-1-yl] amine (see Example 6) (3.96g, 1.23xl0"2 mole) in diethyl ether (20 mL) was added to a stirring solution of maleic acid (3.13g, 2.70xl0"2 mole) in diethyl ether (350 mL). The salt form immediately precipitated, adhering to the sides of the flask to form a gum. After solidification upon standing overnight, the material was collected by vacuum filtration. The solid was re-suspended in fresh diethyl ether, stirred and sonicated, and collected by vacuum filtration. The solid was vacuum dried at 50 °C for four hours, then ground to a fine powder. Drying was continued at 50 °C for 16 hours to give the product as a white solid (6.35g, 93%). Η ΝMR: 1.55-1.83 (m, 2Η), 1.90-2.09 (m, 2H), 2.36 (s, 3H), 2.62-2.92 (m, 3H), 3.00-3.38 (m, 3H), 4.13-4.27 (m, 7H), 7.57-7.63 (m, IH); m/s: 321.
Examples 76-82
Bismaleate salts of the following compounds according to formula XXIII were prepared using the procedure of Example 73. The examples shown in Table 4 are provided by way of illustration and not by way of limitation.
Table 4
S Enantiomer R Enantiomer
Example 83
N-methyl-N-(2- f methyllY IS)- 1 ,2,3,4-tetrahydro- 1 - naphthalenyl1amino)ethyl)benzenesulfonamide.
A solution of the compound of Example 123 (1.61 g, 4.32x10"3 mole) was treated in THF (36 mL) with lithium aluminum hydride (0.66g, 1.74xl0"3 mole). After refluxing for two hours, the mixture was quenched with sodium sulfate decahydrate until effervescence ceased. Additional THF and diethyl ether were added to aid stirring. The quenched mixture was filtered through diatomaceous earth and the filtrate evaporated to a solid/oil mixture which was purified by chromatography, eluting with 3: 1 hexane/ethyl acetate (v/v), to give the title compound as a pale yellow oil ( 0.92 g, 59%). Η ΝMR: 1.42-1.68 (m, 2H), 1.82-1.97 (m, 2H), 2.17 (s, 3H), 2.47-2.59 (m, 2H), 2.66 (s, 5H), 2.96-3.20 (m, 2H), 3.78-3.85 (m, IH), 7.00-7.16 (m, 3H), 7.50-7.80 (m, 6H). m/s: 359.
Example 84 2-|5-fmethyl(2-piperidinoethyl)aminol }-5,6,7,8-tetrahvdro-2-naphthalenyl-2- propanol.
A solution of t-butyllithium (1.7M in pentane, 700 μL, 1.19 mmol) was added to THF which had been precooled to -78 °C and a bright yellow solution was obtained. A precooled solution of the compound of Example 19 (200 mg, 0.569 mmol) in 1.4 mL of THF was then added. Additional t-butyllithium (1.7M in pentane, 500 μL, 0.850 mmol) was added to ensure complete metal-halogen exchange. After 10 min, acetone (420 μL, 5.69 mmol) in 1 mL of THF was added and the reaction turned bright yellow. After 30 min, another 420 μL of acetone was added.
The reaction was then stirred at -78 °C for 2h and allowed to warm slowly to -20 °C. It was quenched after 3h by addition to saturated ΝH4C1 solution (6 mL). The product was then extracted with ether (2 x 5mL). The organic extracts were washed with brine (1 x 20 mL) and dried over Na SO . Removal of solvents gave a yellow oil which was purified by silica gel chromatography (20: 1 methylene chloride/ 2M ammonia in methanol then 10: 1 methylene chloride/2M ammonia in methanol). The title compound was obtained as a thick gum (97 mg, 52%). 1H NMR (300 MHz, CDC13): 1.43 (m, 2H), 1.51-1.67 (m, 13H), 1.99 (m, 2H), 2.27 (s, 3H), 2.33-2.69 (m, 8H), 2.72 (m, 2H), 3.86 (m, IH), 7.17 (s, IH), 7.24 (m, IH), 7.64 (m, IH). m/s = 331.
Example 85
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 μL, 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 μL, 0.267 mmol) was added.
A dark brown suspension was obtained. This was stirred for lh. The reaction was then allowed to warm to room temperature slowly. The reaction mixture was then added to water (6 mL) and methylene chloride (4 mL). An emulsion was formed and so ether was added. The layers were separated. The aqueous layer was acidified with IN HC1 solution and stirred for 3h. Then the pH was adjusted to 14 by addition of IN ΝaOH solution. It was then extracted with methylene chloride. The organic extracts were then washed with brine and dried over Νa2SO4. Removal of solvents yielded a residue which was purified by silica gel chromatography (15: 1 methylene chloride/ 2M ammonia in methanol) to afford the title compound (10 mg). Η NMR (300 MHz, CDC13): 1.42 (m, 2H), 1.53 -1.70 (m, 6H), 1.99 (m, 2H), 2.13 (s, 3H), 2.27 (s, 3H), 2.37 (m, 4H), 2.42 - 2.70 (m, 4H), 2.72 (m, 2H), 3.86 (m, IH), 5.03 (m, IH), 5.34 (m, IH), 7.14 (m, IH), 7.28 (m, IH), 7.64 (m, IH). m/s: 313.
Example 86
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 μL, 0.267 mmol) to a solution of titanium(IV) chloride (l.OM in methylene chloride, 267 μL, 0.267 mmol) in 0.6 mL of methylene chloride at -30 °C, and stirring the resulting orange suspension for 30 min. A solution of a compound according to Example 80 (44 mg, 0.133 mmol) in 0.6 mL of methylene chloride was added dropwise. An additional 0.6 mL of methylene chloride was used to ensure complete transfer of the compound. The reaction mixture turned dark brown. It was allowed to warm up to room temperature slowly. After 4h, the reaction was quenched by addition to ΝH C1 solution and the product was extracted with methylene chloride (3 x 5 mL). The combined organics were washed with brine (1 x 10 mL) and dried over Νa2SO4.
Solvents were removed to yield a residue. Silica gel chromatography (15:1 methylene chloride/2M ammonia in methanol) yielded the title compound (6 mg, 13%). Η NMR (300 MHz, CDC13): 1.30 (s, 9H), 1.45 (m, 2H), 1.56 (m, 4H), 1.66 (m, 2H), 1.98 (m, 2H), 2.27 (s, 3H), 2.41-2.68 (m, 4H), 2.70 (m, 2H), 3.85 (m, IH), 7.03 (s, IH), 7.17 (m, IH), 7.58 (m, IH). m/s: 329.
Preparation of Starting Materials
The following reactions (Examples 87-135) are provided to illustrate but not limit methods for the preparation of intermediate materials used to make compounds of the invention.
Example 87
(S)- 1 -(N-methyl-2-chloroacetamido)- 1 ,2,3,4-tetrahydronaphthalene.
(S)-l-methylamino-l,2,3,4-tetrahydronaphthalene (Smith, R.A.; White, R.L.; Krantz, A., J. Med. Chem., (1988), 31, 1558-66) (3.02g, 1.87xl0"2 mole) and l,8-bis(dimethylamino)naphthalene (6.59g, 3.07xl0"2 mole) were combined in dichloromethane (52 mL) and cooled to 0 °C (ice/water/sodium chloride). Chloroacetyl chloride (2.4 mL, 3.0 lxlO"2 mole) was added in small portions, maintaining the reaction temperature at < 10 °C. Upon complete addition, the mixture was slowly warmed to ambient temperature over 1.5 hours by melting of the bath. The product was partially purified by chromatography of the reaction mixture with 3: 1 hexane:ethyl acetate (v/v), to give the title product as a yellow oil (4.58g). 1H ΝMR: 1.67-2.16 (m, 4H), 2.67-2.84 (m, 5H), 4.43-4.57 (m, 2H), 5.05-5.15 (m, 0.3H), 5.60-5.71 (m, 0.7H), 6.90-7.23 (m, 4H).
Examples 88-91
Compounds of formula XXV shown in Table 5, were prepared using the procedure of Example 87, described above.
Table 5
S Enantiomer R Enantiomer The starting material for Examples 88-91 is described in Smith, R.A.; White, R.L.; Krantz, A. J. Med. Chem., (1988), 31, 1558-66, which description is incorporated herein by reference.
Example 92
(S)- 1 -r2-( 1 ,2,3,4-tetrahvdroisoquinolin-2-yl)-N-methyl-acetamido1-l ,2,3,4-tetrahydro naphthalene.
(S)- 1 -(N-methyl-2-chloroacetamido)- 1 ,2,3,4-tetrahydronaphthalene (prepared by Example 87) (4.58 g, 1.93xl0"2 mole) and 1,2,3,4-tetrahydroisoquinoline (7.74 g, 5.81xl0"2 mole) were combined in acetonitrile (110 mL) and heated at reflux for 14.5 hours. The solvent was evaporated and the residue partitioned between aqueous sodium bicarbonate and ethyl acetate. The aqueous portion was extracted with additional ethyl acetate. The combined extracts were washed (water, brine), dried, and evaporated to yield a residue which was purified by chromatography, eluting with 1:1 hexane:ethyl acetate (v/v), to give the title product as a yellow oil (5.88 g). Η ΝMR: 1.62-2.05 (m, 4H), 2.48 (s, IH), 2.60-2.92 (m, 8H), 3.35-3.80 (m, 4H), 5.36-5.45 (m, 0.5H), 5.66-5.76 (m, 0.5H), 6.86-7.20 (m, 8H).
Example 93
(R)-l-(2-Diethylaminoacetamido)-l,2,3,4-tetrahydronaphthalene. (R)-l-(2-Chloroacetamido)-l,2,3,4-tetrahydronaphthalene (prepared by the method of Example 89) (4.00g, 1.79xl0"2 mole) and diethylamine (5.0 mL, 4.83xl0"2 mole) were combined in acetonitrile (100 mL) and heated at 90 °C for 4 hours. The reaction mixture was evaporated and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The aqueous portion was extracted with additional ethyl acetate. The combined organic extracts were washed (water, brine), dried, and evaporated to give the product as a brown oil (4.59 g). Η NMR: 0.94 (t, 6H), 1.68-1.95 (m, 4H), 2.63-2.87 (m, 2H), 2.98 (m, 2H), 4.91-5.04 (m, IH), 7.03-7.20 (m, 4H), 7.82 (d, IH). m/s: 261.
Examples 94 - 121
The compounds of formula XXVI shown in Table 6, were prepared using a procedure analogous to that described in Example 92 or 93.
Table 6
2 R Enantiomer
M* made by method of Example number
Example 122
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. The combined organic portions were washed (water, brine), dried, and evaporated to a yellow oil which was purified by chromatography, eluting with 1 : 1 hexane/ethyl acetate (v/v) to give the product as a pale yellow oil (3.40 g, 88%). Η ΝMR: 1.30-1.50 (m, 9H), 1.65-2.02 (m, 4H), 2.48 (s, IH), 2.61 (s, 2H), 2.67-2.86 (m, 2H), 3.77-4.00 (m, 2H), 5.00-5.12 (m, 0.4H), 5.63-5.73 (m, 0.6H), 6.73-7.01 (m, 2H), 7.05-7.22 (m, 3H).
A solution of the oil (3.40 g, 1.07xl0"2 mole) in THF (80 mL) was treated with lithium aluminum hydride (1.63 g, 4.30x10" mole) and refluxed for two hours. The reaction mixture was quenched with sodium sulfate decahydrate until effervescence ceased. Additional THF and diethyl ether were added to aid stirring. The quenched mixture was filtered through diatomaceous earth and the filtrate evaporated to a yellow oil which was purified by chromatography, eluting with 10% 2.0M ΝH3 in MeOH: 90% DCM (v/v), to give the title compound as a pale yellow oil (2.24 g, 96%). Η NMR: 1.50-1.67 (m, 2H), 1.83-1.98 (m, 2H), 2.14 (s, 3H), 2.26 (s, 3H), 2.41-2.77 (m, 6H), 3.13-3.50 (m, IH), 3.76-3.85 (m, IH), 6.96-7.18 (m, 3H), 7.58 (d, IH). m/s: 219.
Example 123
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). The coupling agent was washed in with DCM (3 mL), then triethylamine (0.73 mL, 5.24xl0"3 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) (0.70 g, 4.33x10 3 mole) in DCM (18 mL). After stirring at ambient temperature for 18 hours, the reaction mixture was partitioned between water and DCM. The aqueous portion was extracted with additional DCM. The combined organic portions were washed (aqueous sodium bicarbonate, water, brine), dried, and evaporated to a yellow oil which was purified by chromatography, eluting with 1: 1 hexane/ethyl acetate (v/v) to give the title compound as a pale yellow oil (1.61 g, 100%). Η ΝMR: 1.62-2.07 (m, 4H), 2.48 (s, IH), 2.57-2.85 (m, 7H), 4.06-4.20 (m, 2H), 5.10-5.20 (m, 0.3H), 5.56-5.68 (m, 0.7H), 6.88-7.04 (m, IH), 7.07-7.24 (m, 3H), 7.55-7.75 (m, 3H), 7.80-7.91 (m, 2H). m/s: 373.
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). After stirring at ambient temperature for ten minutes, sodium triacetoxyborohydride (0.570g, 2.69xl0"3 mole) was added along with additional methylene chloride (5 mL) and stirring continued for 65 hours. The reaction mixture was partitioned between 0.1 M sodium hydroxide and methylene chloride. The aqueous portion was extracted with additional dichloromethane. The combined organic portions were washed (water, brine), dried, and evaporated to a brown oil which was purified by chromatography, eluting with 1 % ammonium hydroxide:5% methanol: 94% methylene chloride (v/v/v), to give the title compound as a yellow oil (0.613 g). 1H ΝMR: 1.10-1.33 (m, 2H), 1.60-2.02 (m, 8H), 2.07-
2.92 (m, 10H), 3.15 (s, 2H), 4.94-5.05 (m, IH), 7.04-7.34 (m, 9H), 8.07 (d, IH); m/s: 392, M+23+ 414.
Example 125 l-r3-(4-methylpiperazin-l-yl)propyl(N-acetyl)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). The mixture was stirred at ambient temperature for 14 hours. The reaction mixture was partitioned between water and dichloromethane. The aqueous portion was extracted with additional dichloromethane. The combined extracts were washed (water, brine), dried, and evaporated to a yellow oil which was purified by chromatography, eluting with 1% ΝH OH: 5% MeOH: 94% CH2C12 (v/v/v), to give the product as a colourless oil (0.317 g, 94%). Η NMR: 1.42-2.40 (m, 2H), 2.66-2.94 (m, 3H), 3.07-3.40 (m, 2H), 4.95-5.05 (m, 0.5H), 5.53-5.63 (m, 0.5H), 6.86-7.20 (m, 4H); m/s: 330.
Examples 126-127
The compounds of formula XXVII shown in Table 7, were prepared by the procedure of Example 125.
Table 7
Examples 128-133
The compounds of formula XXVIII shown in Table 8, were prepared using the procedure of Example 1.
Table 8
Example 134
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. This was followed immediately by the addition of (S)-l-methy lamino- 1,2,3, 4-tetrahydronaphthalene (2.00 g, 12.4 mmol) in 50 mL of dichloromethane. The reaction was then stirred at room temperature for 22 hours. The reaction was then added to water (150 mL) and the layers were separated. The aqueous layer was extracted with dichloromethane (2 x 100 mL). The combined organics were washed with brine ( 1 x 250 mL) and dried over Νa2SO . Removal of solvents yielded a yellow liquid. Purification by silica gel chromatography (20: 1 dichloromethane/2M ammonia in methanol) yielded the title compound (2.83 g, 76%). Η NMR (300 MHz, CDC13): 1.46 (m, 2H), 1.57 (m, 4H), 1.71-2.03 (m, 4H), 2.46 (m, 4H), 2.60-2.80 (m, 7H), 3.49 (m, IH), 5.08 (m, IH), 5.94 (m, IH), 6.99-7.18 (m, 4H). m/s (M+l)+=301.
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. Η ΝMR (300 MHz, CDC13): 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.
Example 136
Following conventional procedures well known in the pharmaceutical art the following representative pharmaceutical dosage forms containing a compound of formula I can be prepared:
(a) Tablet mg/tablet
Compound of Formula I 50.0
Mannitol, USP 223.75
Croscarmellose sodium 60
Maize starch 15.0
Hydroxypropylmethylcellulose (HPMC), USP 2.25
Magnesium stearate 3.0
(b) Capsule mg/capsule Compound of Formula I 10.0
Mannitol, USP 488.5 Croscarmellose sodium 15.0 Magnesium stearate 1.5
(c) Injection
For intravenous administration, a compound of Formula I is dissolved in an isotonic sterile solution (5 mg/mL).
Claims
1. Any compound according to formula I:
wherein:
R is selected from hydrogen, 
C2. alkenyl, C2.6alkynyl and ρheny!C2_6alkyl; R2 and R3 are independently selected from hydrogen, Cι-6alkyl, phenylsulphonyl, 1- (1,2,3,4-tetrahydronaphthyl), a group of the formula IA: (CH2)—A
IA wherein A is halo, nitro, hydroxy, Cι_6alkoxy, cyano, amino, trifluoromethyl, trifluoromethoxy, carboxy, carbamoyl, mercapto, sulphamoyl, mesyl, N-Cι- alkylamino, N,N- (Cι.6alkyl)2amino, Cι-6alkoxycarbonyl, N-Cι-6alkylcarbamoyl or N,N-(Cι-6alkyl)2carbamoyl, and p is an integer selected from the range 2 to 6, and a group of the formula IB: (CR6R7) — B
IB wherein R6 and R7 are independently selected from hydrogen and C1- alkyl, and B is aryl, a carbon linked heteroaryl, a carbon-linked heterocyclyl, C -12cycloalkyl or C3-12cycloalkyl fused to a benzene ring; q is an integer selected from the range 0 to 6; and wherein 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, Cι-6alkyl, C2-6alkenyl, C2-6alkynyl, Cι-6alkoxy, Cι-6alkanoyl, Cι- alkanoyloxy, N- (C)-6alkyl)amino, N,N-(C1-6alkyl)2amino, Cι- alkanoylamino, N- C όalky carbamoyl, N,N- (C1-6alkyl)2carbamoyl, Cι_6alkylSOa where a is an integer selected from 0, 1 or 2, Cι- alkoxycarbonyl, N-(Cι-6alkyl)sulphamoyl, N,N-(Cι-6alkyl)2sulphamoyl and phenylC1-6alkyl; and a heterocyclyl or a heteroaryl ring having an -NH- group may be optionally substituted on this nitrogen with Cj.6alkyl, C2-6alkenyl, C2_6alkynyl, Cι_6alkanoyl, Cι_ alkylsulphonyl or phenylCι_6alkyl, or
R2 and R3 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 -NH- group that may be substituted on the nitrogen with Cι„6alkyl, C2-6alkenyl, C2-6alkynyl, Cι-6alkanoyl or Cι_6alkylsulphonyl, said heterocyclyl or heteroaryl ring may have an -O- group, said heterocyclyl or heteroaryl ring may be optionally substituted with an ortho-fused aryl moiety, and wherein any aforesaid heterocyclyl, heteroaryl ring or aryl moiety may be optionally substituted on a ring carbon with one or more R9 groups selected from M as heretofore defined, r is 4 and R4 at each occurrence is independently selected from hydrogen, halo, hydroxy, Cj.6alkyl, Cι_ alkoxy, hydroxy Cι.6alkyl, haloCι_6alkyl, cyano, nitro and C2.6alkenyl; s is 7 and R5 at each occurrence is independently selected from hydrogen and Cι_6alkyl, and n is 1 or 2; or a pharmaceutically-acceptable salt or an in v vo-hydrolysable ester, amide or carbamate thereof; provided that said compound of formula I is not N,N-diethyl-N'-(l,2,3,4-tetrahydro-l- naphthalenyl)- 1 ,2-ethanediamine, N-propyl-N-( 1 ,2,3,4-tetrahydro-5-methoxy- 1 - naphthalenyl)- 1 ,2-ethanediamine, N-propyl-N'-( 1 ,2,3,4-tetrahydro-7-methoxy- 1 - naphthalenyl)- 1 ,2-ethanediamine, N-propyl-N'-( 1 ,2,3,4-tetrahydro-8-methoxy- 1 - naphthalenyl)- 1 ,2-ethanediamine or N-propyl-N'-( 1 ,2,3,4-tetrahydro-5,8-dimethoxy- 1 - naphthalenyl)- 1 ,2-ethanediamine.
2. Any compound according to Claim 1, wherein:
R1 is selected from hydrogen, Cι_6alkyl;
R2 and R3 are independently selected from hydrogen, C1- alkyl, phenylsulphonyl, 1- (1,2,3,4-tetrahydronaphthyl), and a group of the formula IB:
-(CR°R7) — B m wherein R6 and R7 are independently selected from hydrogen and Cι-3alkyl, and B is aryl, a carbon linked heteroaryl, a carbon-linked heterocyclyl, C3.ι2cycloalkyl or C3_ι2cycloalkyl fused to a benzene ring; q is an integer selected from the range 0 to 6; and wherein said aryl, heteroaryl or heterocyclyl may be optionally substituted on a ring carbon with one or more groups independently selected from halo, nitro, cyano, hydroxy, trifluoromethyl, amino, Cι_6alkyl and Cι_6alkoxy, or
R2 and R3 together with the nitrogen atom to which they are attached form a heterocyclyl ring, where said heterocyclyl ring may have an -NH- group that may be substituted on the nitrogen with Chalky!, C2_6alkenyl, C2. alkynyl, Cι_ alkanoyl or
Cι_6alkylsulphonyl, said heterocyclyl ring may have an -O- group, said heterocyclyl ring may be optionally substituted with an ortho-fused aryl moiety, and wherein any aforesaid heterocyclyl, heteroaryl ring or aryl moiety may be optionally substituted on a ring carbon with one or more groups independently selected from halo, nitro, cyano, hydroxy, trifluoromethyl, amino, d-βalkyl and Cι.6alkoxy, , r is 4 and R4 at each occurrence is independently selected from hydrogen, halo, Cι-6alkyl; s is 7 and R5 at each occurrence is hydrogen, and n is 1 or 2; or a pharmaceutically-acceptable salt or an in v vo-hydrolysable ester, amide or carbamate thereof; provided that said compound according to Claim 1 is not N,N-diethyl-N'-( 1,2,3,4- tetrahydro- 1 -naphthalenyl)- 1 ,2-ethanediamine, N-propyl-N'-( 1 ,2,3,4-tetrahydro-5-methoxy- 1 - naphthalenyl)- 1 ,2-ethanediamine, N-propyl-N'-( 1 ,2,3,4-tetrahydro-7-methoxy- 1 - naphthalenyl)- 1 ,2-ethanediamine, N-propyl-N'-( 1 ,2,3,4-tetrahydro-8-methoxy- 1 - naphthalenyl)- 1 ,2-ethanediamine or N-propyl-N'-( 1 ,2,3,4-tetrahydro-5,8-dimethoxy- 1 - naphthalenyl)- 1 ,2-ethanediamine.
3. A compound according to Claim 1, of formula XIX 
wherein:
R , ι i •s selected from hydrogen, Ci-6alkyl, C2.6alkenyl, C2. alkynyl and phenylC2_ alkyl, and v is 4 and R9 is independently selected at each occurrence from hydrogen, halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C,_6alkyl, C2.6alkenyl, C2.6alkynyl, Cj.6alkoxy, Cj-6alkanoyl, Cι_6alkanoyloxy, N- (Cι.6alkyl)amino, N,N-(Cι_6alkyl)2amino, Cι-6alkanoylamino, N-(Cι.6alkyl)carbamoyl, N,N- (Cι_6alkyl)2carbamoyl, Cι_6alkylSOa where a is an integer selected from 0, 1 or 2, Cι_6alkoxycarbonyl, N-(Cj.6alkyl)sulphamoyl, N,N-(Cι.6alkyl)2sulphamoyl and phenylCι_6alkyl; r is 4 and R4 at each occurrence is independently selected from hydrogen, halo, hydroxy, Cι.6alkyl, Cι.6alkoxy, hydroxyCj-6alkyl, haloCι_6alkyl, cyano, nitro and C2.6alkenyl; s is 7 and R5 at each occurrence is independently selected from hydrogen and Cι_6alkyl, and n is 1 or 2, t is 0, 1 or 2, and u is 0 or 1; or a pharmaceutically-acceptable salt or an in v/vo-hydrolysable ester, amide or carbamate thereof.
4. A compound according to Claim 1, selected from:
N1 N'-diisopropyl-N^methyl-N2- 1 ,2,3,4-tetrahydro- 1 -naphthalenyl]- 1 ,2- ethanediamine;
N-[2-[3,4-dihydroisoquinolin-2(lH)-yl]ethyl]-N-methyl-N-[(lS)-l,2,3,4- tetrahydronaphthalen- 1 -yl]amine; ( lR)-N-methyl-N-(2-piperidinoethyl)- 1 ,2,3,4-tetrahydronaphthalen- 1 -amine;
Nl-benzyl-N'-methyl-N2-[( IS)- 1 ,2,3,4-tetrahydronaphthalen- 1 -yl]ethane- 1 ,2-diamine; N-[2-[3,4-dihydroisoquinolin-2(lH)-yl]ethyl]-N-methyl-N-[(li?)-l,2,3,4- tetrahydronaphthalen- 1 -yljamine;
N'N'-dimethyl-^-methyl-^-l^^^-tetrahydro-l-naphthalenyl -l^-ethanediamine;
N-(2-piperidinoethyl)-5,8-dimethyl-l,2,3,4-tetrahydronaρhthalen-l -amine;
(lS)-N-[2-(l-azepanyl)ethyl]-l,2,3,4-tetrahydro- 1-naphthalenamine; ( 1 S)-N-methyl-N-(2-piperidinoethyl)- 1 ,2,3,4-tetrahydronaphthalen- 1 -amine;
N1 ,N2-dimethyl-N' -phenethyl-N2-[( 1 S)- 1 ,2,3,4-tetrahydronaphthalen- 1 -yl]ethane- 1 ,2- diamine;
N1 ,N2-dimethyl-N'-phenethyl-N2-[( 1R)- 1 ,2,3,4-tetrahydronaphthalen- 1 -yljethane- 1 ,2- diamine; N-methyl-N-(2-pyrrolidinoethyl)-( 1 S )- 1 ,2,3 ,4-tetrahydro- 1 -naphthalenamine, and
N'.N'-diethyl-^-methyl-^-l^^^-tetrahydro-l-naphthalenyl-l^-ethanediamine.
5. A pharmaceutical composition comprising as an active ingredient an effective amount of a compound according to any of Claims 1 to 3, together with a pharmaceutically-acceptable carrier.
6. Use of a pharmaceutical composition according to Claim 5, for the therapy or treatment of stroke, head trauma, transient cerebral ischaemic attack, Alzheimer's disease, Parkinson's disease, diabetic neuropathy, amyotrophic lateral sclerosis, multiple sclerosis or AIDS-related dementia.
7. A method for treating or preventing neurological diseases by inhibition of the [ [33HH]]--eemmooppaammiill bbiinnddiinngg ssiittee,, ccoommpprriissiinngg aaddmmiinistering to a mammal an effective amount of a compound according to any of Claims 1 to 3.
8. Use of a compound according to any of Claims 1 to 3, for preparation of a therapeutic agent or prophylactic agent for diseases treatable by inhibition of the [3H] -emopamil binding site.
9. A method for treating or preventing diseases treatable by inhibition of the
[ [3HH]] --eemmooppaammiill bbiinnddiinngg ssiittee,, ccoommpprriissiinngg aaddmm:inistering to a mammal an effective amount of ; compound according to any of Claims 1 to 3.
10. A process for preparing compounds of formula I wherein R1, R2, R3, R4, R5 and n, are, as defined in Claim 1, which process comprises: a) reacting a ketone of formula II:
HN
Rc
VII wherein: when R of a compound of formula I is hydrogen Ra is suitable amino protecting group as defined hereafter; or when R of a compound of formula I is not hydrogen Ra is R1 ; or d) if R1 is Cι.6alkyl or phenylC2_6alkyl, reacting a compound of formula VIII:
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU16708/00A AU1670800A (en) | 1998-12-15 | 1999-12-10 | 1,2,3,4-tetrahydronaphthalenes and their pharmaceutical use |
| EP99959569A EP1140852A1 (en) | 1998-12-15 | 1999-12-10 | 1,2,3,4-tetrahydronaphthalenes and their pharamaceutical use |
| JP2000588144A JP2002532475A (en) | 1998-12-15 | 1999-12-10 | 1,2,3,4-tetrahydronaphthalene and their pharmaceutical use |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9827467.3 | 1998-12-15 | ||
| GBGB9827467.3A GB9827467D0 (en) | 1998-12-15 | 1998-12-15 | Chemical compounds |
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Family
ID=10844168
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| PCT/GB1999/004167 WO2000035882A1 (en) | 1998-12-15 | 1999-12-10 | 1,2,3,4-tetrahydronaphthalenes and their pharmaceutical use |
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| Country | Link |
|---|---|
| EP (1) | EP1140852A1 (en) |
| JP (1) | JP2002532475A (en) |
| AU (1) | AU1670800A (en) |
| GB (2) | GB9827467D0 (en) |
| WO (1) | WO2000035882A1 (en) |
Cited By (6)
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| WO2000078718A1 (en) * | 1999-06-17 | 2000-12-28 | Astrazeneca Uk Limited | 4-aminopiperidine derivatives of tetrahydronaphthalene, chromans and thiochromans |
| WO2001068609A1 (en) * | 2000-03-14 | 2001-09-20 | Actelion Pharmaceuticals Ltd. | 1,2,3,4-tetrahydroisoquinoline derivatives |
| US7763638B2 (en) | 2004-03-01 | 2010-07-27 | Actelion Pharmaceuticals Ltd. | Substituted 1,2,3,4-tetrahydroisoquinoline derivatives |
| WO2014012935A1 (en) | 2012-07-20 | 2014-01-23 | Bayer Pharma Aktiengesellschaft | Substituted aminoindane- and aminotetralincarboxylic acids and use thereof |
| WO2014012934A1 (en) | 2012-07-20 | 2014-01-23 | Bayer Pharma Aktiengesellschaft | Novel 5-aminotetrahydroquinoline-2-carboxylic acids and use thereof |
| US12138256B2 (en) | 2021-12-29 | 2024-11-12 | Bayer Aktiengesellschaft | Treatment of cardiopulmonary disorders |
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| WO1999032461A1 (en) * | 1997-12-18 | 1999-07-01 | Astrazeneca Uk Limited | 1,4-diazacycloheptane derivatives |
| WO1999038863A1 (en) * | 1998-01-29 | 1999-08-05 | Astrazeneca Uk Limited | 1,4-diazacycloheptane derivatives for the treatment of neurological disorders |
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- 1998-12-15 GB GBGB9827467.3A patent/GB9827467D0/en not_active Ceased
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- 1999-12-07 GB GBGB9928746.8A patent/GB9928746D0/en not_active Ceased
- 1999-12-10 AU AU16708/00A patent/AU1670800A/en not_active Abandoned
- 1999-12-10 WO PCT/GB1999/004167 patent/WO2000035882A1/en not_active Application Discontinuation
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- 1999-12-10 EP EP99959569A patent/EP1140852A1/en not_active Withdrawn
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| WO1999032461A1 (en) * | 1997-12-18 | 1999-07-01 | Astrazeneca Uk Limited | 1,4-diazacycloheptane derivatives |
| WO1999038863A1 (en) * | 1998-01-29 | 1999-08-05 | Astrazeneca Uk Limited | 1,4-diazacycloheptane derivatives for the treatment of neurological disorders |
| WO1999055677A1 (en) * | 1998-04-29 | 1999-11-04 | Smithkline Beecham Plc | Quinolones used as mrs inhibitors and bactericides |
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| US6703392B2 (en) | 2000-03-14 | 2004-03-09 | Actelion Pharmaceuticals Ltd. | 1,2,3,4-tetrahydroisoquinoline derivatives |
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Also Published As
| Publication number | Publication date |
|---|---|
| JP2002532475A (en) | 2002-10-02 |
| AU1670800A (en) | 2000-07-03 |
| GB9928746D0 (en) | 2000-02-02 |
| GB9827467D0 (en) | 1999-02-10 |
| EP1140852A1 (en) | 2001-10-10 |
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