Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
  • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
  • C07D257/04—Five-membered rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C17/00—Preparation of halogenated hydrocarbons
  • C07C17/26—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton
  • C07C17/263—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton by condensation reactions
  • C07C17/2637—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton by condensation reactions between a compound containing only oxygen and possibly halogen as hetero-atoms and a halogenated hydrocarbon
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
  • C07C229/46—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
  • C07C229/50—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups and carboxyl groups bound to carbon atoms being part of the same condensed ring system
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
  • C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
  • C07C45/30—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation with halogen containing compounds, e.g. hypohalogenation
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
  • C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
  • C07C45/46—Friedel-Crafts reactions
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C61/00—Compounds having carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings
  • C07C61/16—Unsaturated compounds
  • C07C61/39—Unsaturated compounds containing six-membered aromatic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C63/00—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings
  • C07C63/33—Polycyclic acids
  • C07C63/49—Polycyclic acids containing rings other than six-membered aromatic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
  • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
  • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans 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 carbon atoms of the hetero ring
  • C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
  • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
  • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
  • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes 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 carbon atoms of the hetero ring
  • C07D333/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2602/00—Systems containing two condensed rings
  • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
  • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
  • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2602/00—Systems containing two condensed rings
  • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
  • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
  • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Definitions

• the present invention relates to therapeutic active amino acids, a method for preparing the same, pharmaceutical compositions comprising the compounds and a method of treating therewith.
• MGluR metabotropic glutamate receptor
• the Metabotropic glutamate receptor subtypes MGluR, and MGIuR 5 are coupled to phosphoinositide hydrolysis (Johnson, G. and Bigge, C.F. (1991) Annu. Rep. Med. Chem. 26, 11-22, Hansen, J.J. and Krogsgaard- Larsen, P. Med. Res. Rev. 10,55-94, Thomsen, C. and Suzdak, P. (1993) Eur. J. Pharmacol. 245 ,299), while the others are coupled to cyclic AMP formation (Schoepp, D.D., Johnson, B.G. and Monn, J.A. (1992) J. Neurochem. 58, 1184-1186, Cartmell et al. (1992) J. Neurochem. 58, 1964-1966, Manzoni, O. et al. (1992) Eur. J. Pharmacol. 225, 357-358).
• trans-ACPD trans 1S,3R-1-aminocyclopentane-1,3-dicar- boxylic acid
• L-AP3 L-2-amino-3-phosphonopropionic acid
• Palmer E., Monaghan, D.T. and Cotman, C.W. (1989) Eur. J. Pharmacol. 166, 585-587, Desai, M.A. and Conn, P.J. (1990) Neurosci. Lett. 109, 157-162, Schoepp, D.D. et al. (1991), J. Neurochem. 56, 1789-1796, Schoepp D.D. and Johnson B.G. (1989), J. Neurochem.
• L-AP4 L-2-amino-4-phos ⁇ honobutyrate which is an agonist at the MGIuR 4 receptor (Thomsen C. et al. (1992), Eur. J. Pharmacol. 227, 361-362) and some of the isomers of CCG (2-(carboxycyclopropyl)glycines) especially L-CCG-I and L-CCG-II (Hayashi, Y. et al. (1992), Br. J. Pharmacol. 107, 539- 543).
• Literature evidence suggests that compounds selective for the metabotropic glutamate receptors either as agonists or antagonists are useful in the treatment of different neurological diseases.
• Trans-ACPD has been shown to increase release of dopamine in the rat brain which indicates that compounds acting on the metabotropic glutamate receptors might be usable for the treatment of Parkinson's disease and Huntington's Chorea (Sacaan et al. (1992), J. Neurochem. 59, 245).
• Trans-ACPD has been shown to be a neuroprotective agent in an MCAO model in mice (Chiamulera et al. (1992), Eur. J. Pharmacol. 215, 353), and it has been shown to inhibit NMDA induced neurotoxicity in nerve cell cultures (Koh et al., (1991), Proc. Natl. Acad. Sci. USA 88, 9431).
• metabotropic glutamate receptor active compounds seem of interest, proved by the fact that antagonists at the metabotropic glutamate receptors antagonises sensory synaptic response to noxious stimuli of thalamic neurons (Eaton, S.A. et al. (1993), Eur. J. Neurosci. 5, 186).
• the present invention relates to compounds of formula I
• n 0, 1 or 2;
• X is -0-, -S, -N(R 5 )- or -CH 2 -;
• R 1 is H, NH 2 , NHR 5 or OH
• R 2 and R 3 independently are H, COOH, COOR 5 , CONH 2 , CONHR 5 , CON(R 5 ) 2> CONHSO 2 R 5 or tetrazole;
• R 4 is H, OH, NH 2 , NHR 5 , CF 3 , C ⁇ -alkyl, C ⁇ -alkenyl, C ⁇ -alkynyl, C M - cycloalkyl, phenyl or C ⁇ -alkoxy;
• R 5 is H, C ⁇ -alkyl, C M -alkenyl, C ⁇ -alkynyl, phenyl or C M -cycloalkyl; and ring A can be partly or completely saturated or aromatic, or a salt thereof with a pharmaceutically acceptable acid or base.
• salts include pharmaceutically acceptable acid addition salts, phar ⁇ maceutically acceptable metal salts or optionally alkylated ammonium salts, such as hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, trifluo- roacetic, trichloroacetic, oxalic, maleic, pyruvic, malonic, succinic, citric, mandelic, benzoic, cinnamic, methanesulfonic, ethane sulfonic, picric and the like, and include acids related to the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2 (1977) and incorporated herein by reference, or lithium, sodium, potassium, magnesium and the like.
• pharmaceutically acceptable acid addition salts such as hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, trifluo- roacetic, trichloroacetic, oxalic, maleic, pyruvic, malonic, succinic
• Alkyl, alkenyl and alkynyl are intended to mean a straight or branched alkyl, alkenyl or alkynyl chain.
• the invention also relates to a method of preparing the above mentioned compounds. These methods comprise
• X, n, R 3 , R 4 have the meanings defined above with reagents well known for converting oxo groups to amino acids or hydroxy acids either through hydantoin formation, through hydroxy nitrile or through aminonitrile formation, or
• X, n, R 1 , R 3 and R 4 have the meanings defined above with reagents known to transform a cyano group into a R 2 group wherein R 2 has the meaning defined above provided that R 2 must not be H.
• the compounds of the invention were studied in an in vitro assay for measuring inhibition of Pl-hydrolysis in BHK 570 cells expressing mGluR ⁇ receptors.
• the metabotropic glutamate receptor (mGluR) is selectively activated by trans-aminocyclopentane dicarboxylic acid and is coupled to the hydrolysis of inositol phosphates via a GTP-binding protein.
• mGluRl ⁇ The first subtype isolated (Houamed et al., 1991, Science 252, 1318), termed the mGluRl ⁇ , has been shown to be coupled to Pl-hydrolysis when expressed in baby hamster kidney cells (BHK) (Thomsen et al., Brain Res. (in press)). In these cells no stimulation by 1 mM quisqualate or glutamate was observed with control BHK cells whereas a 6-8 fold increase over basal Pl- hydrolysis was seen with BHK cells expressing rnGluRI ⁇ .
• BHK570 cells expressing mGluRl ⁇ are cultured in DMEM (4.5 g/1 glucose, 2mM glutamin); 5% foetal calf serum; 0J0 mg/ml neomycin; 0.5 mg/ml G418; 1 ⁇ M methotrexate; 50 ⁇ g/ml gentamycin. Cells are subcultured every 5 days using 0.05% trypsin/EDTA in PBS.
• the protocol for Pl-hydrolysis was measured using a modification of a method previously described (Berridge et al., 1982, Biochem. J. 206,587).
• Cells were plated in 16 mm wells (24 well multidish, Costar) with 1 confluent 100 mm dish per multidish.
• Replace the medium 24 h before the experiment with 500 ⁇ l fresh growth medium containing 4 ⁇ Ci/ml myo-[2- 3 H]inositol (specific activity 18 Ci/mmol, Amersham).
• the cells were washed twice with Krebs-Henseleit buffer (Sigma cat.
• IP1 to IP4 fractions may be collected with 5 ml 0.05; 0J0; 0J7 and 0.25 M KHC0 3 , respectively. Usually IP1 and IP2 fractions are collected simultaneously. Scintillation liquid: use 12-15 ml Ultima Gold (Packard). Testorocedure
• Testcompounds are dissolved in DMSO, DMSO and Pluronic F-127 or ethanol and diluted in assay buffer. Glutamate (10 ⁇ M and 1000 ⁇ M) and buffer alone are included as a control.
• the stimulation by 10 ⁇ M shall represent a submaximal stimulation.
• the response by 10 ⁇ M glutamate should exceed 3-fold the basal level and should be below maximal stimulation (glutamate at 1 mM).
• the results are calculated relative to be stimulation by 10 ⁇ M glutamate and a dose response curve is generated.
• test results obtained by testing some compounds of the present invention in the above mentioned assay appear from the following
• the compounds according to the invention are effective over a wide dosage range.
• dosages from about 0.05 to about 100 mg, preferably from about 0J to about 100 mg, per day may be used.
• a most preferable dosage is about 10 mg to about 70 mg per day.
• the exact dosage will depend upon the mode of administration, form in which administered, the subject to be treated and the body weight of the subject to be treated, and the preference and experience of the physician or veterinarian in charge.
• the route of administration may be any route, which effectively transports the active compound to the appropriate or desired site of action, such as oral or parenteral e.g. rectal, transdermal, subcutaneous, intravenous, intramuscular or intranasal, the oral route being preferred.
• oral or parenteral e.g. rectal, transdermal, subcutaneous, intravenous, intramuscular or intranasal, the oral route being preferred.
• compositions include a compound of formula I or a pharmaceuti ⁇ cally acceptable acid addition salt thereof, associated with a pharmaceuti- cally acceptable carrier.
• the active compound will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a ampoule, capsule, sachet, paper, or other container.
• the carrier serves as a diluent, it may be solid, semi-solid, or liquid material which acts as a vehicle, excipient, or medium for the active compound.
• the active compound can be adsorbed on a granular solid container for example in a sachet.
• suitable carriers are water, salt solutions, alco ⁇ hols, polyethylene glycols, polyhydroxyethoxylated castor oil, gelatine, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid monogly- cerides and diglycerides, pentaerythritol fatty acid esters, hydroxymethyl- cellulose and polyvinylpyrrolidone.
• the pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or coloring substances and the like, which do not deleteriously react with the active compounds.
• injectable solutions or suspensions preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
• Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application.
• Preferable carriers for tablets, dragees, or capsules include lactose, corn starch, and/or potato starch.
• a syrup or elixir can be used in cases where a sweetened vehicle can be employed.
• the compounds are dispensed in unit form comprising from about 1 to about 100 mg in a pharmaceutically acceptable carrier per unit dosage.
• a typical tablet appropriate for use in this method, may be prepared by conventional tabletting techniques and contains:
• AICI 3 (1.706 g, 12.8 mmol) was added portionwise in 20 min to a solution of indan (1.50 g, 12.7 mmol) and AcCI (0.996 g, 12.7 mmol) in benzene (7.6 ml) kept under vigorous magnetic stirring at 0°C in an argon atmosphere. The resulting mixture was reacted at room temperature for 2 h after which cold (0°C) water was added (30 ml). The reaction mixture was then acidified with 3N HCI and extracted with AcOEt (3x20 ml).
• AICI 3 (15.3 g, 114.8 mmol) was added portionwise in 40 min. to a solution of 1 ,2,3,4-tetrahydronaphthalene (15.0 g, 113.5 mmol) and AcCI (8.9 g, 113.5 mmol) in benzene (45 ml) kept under vigorous magnetic stirring at 0°C in an argon atmosphere. The resulting mixture was reacted at room tempera ⁇ ture for 30 min. after which cold (0°C) water was added (100 ml). The reaction mixture was then acidified with 3N HCI and extracted with AcOEt (3x50 ml). The combined organic phases were washed with brine (60 ml) and dried over anhydrous Ne ⁇ SO ⁇ Evaporation of the solvent yielded 19 as a yellow oil (20 g) which was used in the next step without any further purification.

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Cited By (24)

Citations (7)

• 1994
  • 1994-11-09 AU AU11061/95A patent/AU1106195A/en not_active Abandoned
  • 1994-11-09 WO PCT/DK1994/000421 patent/WO1996015099A1/en active Application Filing
• 1995
  • 1995-11-08 AU AU38398/95A patent/AU3839895A/en not_active Abandoned
  • 1995-11-08 WO PCT/DK1995/000444 patent/WO1996015100A1/en active Application Filing

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