WO2000013682A2 - 4-quinolinemethanol derivatives as purine receptor antagonists.(ii) - Google Patents
4-quinolinemethanol derivatives as purine receptor antagonists.(ii) Download PDFInfo
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- WO2000013682A2 WO2000013682A2 PCT/GB1999/002924 GB9902924W WO0013682A2 WO 2000013682 A2 WO2000013682 A2 WO 2000013682A2 GB 9902924 W GB9902924 W GB 9902924W WO 0013682 A2 WO0013682 A2 WO 0013682A2
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- trifluoromethyl
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- XEEQGYMUWCZPDN-IUODEOHRSA-N O[C@@H]([C@@H]1NCCCC1)c1cc(C(F)(F)F)nc2c1cccc2C(F)(F)F Chemical compound O[C@@H]([C@@H]1NCCCC1)c1cc(C(F)(F)F)nc2c1cccc2C(F)(F)F XEEQGYMUWCZPDN-IUODEOHRSA-N 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
Definitions
- the present invention relates to 4-quinolinylmethanol derivatives and their use in therapy.
- the present invention relates to the treatment of disorders in which the reduction of purinergic neurotransmission could be beneficial.
- the invention relates in particular to adenosine receptors and particularly adenosine A_ A receptors, and to the treatment of movement disorders such as Parkinson's disease.
- Movement disorders constitute a serious health problem, especially amongst the elderly sector of the population. These movement disorders are often the result of brain lesions. Disorders involving the basal ganglia which result in movement disorders include Parkinson's disease, Alzheimer's disease, Huntington's chorea and Wilson's disease. Furthermore, dyskinesias often arise as sequelae of cerebral ischaemia and other neurological disorders.
- Parkinson's disease There are four classic symptoms of Parkinson's disease: tremor, rigidity, akinesia and postural changes. The disease is also commonly associated with depression, dementia and overall cognitive decline. Parkinson's disease has a prevalence of 1 per 1,000 of the total population. The incidence increases to 1 per 100 for those aged over 60 years. Degeneration of dopaminergic neurones in the substantia nigra and the subsequent reductions in interstitial concentrations of dopamine in the striatum are critical to the development of Parkinson's disease. Some 80% of cells from the substantia nigra need to be destroyed before the clinical symptoms of Parkinson's disease are manifested.
- L-dihydroxyphenylacetic acid L-DOPA
- L-DOPA L-dihydroxyphenylacetic acid
- DPA monoamine oxidase
- dopamine receptor agonists e.g. bromocriptine and apomorphine
- anticholinergics e.g. benztrophine, orphenadrine
- Transmitter replacement therapy in particular does not provide consistent clinical benefit, especially after prolonged treatment when "on-off ' symptoms develop, and this treatment has also been associated with involuntary movements of athetosis and chorea, nausea and vomiting. Additionally current therapies do not treat the underlying neurodegenerative disorder resulting in a continuing cognitive decline in patients.
- Blockade of A 2 adenosine receptors has recently been implicated in the treatment of movement disorders such as Parkinson's disease (Richardson, PJ. et al., Trends Pharmacol. Sci. 1997, 18, 338-344) and in the treatment of cerebral ischaemia (Gao, Y. and Phillis, J.W., Life Sci. 1994, 55, 61-65).
- the potential utility of adenosine A 2A receptor antagonists in the treatment of movement disorders such as Parkinson's Disease has recently been reviewed (Mally, J. and Stone, T.W., CNS Drugs, 1998, 10, 311-320).
- Adenosine is a naturally occurring purine nucleoside which has a wide variety of well- documented regulatory functions and physiological effects.
- the central nervous system (CNS) effects of this endogenous nucleoside have attracted particular attention in drug discovery, owing to the therapeutic potential of purinergic agents in CNS disorders (Jacobson, K.A. et al., J. Med. Chem. 1992, 35, 407-422).
- This therapeutic potential has resulted in considerable recent research endeavour within the field of adenosine receptor agonists and antagonists (Bhagwhat, S.S.; Williams, M. Exp. Opin. Ther. Patents 1995, 5,547-558).
- Adenosine receptors represent a subclass (P of the group of purine nucleotide and nucleoside receptors known as purinoreceptors.
- the main pharmacologically distinct adenosine receptor subtypes are known as A 1? A 2A , A_ B (of high and low affinity) and A 3 (Fredholm, B.B., et al, Pharmacol. Rev. 1994, 46, 143-156).
- the adenosine receptors are present in the CNS (Fredholm, B.B., News Physiol. Sci., 1995, 10, 122- 128).
- Pi receptor-mediated agents The design of Pi receptor-mediated agents has been reviewed (Jacobson, K.A., Suzuki, F., Drug Dev. Res., 1997, 39, 289-300; Baraldi, P.G. et al., Curr. Med. Chem. 1995, 2, 707-722), and such compounds are claimed to be useful in the treatment of cerebral ischemia or neurodegenerative disorders, such as Parkinson's disease (Williams, M. and Burnstock, G. Purinergic Approaches Exp. Ther. (1997), 3-26. Editor: Jacobson,
- adenosine A 2A receptors The pharmacology of adenosine A 2A receptors has been reviewed (Ongini, E.; Fredholm, B.B. Trends Pharmacol. Sci. 1996, 17(10), 364-372).
- One potential underlying mechanism in the aforementioned treatment of movement disorders by the blockade of A 2 adenosine receptors is the evidence of a functional link between adenosine A 2A receptors to dopamine D 2 receptors in the CNS.
- Some of the early studies e.g. Ferre, S. et al, Stimulation of high-affinity adenosine A 2 receptors decreases the affinity of dopamine D 2 receptors in rat striatal membranes. Proc. Natl. Acad. Sci.
- adenosine A 2A antagonist therapy While many of the potential drugs for treatment of Parkinson's disease have shown benefit in the treatment of movement disorders, an advantage of adenosine A 2A antagonist therapy is that the underlying neurodegenerative disorder is also treated.
- the neuroprotective effect of adenosine A 2A antagonists has been reviewed (Ongini, E.; Adami, M.; Ferri, C; Bertorelli, R., Ann. N. Y. Acad. Sci. 1997, 825(Neuroprotective Agents), 30-48).
- Xanthine derivatives have been disclosed as adenosine A 2 receptor antagonists as useful for treating various diseases caused by hyperfunctioning of adenosine A 2 receptors, such as Parkinson's disease (see, for example, EP-A-565377).
- One prominent xanthine-derived adenosine A 2A selective antagonist is CSC [8-(3- chlorostyryl)caffeine] (Jacobson et al, FEBS Lett., 1993, 323, 141-144).
- Theophylline (1,3-dimethylxanthine), a bronchodilator drug which is a mixed antagonist at adenosine Ai and A 2A receptors, has been studied clinically.
- the patients exhibited significant improvements in mean objective disability scores and 11 reported moderate or marked subjective improvement (Mally, J., Stone, T.W. J. Pharm. Pharmacol. 1994, 46, 515-517).
- KF 17837 [(E)-8-(3,4-dimethoxystyryl)-l,3-dipropyl-7-methylxanthine] is a selective adenosine A 2A receptor antagonist which on oral administration significantly ameliorated the cataleptic responses induced by intracerebroventricular administration of an adenosine A 2A receptor agonist, CGS 21680. KF 17837 also reduced the catalepsy induced by haloperidol and reserpine.
- KF 17837 potentiated the anticataleptic effects of a subthreshold dose of L-DOPA plus benserazide, suggesting that KF 17837 is a centrally active adenosine A 2A receptor antagonist and that the dopaminergic function of the nigrostriatal pathway is potentiated by adenosine A 2A receptor antagonists (Kanda, T. et al., Eur. J. Pharmacol. 1994, 256, 263-268).
- SAR structure activity relationship
- Recent data has also been provided on the A 2A receptor antagonist KW-6002 (Kuwana, Y et al., Soc. Neurosci. Abstr.
- New non-xanthine structures sharing these pharmacological properties include SCH 58261 and its derivatives (Baraldi, P.G. et al, Pyrazolo[4,3-e]-l,2,4-triazolo[l,5- cjpyrimidine Derivatives: Potent and Selective A 2A Adenosine Antagonists. J. Med. Chem. 1996, 39, 1164-71).
- SCH 58261 (7-(2-phenylethyl)-5-amino-2-(2-furyl)- pyrazolo-[4,3-e]-l,2,4-triazolo[l,5-c] pyrimidine) is reported as effective in the treatment of movement disorders (Ongini, E. Drug Dev. Res. 1997, 42(2), 63-70) and has been followed up by a later series of compounds (Baraldi, P.G. et al., J. Med. Chem. 1998, 41(12), 2126-2133
- 4-quinolinylmethanol derivatives which are structurally unrelated to known adenosine receptor antagonists, exhibit unexpected antagonist binding affinity at adenosine (Pi) receptors, and in particular at the adenosine A 2A receptor.
- Such compounds may therefore be suitable for the treatment of movement disorders, such as disorders of the basal ganglia which result in dyskinesias. These may include Parkinson's disease, Alzheimer's disease, spasticity, Huntingdon's chorea and Wilson's disease.
- Ri is hydrogen or alkyl
- R 2 is selected from hydrogen, alkyl, aryl and 4, 5, 6, 7 or 8 membered saturated and partially unsaturated heterocyclic rings containing one or more heteroatoms selected from O, S and N;
- R 3 and R 4 are independently selected from hydrogen, alkyl, aryl, COR ⁇ , CO 2 R ⁇ , CONR ⁇ 3 R 14 , CONR13NR14R15, SO 2 Ri 3 , SO 2 NR 13 R M , SO 2 NR ⁇ 3 NR 14 R 15 and 4,
- R 2 and R 3 together may form a 4, 5, 6 or 7 membered saturated or partially unsaturated heterocyclic ring optionally containing one or more additional heteroatoms selected from O, S and N;
- R 5 and R$ are independently selected from hydrogen, alkyl, aryl and 4, 5, 6, 7 or 8 membered saturated and partially unsaturated heterocyclic rings containing one or more heteroatoms selected from O, S and N, or together may form a 3, 4, 5, 6 or 7 membered saturated or partially unsaturated carbocyclic ring or a 4, 5, 6, 7 or 8 membered saturated or partially unsaturated heterocyclic ring containing one or more heteroatoms selected from O, S and N; or R 3 and R 5 together may form a 4, 5, 6 or 7 membered unbridged, saturated or partially unsaturated heterocyclic ring optionally containing one or more additional heteroatoms selected from O, S and N; wherein said carbocyclic or said heterocyclic ring when partially unsaturated or aromatic may be fused to an aryl ring; with the proviso that where R 3 and R 5 together form a ring, then R 3 and R 4 do not also form a ring;
- R 7> Rs, R 9 , R 10 , R ⁇ and R ⁇ 2 are independently selected from hydrogen, alkyl, aryl, 4, 5, 6, 7 or 8 membered saturated and partially unsaturated heterocyclic rings containing one or more heteroatoms selected from O, S and N, hydroxy, halogen, nitro, cyano, alkoxy, aryloxy, COR ⁇ , OCOR ⁇ 3 , CO 2 R 13 , SR 13 , SOR 13 , SO 2 R 13 , SO 2 NR ⁇ 3 R ⁇ 4 , CONR ⁇ 3 R ]4 , CONR.3NR1 R15.
- R ⁇ 3 , R M , R 15 and R ⁇ 6 are independently selected from hydrogen, alkyl and aryl, or a pharmaceutically acceptable salt or prodrug thereof, in the manufacture of a medicament for the treatment or prevention of a disorder in which the blocking of purine receptors, particularly adenosine receptors and more particularly A 2A receptors, may be beneficial.
- alkyl means a branched or unbranched, cyclic or acyclic, saturated or unsaturated (e.g. alkenyl or alkynyl) hydrocarbyl radical.
- the alkyl group is preferably C 3 to C 12 , more preferably C 5 to Cio, more preferably C 5 , C 6 or
- the alkyl group is preferably Cj to do, more preferably Ci to C 6 , more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or t-butyl.
- aryl means an aromatic group, such as phenyl or naphthyl, or a heteroaromatic group containing one or more heteroatom, such as pyridyl, pyrrolyl, quinolinyl, furanyl, thienyl, oxadiazolyl, thiadiazolyl, thiazolyl, oxazolyl, isoxazolyl, pryazolyl, triazolyl, imidazolyl or pyrimidinyl.
- the alkyl and aryl groups may be substituted or unsubstituted.
- Substituents may include: carbon-containing groups such as alkyl, aryl, arylalkyl (e.g. substituted and unsubstituted phenyl, substituted and unsubstituted benzyl); halogen atoms and halogen-containing groups such as haloalkyl (e.g. trifluoromethyl); oxygen-containing groups such as alcohols (e.g. hydroxy, hydroxyalkyl, aryl(hydroxy)alkyl), ethers (e.g.
- alkoxy, aryloxy, alkoxyalkyl, aryloxyalkyl alkoxy, aryloxy, alkoxyalkyl, aryloxyalkyl
- aldehydes e.g. carboxaldehyde
- ketones e.g. alkylcarbonyl, alkylcarbonylalkyl, arylcarbonyl, arylalkylcarbonyl, arylcarbonylalkyl
- acids e.g. carboxy, carboxyalkyl
- acid derivatives such as esters
- alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl e.g. alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl
- amides e.g. aminocarbonyl, mono- or di- alkylaminocarbonyl, aminocarbonylalkyl, mono- or di-alkylaminocarbonylalkyl, arylaminocarbonyl
- carbamates e.g. alkoxycarbonylamino, aryloxycarbonylamino, aminocarbonyloxy, mono- or di-alkylaminocarbonyloxy, arylaminocarbonyloxy
- ureas e.g.
- amines e.g. amino, mono- or di-alkylamino, aminoalkyl, mono- or di-alkylaminoalkyl
- azides e.g. cyano, cyanoalkyl
- sulfur-containing groups such as thiols, thioethers, sulfoxides and sulfones
- thienyl furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, aziridinyl, azetidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, tetrahydrofuranyl, pyranyl, pyronyl, pyridyl, pyrazinyl, pyridazinyl, piperidyl, hexahydroazepinyl, piperazinyl, mo holinyl, thianaphthyl, benzofuranyl, isobenzofuranyl, indolyl, oxyindolyl, isoindolyl, indazolyl, indolinyl, 7-
- alkoxy means alkyl-O- and "alkoyl” means alkyl-CO-.
- Alkoxy substituent groups or alkoxy-containing substituent groups may be substituted by one or more alkyl groups.
- halogen means a fluorine, chlorine, bromine or iodine radical, preferably a fluorine, chlorine or bromine radical.
- prodrug means any pharmaceutically acceptable prodrug of the compound of formula (I).
- salts may be prepared from pharmaceutically acceptable non-toxic acids and bases including inorganic and organic acids and bases. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, dichloroacetic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, oxalic, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, oxalic, p-toluenesulfonic and the like.
- acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, dichloroacetic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydro
- hydrochloric hydrobromic, phosphoric, sulfuric and methanesulfonic acids
- hydrochloric salt particularly preferred is the hydrochloric salt.
- Acceptable base salts include alkali metal (e.g. sodium, potassium), alkaline earth metal (e.g. calcium, magnesium) and aluminium salts.
- saturated heterocyclic ring means a heterocyclic ring wherein the bonds between the atoms forming the ring are single bonds.
- saturated heterocyclic rings include aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, hexahydroazepinyl, heptamethyleneiminyl, oxiranyl, oxetanyl tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyran, piperazinyl, morpholinyl, dioxanyl and thiomorpholinyl.
- partially unsaturated heterocyclic ring means a heterocyclic ring wherein one or more of the bonds between the atoms forming the ring are unsaturated bonds and wherein the ring is non-aromatic in character.
- partially unsaturated rings include 3-pyrrolinyl, imidazolinyl, oxazolinyl, thiazolinyl, pyrrazolinyl, dihydropyranyl, pyranyl, dihydropyridinyl and tetrahydropyridinyl.
- the term "carbocyclic ring” means a ring wherein the atoms forming the ring are carbon atoms and wherein the ring is either (a) a saturated ring in which the bonds between the ring atoms are single bonds (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, or a bicyclic ring such as norbornanyl); or (b) a partially unsaturated ring wherein one or more of the bonds between the ring atoms are unsaturated bonds and wherein the ring is non-aromatic in character (such as cyclop entenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclopentadienyl, cyclohexadienyl and cycloheptadienyl); or (c) an aromatic
- bridged refers to a ring or ring system which is not bridged; the term “bridged” referring to a ring system in which two or more rings share non-adjacent atoms to form a multicyclic ring system.
- bridged ring system examples include adamantane, norbornane and 5-ethenyl-l-azabicyclo[2.2.2]octane.
- fused refers to a ring system in which two rings or ring systems share only adjacent ring atoms.
- Examples of a fused ring system include naphthalene, quinoline, indan and benzofuran.
- R 2 to R ⁇ 2 are selected from 4, 5, 6, 7 or 8 membered heterocyclic rings containing a plurality of heteroatoms selected from O, S and N, the heteroatoms may be the same or different.
- R 3 and R 4 ; or Ri and R 4 ; or R 2 and R 3 ; or R 5 and R ; or R 3 and R 5 together form a heterocyclic ring containing a plurality of heteroatoms selected from O, S and N, the heteroatoms may be the same or different.
- R 3 and together form a 3 membered heterocyclic ring it is preferred that said ring is saturated and contains no more than one heteroatom.
- Ri is hydrogen or alkyl
- R 2 is selected from hydrogen, alkyl, aryl and 4, 5, 6, 7 or 8 membered saturated and partially unsaturated heterocyclic rings containing one or more heteroatoms selected from O, S and N
- R 3 and R 4 are independently selected from hydrogen, alkyl, aryl, COR 13 , CO 2 R 13 , CONR ⁇ 3 R 14 , CONR 13 NR 14 R ⁇ 5 , SO 2 R 13 , SO 2 NR 13 R 14 , SO 2 NR ⁇ 3 NR 14 R ⁇ 5 and 4, 5, 6, 7 or 8 membered saturated and partially unsaturated heterocyclic rings containing one or more heteroatoms selected from O, S and N, wherein said heterocyclic ring(s) when partially unsaturated may be fused to an aryl ring.
- Ri is hydrogen or alkyl
- R 2 is selected from hydrogen, alkyl, aryl and 4, 5, 6, 7 or 8 membered saturated and partially unsaturated heterocyclic rings containing one or more heteroatoms selected from O, S and N
- R 3 and R 4 together form a 3, 4, 5, 6, 7 or 8 membered saturated, partially unsaturated or aromatic heterocyclic ring optionally containing one or more additional heteroatoms selected from O, S and N, wherein said heterocyclic ring(s) when partially unsaturated or aromatic may be fused to an aryl ring.
- R ⁇ and R 4 together form a 5, 6 or 7 membered saturated or partially unsaturated heterocyclic ring optionally containing an additional heteroatom selected from O, S and N;
- R 2 is selected from hydrogen, alkyl, aryl and 4,
- R 3 is selected from hydrogen, alkyl, aryl, COR 13 , CO 2 R ⁇ 3 , CONR ⁇ 3 R ⁇ 4 , CONR ⁇ 3 NR 14 R ⁇ 5 , SO 2 R 13 ,
- R is hydrogen or alkyl; R 2 and R 3 together form a 4, 5, 6 or 7 membered saturated or partially unsaturated heterocyclic ring optionally containing one or more additional heteroatoms selected from O, S and N; and R 4 is selected from hydrogen, alkyl, aryl, COR ⁇ , CO 2 R 13 , CONR 13 R 14 , CONR 13 NR ] Ri 5 , SO2R13, SO 2 NR ⁇ 3 R ⁇ , SO2NR13 R14R15 and 4, 5, 6, 7 or 8 membered saturated and partially unsaturated heterocyclic rings containing one or more heteroatoms selected from O, S and N, wherein said heterocyclic ring(s) when partially unsaturated may be fused to an aryl ring.
- R 5 and Re are independently selected from hydrogen, alkyl (including cycloalkyl, ara-alkyl and heteroara-alkyl), aryl (including heteroaryl) and 4, 5, 6, 7 or 8 membered saturated and partially unsaturated heterocyclic rings containing one or more heteroatoms selected from O, S and N, or together may form a 3, 4, 5, 6 or 7 membered saturated or partially unsaturated carbocyclic ring or a 4, 5, 6, 7 or 8 membered saturated or partially unsaturated heterocyclic ring containing one or more heteroatoms selected from O, S and N, wherein said carbocyclic ring or said heterocyclic ring when partially unsaturated may be fused to an aryl ring.
- Ri is hydrogen or alkyl
- R 2 is selected from hydrogen, alkyl, aryl and 4, 5, 6, 7 or 8 membered saturated and partially unsaturated heterocyclic rings containing one or more heteroatoms selected from O, S and N
- R4 is selected from hydrogen, alkyl, aryl, COR 13 , CO 2 R B , CONR ⁇ 3 R ⁇ 4 , CONR 13 NR 14 R 15 , SO 2 R ⁇ 3 , SO 2 NR ⁇ 3 R ]4 , SO 2 NR] 3 NR ⁇ 4 Ri5 and 4, 5, 6, 7 or 8 membered saturated and partially unsaturated heterocyclic rings containing one or more heteroatoms selected from O, S and N
- Re is selected from hydrogen, alkyl, aryl and 4, 5, 6, 7 or 8 membered saturated and partially unsaturated heterocyclic rings containing one or more heteroatoms selected from O, S and N
- R 3 and R 5 together form a 4, 5, 6 or 7 membered unbridged, saturated or partially unsaturation
- R 7 , R 8 , R 9 , Rio, Ri i and R ⁇ 2 are independently selected from hydrogen, alkyl (including cycloalkyl, halo-alkyl (such as trifluoromethyl), ara-alkyl and heteroara-alkyl), aryl (including heteroaryl), 4, 5, 6, 7 or 8 membered saturated and partially unsaturated heterocyclic rings containing one or more heteroatoms selected from O, S and N, hydroxy, halogen, nitro, cyano, alkoxy, aryloxy, COR ⁇ , OCORn, CO 2 Ri3, SR !3 , SOR ⁇ 3 , SO 2 R 13 , SO 2 NR ⁇ 3 R ⁇ 4 , CONR 13 R 14 , CONR ⁇ 3 NR 1 R 15 , OCONR !3 R ⁇ 4 , NR 13 R 14 , NR 13 COR 14 , NR 15 CONR 13 R 14 , NR ⁇
- any of R 2 , R 3 , R 4 , R 5 and R$ are selected from 4, 5, 6, 7 or 8 membered saturated and partially unsaturated heterocyclic rings containing one or more heteroatoms selected from O, S and N
- said heterocyclic ring is preferably unbridged; preferably monocyclic; and is preferably a 5 or 6 membered ring.
- said heterocyclic ring is partially unsaturated and is fused to an aryl ring, said aryl ring is preferably phenyl.
- any of R 7 to Rj 2 are selected from 4, 5, 6, 7 or 8 membered saturated and partially unsaturated heterocyclic rings containing one or more heteroatoms selected from O, S and N
- said heterocyclic ring is preferably unbridged; preferably monocyclic; and is preferably a 5 or 6 membered ring.
- said ring is preferably unbridged; preferably monocyclic; and is preferably a 4, 5 or 6 membered ring, preferably a 5 or 6 membered ring.
- said aryl ring is preferably phenyl.
- the compounds of formula (I) are selected from compounds in which R ⁇ is hydrogen or methyl or from compounds in which Ri forms a 5 or 6 membered heterocyclic ring with R .
- the compounds of formula (I) are selected from compounds in which R 2 is hydrogen or from compounds in which R 2 forms a 4, 5 or 6 membered, preferably a 4 membered, heterocyclic ring with R 3 .
- R 3 and 1 ⁇ are independently selected from hydrogen, alkyl (including cycloalkyl, ara- alkyl and heteroara-alkyl), aryl (including heteroaryl) COR ⁇ , CO 2 R ⁇ 3 , CONR 13 R 14 , SO .
- R ⁇ , SO 2 NR ⁇ 3 R ⁇ 4 , SO 2 NR 13 NR ⁇ 4 R 15 and 4, 5, 6, 7 or 8 membered saturated and partially unsaturated heterocyclic rings containing one or more heteroatoms selected from O, S and N, or together may form a 3, 4, 5, 6, 7 or 8 membered saturated, partially unsaturated or aromatic heterocyclic ring optionally containing one or more additional heteroatoms selected from O, S and N, wherein said heterocyclic ring when partially unsaturated or aromatic may be fused to an aryl ring.
- the compounds of formula (I) are selected from compounds in which R 3 is hydrogen, alkyl (preferably methyl, benzyl, cyclobutyl or isobutyl), aryl (preferably phenyl), COR ⁇ 3 (preferably wherein R 13 is alkyl, preferably methyl) or CO 2 R 13 (preferably where R ⁇ 3 is alkyl, preferably t-butyl), or from compounds in which R forms a 5 or 6 membered ring with R 4 or from compounds in which R 3 forms a 5 or 6 membered heterocyclic ring with R 5 or from compounds in which R 3 forms a 4, 5 or 6 membered heterocyclic ring with R 2 .
- R 3 is hydrogen, alkyl (preferably methyl, benzyl, cyclobutyl or isobutyl), aryl (preferably phenyl), COR ⁇ 3 (preferably wherein R 13 is alkyl, preferably methyl) or CO 2 R 13 (preferably where R ⁇ 3 is alkyl, preferably t-
- the compounds of formula (I) are selected from compounds in which R 4 is hydrogen, alkyl (preferably methyl, cyclobutyl or isobutyl, or ara-alkyl (preferably benzyl or phenylethyl)), aryl (preferably phenyl), COR ⁇ 3 (preferably wherein R J3 is alkyl, preferably methyl) or CO_Rn (preferably where R ⁇ 3 is alkyl, preferably t-butyl), or from compounds in which * forms a 5 or 6 membered heterocyclic ring with R 3 or from compounds in which R forms a 5 or 6 membered heterocyclic ring with R ⁇ .
- R 4 is hydrogen, alkyl (preferably methyl, cyclobutyl or isobutyl, or ara-alkyl (preferably benzyl or phenylethyl)), aryl (preferably phenyl), COR ⁇ 3 (preferably wherein R J3 is alkyl, preferably methyl) or CO_Rn
- the compounds of formula (I) are selected from compounds in which R 5 is hydrogen, alkyl (preferably methyl, secondary butyl or isobutyl or ara-alkyl (preferably benzyl)) or from compounds in which R 5 forms a 5 or 6 membered heterocyclic ring with R 3 .
- the compounds of formula (I) are selected from compounds in which R ⁇ is hydrogen or alkyl (preferably methyl, secondary butyl or isobutyl or ara-alkyl (preferably benzyl)).
- R ⁇ 3 of the or each NR 13 COR 14 group is hydrogen.
- At least one of R 7 to R 12 is a group other than hydrogen.
- the compounds of formula (I) are selected from compounds other than compounds in which both R and R 12 are halo-alkyl (including trifluoromethyl).
- R 7 and/or R ⁇ 2 are selected from hydrogen, hydroxy, alkyl (preferably unsubstituted alkyl, preferably methyl), alkoxy (preferably methoxy) and NRoR ⁇ 4 (preferably where Rj 3 and R] are selected from hydrogen and alkyl (preferably methyl)).
- R 7 is selected from hydroxy, NR ⁇ R ⁇ 4 (preferably where R 13 and R ⁇ 4 are selected from hydrogen and alkyl (preferably methyl), and preferably hydrogen) and alkoxy (preferably methoxy).
- Rj 2 is selected from hydrogen and alkyl (preferably methyl).
- the compounds of formula (I) are selected from compounds in which Rg, R 9 Rio and/or R u is hydrogen.
- the compounds of formula (I) are selected from (lR,8aS)-l,5,6,7,8,8a-hexahydro-l-(2,8-bis(trifluoromethyl)-4-quinolinyl)-3H- oxazolo[3,4-a]pyridine, (HR, 2'S)- ⁇ -(l-methyl-2-piperidinyl)-2,8- bis(trifluoromethyl)-4-quinolinemethanol, (-)-(HR, 2'S)- ⁇ -2-piperidinyl-2,8- bis(trifluoromethyl)-4-quinolinemethanol, (-)-(HR, 2'R)- ⁇ -2-piperidinyl-2,8- bis(trifluoromethyl)-4-quinolinemethanol and (US*, 2'R*)- ⁇ -(2-Piperidinyl
- the compounds of formula (I) may be in the form of a racemic mixture of pairs of enantiomers or in enantiomerically pure form.
- R is H or alkyl
- the compounds of formula (I) are selected from compounds in which the stereochemical configuration at the carbon atom bound to the 4- position of the quinoline ring is R.
- a method of treating or preventing a disorder in which the blocking of purine receptors, particularly adenosine receptors and more particularly adenosine A 2A receptors, may be beneficial comprising administration to a subject in need of such treatment an effective dose of a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof.
- the disorder may be caused by the hyperfunctioning of the purine receptors.
- a method of treating or preventing movement disorders comprising administration to a subject in need of such treatment an effective dose of a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof.
- a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof in the manufacture of a medicament for neuroprotection in a subject.
- a method of neuroprotection comprising administration to a subject in need of such treatment an effective dose of a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof.
- the medicament for or method of neuroprotection may be of use in the treatment of subjects who are suffering from or at risk from a neurodegenerative disorder, such as a movement disorder.
- a compound of formula (I) wherein R ⁇ and R 4 together may form a 5, 6 or 7 saturated, partially unsaturated or aromatic membered heterocyclic ring optionally containing one or more additional heteroatoms selected from O, S and N, or a pharmaceutically acceptable salt or prodrug thereof.
- the present invention may be employed in respect of a human or animal subject, more preferably a mammal, more preferably a human subject.
- Parkinson's disease drugs-induced Parkinsonism, post-encephalitic Parkinsonism, Parkinsonism induced by poisoning (for example MPTP, manganese, carbon monoxide) and post-traumatic Parkinson's disease (punch- drunk syndrome).
- Other movement disorders in which the therapy may be of benefit include progressive supernuclear palsy, Huntingtons disease, multiple system atrophy, corticobasal degeneration, Wilsons disease, Hallerrorden-Spatz disease, progressive pallidal atrophy, Dopa-responsive dystonia-Parkinsonism, spasticity, Alzheimer's disease or other disorders of the basal ganglia which result in abnormal movement or posture.
- a further example of a disorder in which the blocking of purine receptors may be beneficial is depression.
- the compound of formula (I) may be used or administered in combination with one or more additional drugs useful in the treatment of movement disorders, such as L-DOPA, the components being in the same formulation or in separate formulations for administration simultaneously or sequentially.
- additional drugs useful in the treatment of movement disorders such as L-DOPA
- the present invention may also be effective in treating Parkinson's with on-off phenomena; Parkinson's with freezing (end of dose deterioration); and Parkinson's with prominent dyskinesias.
- a compound of formula (I) wherein Ri and R 4 together may form a 5, 6 or 7 saturated, partially unsaturated or aromatic membered heterocyclic ring optionally containing one or more additional heteroatoms selected from O, S and N, or a pharmaceutically acceptable salt or prodrug thereof.
- Compoimds of formula (1) where Ri is an alkyl group are prepared from compounds of formula (2) (Reaction Scheme 1) by standard methods such as alkylation with an alkyl halide in the presence of a suitable base such as NaH.
- Compounds of formula (2) where * is an alkyl group are prepared from compounds of formula (3) in two steps by standard methods such as removal of the protecting group using, for example TFA, followed by reductive alkylation of the resulting amine using an appropriate aldehyde or ketone in the presence of a suitable reducing agent such as NaCNBH 3 .
- Compounds of formula (2) where R 4 is hydrogen are prepared from compounds of formula (3) by deprotection as described above.
- Grignard reagent or an alkyl or aryl lithium reagent.
- reaction of a nucleophile such as a Grignard reagent, an alkyl or aryl lithium reagent or a hydride reducing agent may lead to compounds of formula (3) where one of the two possible stereo chemical configurations at the chiral centre to which R 2 is attached, is formed selectively.
- a nucleophile such as a Grignard reagent, an alkyl or aryl lithium reagent or a hydride reducing agent
- suitable hydride reducing agents may be, for example DIBAL which may give a compound of formula (3) with a specific configuration at the carbon to which R 2 is attached, or alternatively K-selectride which may give a compound of formula (3) with the opposite configuration at the carbon to which R 2 is attached.
- the absolute configuration of the carbon to which R 2 is attached in the compound of formula (3) will also be determined by the absolute configuration of the carbon to which R 5 and R are attached.
- Compounds of formula (3) may also be prepared directly from compounds of formula (5), initially by metallation using a suitable metallating agent such as BuLi, followed by addition of a suitably N-protected ⁇ -aminoketone or aldehyde such as a compound of formula (19) where R 2 , R 3 , R 5 and R ⁇ are as defined above.
- a suitable metallating agent such as BuLi
- a suitably N-protected ⁇ -aminoketone or aldehyde such as a compound of formula (19) where R 2 , R 3 , R 5 and R ⁇ are as defined above.
- Compounds of formula (4) where R 3 is alkyl are synthesised by standard methods from compounds of formula (4) where R 3 is hydrogen for example by alkylation with a suitable alkyl halide in the presence of a base such as NaH.
- Compounds of formula (4) are synthesised from compounds of formula (5) by standard methods such as initial metallation by using a suitable metallating agent such as BuLi, followed by addition of a suitably N-protected ⁇ -amino acid derivative such as an ester, lactone, acid chloride, acid anhydride, amide or N,O-dialkylhydroxamic acid derivative.
- R 3 or R 4 are COR ⁇ 3 , CO 2 R ⁇ , CONR 13 R ⁇ 4 or SO 2 R 13 may be prepared from compounds of formula (1) where R 3 or R4 are hydrogen by standard literature methods such as treatment with an acid chloride (R 13 COCl), chloro formate (CICO 2 R 13 ), isocyanate (R13NCO), chloroformamide (CICONR 0 R 14 ) or sulphonyl chloride (ClSO 2 R ⁇ 3 ).
- R 13 COCl an acid chloride
- CICO 2 R 13 chloro formate
- R13NCO isocyanate
- chloroformamide CICONR 0 R 14
- sulphonyl chloride ClSO 2 R ⁇ 3
- R 3 or R 4 are CONR ⁇ 3 NR ⁇ 4 Ri 5
- R 3 or R 4 are hydrogen by standard literature methods such as treatment with phosgene at low temperature followed by treatment with a suitable substituted hydrazine derivative
- Compounds of formula (9) are synthesised from compounds of formula (10) by standard literature methods such as reduction with a suitable reducing agent such as borane.
- Compounds of formula (10) are synthesised from compounds of formula (2) by standard literature methods such as treatment with a suitable ⁇ -halo acid halide such as chloroacetyl chloride in the presence of a suitable base such as NaOH.
- a suitable ⁇ -halo acid halide such as chloroacetyl chloride in the presence of a suitable base such as NaOH.
- a suitably substituted ⁇ -halo acid halide would lead to a compound of formula (11) which is additionally substituted in the azapyran ring.
- Compounds of formula (7) are known in the literature or are prepared from ketones of formula (14) (Reaction Scheme 5) by standard literature methods such as by ⁇ - bromination of the ketone using a suitable brominating agent, followed by treatment with NaOMe.
- Compounds of formula (14) are known in the literature or are prepared from bromoquinolines of formula (5) by standard literature methods such as by initial metallation with a suitable metallating agent such as BuLi, followed by addition of a suitably activated carboxylic acid derivative such as an ester, lactone, acid chloride, acid anhydride, amide or an N,O-dialkylhydroxamic acid derivative.
- Compounds of formula (5) are known in the literature or are prepared from compounds of formula (15) by standard methods such as treatment with POBr 3 .
- Compounds of formula (5) where R is bromine are known in the literature or are prepared directly from anilines of formula (16) by treatment with, for example malonic acid or a suitably substituted malonic acid derivative in the presence of POBr 3 .
- 4-Bromoquinolines (5) where R is bromine may also be prepared from 4-hydroxyquino lines (15) where R 7 is hydroxy, by treatment with POBr 3 .
- 4-Hydroxyquinolines (15) are either known in the literature or are prepared from anilines (16) by standard literature methods such as reaction with a suitably substituted acetoacetate ester derivative in the presence of a suitable acid catalyst or dehydrating agent such as polyphosphoric acid.
- Anilines (16) are commercially available, are known in the literature or may be prepared by standard literature methods.
- Synthetic preparation of some of the compounds of formula (I) where Rj - R 12 are as defined above, may require the use of protecting groups to avoid certain functional groups interfering in the normal course of a reaction.
- the protecting groups used in the preparation of the compounds of formula (I) are selected from a range of protecting groups commonly used in organic synthesis. This may include, for example the protection of amines with benzyl, substituted benzyl, diphenylmethyl or butoxycarbonyl groups or as a nitro group, the protection of alcohols with, for example benzyl, substituted benzyl, t-butyl or trialkylsilyl groups, and the protection of ketones as ketals or thioketals. In all cases deprotection of these functional groups is carried out by standard literature procedures known to those skilled in the art.
- the invention further relates to the compounds disclosed herein.
- a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof, in combination with a pharmaceutically acceptable carrier or excipient and a method of making such a composition comprising combining a compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof, with a pharmaceutically acceptable carrier or excipient.
- compositions employed in the present invention comprise a compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof, and may also contain other therapeutic ingredients known to those skilled in the art.
- Any suitable route of administration may be employed for providing the patient with an effective dosage of a compound of formula (I).
- oral, rectal, parenteral (intravenous, intramuscular), transdermal, subcutaneous, and the like may be employed.
- Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, patches, and the like.
- the most suitable route in any given case will depend on the severity of the condition being treated.
- the most preferred route of administration of the present invention is the oral route.
- the compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
- the compounds of formula (I), or a pharmaceutically acceptable salt or prodrug thereof can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
- the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g. oral or parenteral (e.g. intravenous).
- any of the usual pharmaceutical media may be employed as carriers, such as, for example, water, glycols, oils, alcohols, flavouring agents, preservatives, colouring agents, and the like in the case of oral liquid preparations (such as suspensions, solutions and elixirs) or aerosols; or carriers such as starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used in the case of oral solid preparations such as, for example, powders, capsules, and tablets, with the solid oral preparations being preferred over the liquid preparations. The most preferred solid oral preparation is tablets.
- tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are employed. If desired, tablets may be coated by standard aqueous or non-aqueous techniques.
- the compounds of the present invention may also be administered by controlled release means and/or delivery devices such as those described in United States Patent Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; 3,630,200; 4,008,719; 4,687,660; and 4,769,027, the disclosures of which are hereby incorporated by reference.
- compositions employed in the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, or tablets, or aerosol sprays each containing a predetermined amount of the active ingredient as a powder or granules, a solution or a suspension in an aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion.
- Such compositions may be prepared by any of the methods of pharmacy, but all methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more necessary ingredients.
- the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.
- a tablet may be prepared by compression or moulding, optionally with one or more accessory ingredients.
- Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, a lubricant, an inert diluent, and/or a surface active or dispersing agent.
- Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
- N-Benzyl- ⁇ -methoxy-2,8-bis(trifluoromethyl)-4-quinolineethanamine hydrochloride To N-Benzyl-N-tert-butoxycarbonyl- ⁇ -methoxy-2,8-bis(trifluoromethyl)-4- quinolineethanamine (113 mg, 0.21 mmol) in dioxan (1 mL) was added HCl (4-M in dioxan, 0.25 mL, 1 mmol) and the mixture stirred at room temperature for 1 h.
- adenosine antagonists such as theophylline
- dopamine antagonists such as haloperidol
- rodents rodents
- haloperidol dopamine antagonists
- This approach is also considered a valid method for screening drugs with potential antiparkinsonian effects.
- novel adenosine antagonists to block haloperidol-induced deficits in locomotor activity in mice can be used to assess both in vivo and potential antiparkinsonian efficacy.
- mice 25-30g obtained from TUCK, UK, are used for all experiments.
- Animals are housed in groups of 8 [cage size - 40 (width) x 40 (length) x 20 ( height)cm] under 12hr light/dark cycle (lights on 08:00hr), in a temperature (20 ⁇ 2°C) and humidity (55 ⁇ 15%) controlled environment. Animals have free access to food and water, and are allowed at least 7 days to acclimatize after delivery before experimental use.
- Liquid injectable haloperidol (1 ml Serenance ampoules from Baker Norton, Harlow,
- mice are administered 0.2 mg/kg haloperidol, a dose that reduces baseline locomotor activity by at least 50%.
- Test substances are typically administered 5-60 minutes prior to testing.
- the animals are then placed individually into clean, clear polycarbonate cages [20 (width) x 40 (length) x 20 (height) cm , with a flat perforated, Perspex lid].
- Horizontal locomotor activity is determined by placing the cages within a frame containing a 3 x 6 array of photocells linked to a computer, which tabulates beam breaks. Mice are left undisturbed to explore for 1 hour, and the number of beams breaks made during this period serves as a record of locomotor activity which is compared with data for control animals for statistically significant differences.
- Example 39 administered intraperitoneally at a dose of 10 mg/kg, significantly reversed haloperidol-induced hypolocomotion.
- Parkinson's disease is a progressive neurodegenerative disorder characterised by symptoms of muscle rigidity, tremor, paucity of movement (hypokinesia), and postural instability. It has been established for some time that the primary deficit in PD is a loss of dopaminergic neurones in the substantia nigra which project to the striatum, and indeed a substantial proportion of striatal dopamine is lost (ca 80-85%) before symptoms are observed. The loss of striatal dopamine results in abnormal activity of the basal ganglia, a series of nuclei which regulate smooth and well co-ordinated movement (Blandini et al, 1996 Mol. Neurobiol. 1996, 12, 73 - 94). The neurochemical deficits seen in Parkinson's disease can be reproduced by local injection of the dopaminergic neurotoxin 6-hydroxydopamine into brain regions containing either the cell bodies or axonal fibres of the nigrostriatal neurones.
- mice Male Sprague-Dawley rats, obtained from Charles River, were used for all experiments. Animals were housed in groups of 5 under 12hr light/dark cycle (lights on 08:00hr), in a temperature (20 ⁇ 2°C) and humidity (55 ⁇ 15%) controlled environment. Animals had free access to food and water, and allowed at least 7 days to acclimatize after delivery before experimental use.
- Drugs Ascorbic acid, desipramine, 6-OHDA and apomorphine were obtained from Sigma- Aldrich, Poole, UK. 6-OHDA was freshly prepared as a solution in 0.2% ascorbate at a concentration of 4 mg/mL prior to surgery. Desipramine was dissolved in warm saline, and administered in a volume of 1 ml/kg. Apomorphine was dissolved in 0.02% ascorbate and administered in a volume of 2 mL/kg. Test compounds were suspended in 8%Tween and injected in a volume of 2 mL/kg.
- mice 15 minutes prior to surgery, animals were given an intraperitoneal injection of the noradrenergic uptake inhibitor desipramine (25 mg/kg) to prevent damage to non- dopamine neurones. Animals were then placed in an anaesthetic chamber and anaesthetised using a mixture of oxygen and isoflurane. Once unconscious, the animals were transferred to a stereotaxic frame, where anaesthesia was maintained through a mask. The top of the animal's head was shaved and sterilised using an iodine solution. Once dry, a 2 cm long incision was made along the midline of the scalp and the skin retracted and clipped back to expose the skull. A small hole was then drilled through the skill above the injection site.
- desipramine 25 mg/kg
- the injection cannula was slowly lowered to position above the right medial forebrain bundle at -3.2 mm anterior posterior, -1.5 mm medial lateral from bregma, and to a depth of 7.2 mm below the duramater. 2 minutes after lowing the cannula, 2 ⁇ L of 6- OHDA was infused at a rate of 0.5 ⁇ L/min over 4 minutes, yeilding a final dose of 8 ⁇ g. The cannula was then left in place for a further 5 minutes to facilitate diffusion before being slowly withdrawn. The skin was then sutured shut using Ethicon W501 Mersilk, and the animal removed from the strereotaxic frame and returned to its homecage. The rats were allowed 2 weeks to recover from surgery before behavioural testing. Apparatus
- Rotational behaviour was measured using an eight station rotameter system provided by Med Associates, San Diego, USA. Each station was comprised of a stainless steel bowl (45 cm diameter x 15 cm high) enclosed in a transparent Plexiglas cover running around the edge of the bowl, and extending to a height of 29 cm. To assess rotation, rats were placed in cloth jacket attached to a spring tether connected to optical rotameter positioned above the bowl, which assessed movement to the left or right either as partial (45°) or full (360°) rotations. All eight stations were interfaced to a computer that tabulated data.
- rats were initially habituated to the apparatus for 15 minutes on four consecutive days. One the test day, rats were given an intraperitoneal injection of test compound 30 minutes prior to testing. Immediately prior to testing, animals were given a subcutaneous injection of a subthreshold dose of apomorphine, then placed in the harness and the number of rotations recorded for one hour. The total number of full contralatral rotations during the hour test period served as an index of antiparkinsonian drug efficacy.
Abstract
Description
Claims
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US09/786,472 US6608085B1 (en) | 1998-09-04 | 1999-09-03 | 4-quinolinemethanol derivatives as purine receptor antagonists (II) |
AU56402/99A AU5640299A (en) | 1998-09-04 | 1999-09-03 | 4-quinolinemethanol derivatives as purine receptor antagonists.(ii) |
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AU5640299A (en) | 2000-03-27 |
US6608085B1 (en) | 2003-08-19 |
WO2000013682A3 (en) | 2000-06-02 |
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