Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • 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
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/08—Antiepileptics; Anticonvulsants
• • 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
• • 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
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• • 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
• • 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
  • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • 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
  • C07D261/10—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 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
  • C07D261/12—Oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
  • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
  • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
  • C07D261/10—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 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
  • C07D261/18—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
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

• the present invention relates to a novel class of (5-arylisoxazol-4-yl)-substituted 2- amino carboxylic acid derivatives, which are excitatory amino acid (EAA) receptor ligands useful in the treatment of cerebral ischaemia, Huntington's disease, epileptic disorders, Parkinson's disease, Alzheimer's disease, schizophrenia, pain, depression and anxiety.
• EAA excitatory amino acid
• Excitatory Amino Acid Receptors Design of Agonist and Antagonists. E. Horwood: Chiches ⁇ ter, 1992).
• Glu-operated neurotransmission is mediated by a large number of receptors, classified into at least five heterogeneous families of receptors named NMDA, AMPA, kainic acid, metabotropic, and L-AP4 classes of receptors (Monag- han, D.T., et al. Ann. Rev. Pharmacol. Toxicol. 1989,29, 365-402; Watkins, J.C.; Krogsgaard-Larsen, P.; Honore, T. Trends Pharmacol. Sci. 1990, 77, 25-33; Simon, R.P. Excitatory Amino Acids. Thieme Med. Publ: New York, 1992).
• EAA receptor antagonists are potential therapeutic agents in these conditions.
• central EAA receptors may be involved in the synaptic mechanisms 15 underlying schizophrenia (Reynolds, G.P. Trends. Pharmacol. Sci. 1992, 73, 116- 121), pain and anxiety (Drejer, J. In: Excitatory Amino Acid Receptors: Design of Agonists and Antagonists (Eds. Krogsgaard-Larsen, P.; Hansen, J.J.) E. Horwood: Chichester 1992, pp. 352-375) and depression (Trullas, R., Skolnick, P., Eur. J. Pharmacol. 1990, 755, 1 -10 and Trullas et al., Eur. J. Pharmacol.
• EAA hypoactivity seems to play a role in, for example, schizophrenia (Deutsch, S.I.; et al. Clin. Neuropharmacol. 1989, 72, 1-13) and some of the clinical symptoms seen in Alzheimer's disease (Greena ⁇ myre, J.T.; et al. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1988, 72, 421 - 430 ).
• EAA hypoactivity is involved in 5 the complex mechanisms associated with Alzheimer's disease (Greenamyre, J.T.; 1988 supra; Greenamyre, J.T.; Maragos, W.F., 1993, supra).
• EEA receptor ligands are considered to be useful in the treatment of cerebral ischaemia, Huntington's disease, epileptic disorders, Parkinson's disease, 0 Alzheimer's disease, anxiety, schizophrenia, depression and pain.
• EAA receptor agonists so far tested, show more or less pronounced neuroto- xicity in model systems and consequently clinical uses of such compounds may be limited (Carlsson, M.; Carlsson, A. Trends. Neurosci. 1990, 73, 272-276) (Willetts, J.; Balster, R.L.; Leander, J.D. Trends. Pharmacol. Sci. 1990,11 ,423-428).
• Partial EAA agonists showing appropriate balance between agonism and antago ⁇ nism may on the other hand, have considerable therapeutic interest, cf. the above indications, (Greenamyre, J.T.; 1988 supra;; Christensen, I.T.; et al. Drug. Des. Del. 1989,5, 57-71 ; Francis, P.T.; et al. J. Neurochem. 1993,60, 1589-1604).
• Partial agonists may, by virtue of their EAA antagonist profile, show therapeutically useful neuroprotection and, at the same time, be sufficiently agonistic to prevent total blockade of the neurotransmission mediated by the particular EAA receptor.
• ATPA the 5-tet ⁇ -butyl analogue of AMPA (( flS)-2-amino-3-(3-hydroxy-5-methylis- oxazol-4-yl)propionic acid), has been disclosed to be systemically active whereas it has not been reported to show neurotoxic effects in animals (Omstein, P.L.; et al. J. Med. Chem. 1993,36, 2046-2048; Lauridsen, J.; Honore, T.; Krogsgaard-Larsen, P. J. Med. Chem. 1985, 28, 668-672).
• AMPA Like AMPA itself, a number of mono- and bicyclic AMPA analogues have been found to show selective agonist effects at AMPA receptors (Hansen, J.J.; Krogs ⁇ gaard-Larsen, P. Med. Res. Rev. 1990, 70, 55-94; Krogsgaard-Larsen, P.; Hansen, J.J., 1992 supra;).
• CNS-active EEA receptor ligands with good penetration into the CNS are highly desirable for treating the various diseases mentioned and, accordingly, it is the object of the present invention to provide such new drugs.
• A is a bond or a spacer group selected from C* ⁇ -6 alkylene, C2-6 alkenylene or C 2 -6 alkynylene, and cycloalkylene;
• B is selected from a group -CH(NR'R")-COOH wherein R' and R" are independent ⁇ ly hydrogen or C- ⁇ -6 alkyl, and a group of Formula II
• R2, R3 and R4 are independently selected from the group consisting of a) hydrogen ⁇ C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, cycloalk(en)yl, cycloalk(en)yl-C ⁇ -6 alk(en/yn)yl, phenyl-C-
• R4 and R2 are connected in order to form a C1-C3 alkylene, C2-C3 alkenylene or
• C2-C3 alkynylene group optionally mono- or di-substituted with hydroxy or methyl, or CH2-O-CH2;
• E is O, S, COO, (CH 2 ) n -COO, 0-(CH 2 ) n -COO, or S-(CH 2 ) n -COO in which groups n is an integer of 1 -6, a 5-tetrazolyl group, a 5-tetrazolyl-C ⁇ -6 alkyl group, a 3-hydroxy- isoxazolyl group or a 3-hydroxyisoxazo.yl-C ⁇ _ 6 alkyl group;
• D is O or S
• R1 is an aryl or heteroaryl group or an aryl or heteroaryl group substituted with one or more substituents selected from halogen, C- ⁇ - 6 alkyl, C ⁇ - 6 alkoxy, hydroxy, C 1 - 6 alkylthio, C- ⁇ - 6 alkylsulfonyl, C ⁇ - 6 alkylamino or di-(C ⁇ . ⁇ alkyl)amino, cyano, nitro, tri- fluoromethyl, or trifluoromethylthio; provided that when A is methylene, B is a group -CH(NH 2 )-COOH, E is O, D is O, and R* ⁇ is phenyl or phenyl substituted with halogen or methoxy; then the com ⁇ pound must be in an enantiomeric pure form.
• the invention relates to a method for the preparation of the novel compounds of Formula I.
• the invention relates to a pharmaceutical composition com ⁇ prising a novel compound of Formula I together with a suitable pharmaceutically acceptable carrier or diluent.
• the invention relates to the use of a compound of Formula I for preparing a pharmaceutical composition for treatment of cerebral ischaemia, Huntington's disease, epileptic disorders, Parkinson's disease, Alzheimer's disease, schizophrenia, pain, depression or anxiety.
• the compounds of the invention have been found to be selective AMPA receptor ligands in vitro with affinities in the low micromolar concentrations whereas other compounds have been found selectively to bind to NMDA receptors in vitro.
• Other compounds of the invention have been found to show affinity to both AMPA and NMDA receptors, respectively, in vitro.
• some of the compounds of the invention were found to be agonists whereas others were found to be antagonists.
• the compounds of the invention are useful in the treatment of cerebral ischaemia, Huntington's disease, epileptic disorders, Parkinson's disease, Alzheimer's disease, schizophrenia, pain, depression and anxiety.
• . 6 alkyl is intended to mean a straight chain or branched alkyl group having from 1 to 6 C atoms, inclusive, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl etc.
• C 2 - 6 alkenyl and C 2 - 6 alkynyl designate such straight chain or branched groups having 2 to 6 C- atoms and C 1 - 6 alkylene
• C 2 - 6 alkenylene and C2-6 alkynylene designate such branched or straight chain divalent groups.
• Cycloalkyl designates such a group having 3-7 carbon atoms.
• alk(en/yn)yl means that the group may be an alkyl, alkenyl or alkynyl group.
• bond (defined for A) means that B may be attached directly to the 4- position of the isoxazole ring.
• Halogen means fluoro, chloro, bromo or iodo.
• aryl is intended to mean a carbocyclic aromatic monocyclic or fused bicyclic group or a biphenyl group and the term heteroaryl is intended to mean an aromatic monocyclic or bicyclic group containing at least one heteroatom.
• 5-membered aromatic heteroaryl groups comprising 1 -4 heteroatoms selected from N, O and S such as thienyl, furyl, pyrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl, oxadiazolyl, thiadiazolyl and tetrazolyl.
• benzothienyl benzofuranyl, indolyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, naphthyl, quinolyl, quinazolinyl, quinoxalinyl and cinnolinyl.
• the salts of the compounds of the general Formula I are salts formed with non- toxic organic acids, e.g. maleic, fumaric, benzoic, ascorbic, oxalic, tartaric, lactic and malic acid, or inorganic acids, e.g. hydrochloric, hydrobromic, sulfuric, phos- phoric and nitric acid or they may be salts of inorganic bases such as alkali metal salts, e.g. sodium, potassium, or lithium salts, alkaline earth metal salts, e.g. calcium or magnesium salts, or ammonium salts or salts of organic bases.
• non- toxic organic acids e.g. maleic, fumaric, benzoic, ascorbic, oxalic, tartaric, lactic and malic acid
• inorganic acids e.g. hydrochloric, hydrobromic, sulfuric, phos- phoric and nitric acid
• inorganic bases e.g. hydrochlor
• A is preferably a bond or C 1 -C 3 alkylene.
• B is preferably -CH(NR'R")-COOH wherein R' and R" are hydrogen or a group of Formula II wherein R .
• R 3 and R 4 are hydrogen or lower alkyl, or R 4 and R 2 are connected in order to form a C 1 -C 3 alkylene group.
• B is -CH( NH2)-COOH or a group of Formula II wherein each of R 2 - R3 and R 4 are hydro ⁇ gen.
• R-- groups are thienyl, substituted thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, substituted oxadiazolyl, thia- diazolyl, tetrazolyl, triazolyl, pyridyl, phenyl, biphenyl and naphthyl.
• Preferred groups are 2-thienyl, 3-thienyl, phenyl, 2-pyridyl and 4-pyridyl, and 2-thienyl and phenyl substituted with halogen or methyl.
• A is a bond or C 1 -C 3 alkylene
• B is -CH(NH 2 )-COOH or a group of Formula II wherein each of R 3 .
• R 4 and R 2 are hydrogen, E and D are both oxygen, and R* ⁇ is 2-pyridyl, 4-pyridyl, thienyl, phenyl, substituted thienyl or substituted phenyl.
• novel compounds of formula I are prepared by a method comprising:
• R-j, R 5 , A, D and E are as previously defined;
• R* ⁇ , R , R 3 , R 4 , A, D and E are as previously defined, at least one of R 2 - R however being hydrogen and R' 5 is hydrogen or a protection group.
• protection groups are as follows: R 5 and R' 5 : lower alkyl, benzyl or a benzenesulfonyl group; R 6 : lower alkoxycarbo- nyl, R 7 : lower alkyl and Re: lower alkylcarbonyl.
• the one step deprotection according to method a) is carried out by treatment of the compound of Formula III with a suitable aqueous acid, conveniently in an aqueous solution of 48 % HBr, a saturated solution of HBr i acetic acid or a 2-12 N aqueous solution of HCI.
• the deprotection may also be carried out in successive steps by using aqueous acids and aqueous bases, conveniently successively in an 5 aqueous acid such as 1-12 N HCI, an aqueous base such as 1-8 N NaOH and an aqueous acid such as 1-12 N HCI, or successively in an aqueous base such as 1-8 N NaOH and an aqueous acid such as 1-12 N HCI.
• R 5 is benzyl
• the deprotec ⁇ tion of the E-group is alternatively accomplished by catalytic hydrogenation, conveniently by using palladium as a catalyst, either before or after the deprotec-
• E is COO, (CH 2 ) n -COO, 0-(CH 2 ) n -COO, S-(CH 2 ) n -COO 15 wherein n is 1-6, a 5-tetrazolyl-C-
• 25 hydroxyisoxazole group may or may not be reprotected with a suitable protection group like e.g. the benzenesulfonyl group before, during or after the synthesis of the heteroaryl in the 5-position of the isoxazole.
• a suitable protection group like e.g. the benzenesulfonyl group before, during or after the synthesis of the heteroaryl in the 5-position of the isoxazole.
• (3-Alkoxy-4-methylisoxazol-5- yl)carboxylic acid is conveniently obtained from 3-alkoxy-4,5-dimethylisoxazole prepared as described by Hansen, J. J., J. Chem. Soc, Perkin Trans. 7, 1980,
• the one step deprotection is carried out by treatment of a compound of Formula IV with a suitable aqueous acid or aqueous base, conveniently in 2-8 N aqueous hydrochloric acid.
• the deprotection may also be performed in successive steps by using aqueous acids and aqueous bases as mentioned above for method a).
• the hydantoin ring may also be cleaved by the use of a aqueous solution of Ba(OH) 2 , aqueous 10-70 % sulphuric acid or by the use of enzymes such as hydantoinases. The cleavage of the hydantoin ring may be carried out either before or after the deprotection of the E-group.
• the hydantoin rings in the compounds of the general Formula IV are conveniently formed according to the methods described by Ware, E., Chem. Rev. 1950, 46, 403-470.
• the cleavage of the hydantoin ring is conveniently performed in analogy with the methods described by Curry, K. et al J.Med.Chem. 1988, 37, 864-867, Farrington, G.K. et al, J.Med.Chem. 1987, 30, 2062-2067, Grunewald, G.L. et al, J.Med.Chem. 1980, 23, 754-758, Hiroi, K. et al, Chem. Pharm.Bull. 1968, 7 6, 444.447 or Stark, G.R. et al, J.Biol.Chem. 1963, 238, 214-226.
• the starting material for preparation of compounds of Formula IV may be obtained in analogy with the method described by Madsen, U., Eur. J. Med. Chem. 1993, 26, 791-800.
• R 5 is benzyl the deprotection of the E-group is conveniently performed by hydrogenation using palladium as a catalyst.
• the addition-elimination reaction according to method c) is conveniently performed in a protic organic solvent such as an alcohol, preferably in the presence of a suitable inorganic base such as aqueous NaOH at room temperature.
• a protic organic solvent such as an alcohol
• a suitable inorganic base such as aqueous NaOH at room temperature.
• the interme ⁇ diates of Formula VI may be prepared by the methods described by Cohen, S. et al, J.Amer.Chem.Soc. 1966, 88, 1533-1536, EP-A2-0496561 or Kinney, W.A. et al, J.Med.Chem. 1992, 35, 4720-4726.
• the intermediate of the general formula V is readily obtained by a Gabriel synthe ⁇ sis of primary amines as described by Sheehan, J. C. et al, J. Am. Chem. Soc, 1950, 72, 2786-88.
• the alkyl halogenide starting materials for this synthesis is 5 conveniently obtained
• the deprotection is conveniently preformed by the use of an aqueous acid or an aqueous base, preferably 0.5-8 N HCI or aqueous 0.5-8 N NaOH, either at room ⁇ o temperature or at elevated temperatures.
• R' 5 is benzyl the deprotection is alternatively performed by hydrogenation using palladium as a catalyst.
• reaction and the subsequent ringclosure and deprotection are performed as described by Kinney et al., EP-A2-0496561.
• the starting materials of formula VII may be obtained by reacting e.g. 4-bromome- thyl isoxazole obtained as described with respect to the starting materials in method a) with a mono-BOC-proteted alkylene diamine cf. EP-A2-0496561.
• the alkylation of compounds of the general Formula VIII according to method e) 20 is conveniently performed in an inert organic solvent such as a suitable alcohol, ketone or dimethylformamide preferably in the presence of a suitable base such as sodium hydride, potassium carbonate or triethylamine, as described by Kinney, W.A., EP-A2-0496561.
• the starting materials of formula VIII are obtained by method c).
• ⁇ -keto esters are used as starting materials for the formation of 3-hydroxy- isoxazoles, which again are used as starting material for obtaining compound III- V and VII-VIII, are either commercially avaible or they may conveniently be prepared according to the methods described by Cason, J. et al, J.Org.Chem. 30 1953, 18, 1594-1600 and Hannick, S.M. et al, J.Org.Chem. 1983, 48, 3833-3835.
• Corresponding isothiazole starting materials may be prepared according to the methods described in EP-A1 -0 336 555.
• Resolution of the compounds of general formula I is conveniently performed by diastereomeric saltformation using optical active acids or bases, e.g. 1-phenylethyl- amine. In some cases the resolution is convenientlyly performed by formation of diastereomeric compounds and subsequently separation of the diastereomers by flash chromatography or crystallisation.
• Salts of the compounds of the invention are easily prepared by methods well known in the art, i.e. by reacting the compound with either the equivalent amount of acid or base in an aqueous miscible solvent, such as acetone or ethanol, with isolation of the salt by concentration and cooling, or reacted with an excess of the acid or base in an aqueous immiscible solvent such as ethyl ether or chloroform, with the desired salt separating directly.
• aqueous miscible solvent such as acetone or ethanol
• an aqueous immiscible solvent such as ethyl ether or chloroform
• the compounds of general Formula I and the pharmaceutically acceptable acid addition salts thereof may be administered in any suitable way, e.g. orally or parenterally, and the compounds may be presented in any suitable form for such administration, e.g. in the form of tablets, capsules, powders, syrups or solutions or dispersions for injection.
• An effective daily dose of a compound of general Formula I or a pharmaceutically acceptable salt thereof is from 10 ⁇ g/kg to 50 mg/kg body weight.
• Mass spectra were obtained on a Quattro MS-MS system from VG Biotech, Fisons Instruments, Manchester, GB.
• the MS-MS system was connected to an HP 1050 modular HPLC system.
• aqueous ammonia (25 %) 25:25:1 (v/v/v) was introduced via the autosampler at a flow of 30 ⁇ l/min into the Electrospray Source.
• Spectra were obtained at standard operating conditions to obtain molecular weight information (MH+). The background was subtracted.
• the enantiomeric excess (ee) of the enantiomeric compounds were determined by chiral HPLC using a chiral crown ether column.
• the chiral HPLC was performed on a 150- x 4-mm Crownpak CR(-) or Crownpak CR(+) column (Daicel) eluted at 15- 40 °C with 0.4-1.0 mUmin. of aqueous perchloric acid/methanol (100-85 %/0-15 %).
• One of the following instrumentations were used:
• Jasco 880-PU pump Jasco 880-PU pump, a Rheodyne 7125 injector, and a Waters 480 UV detector, set at 210 nm, connected to a Merck-Hitachi D-2000 Chromato-lntegrator.
• Hitachi-Merch L-6200 pump a Hitachi-Merch 655A-40 autosampler and a Hitachi-Merch L-4000 UV detektor, set at 205 nm, connected to a Hitachi-Merch D-2500 Integrator.
• the THF was evaporated in vacuo and pH was adjusted to 6.5 with 0.1 N aqueous HCI.
• the aqueous phase was extracted with diethyl ether which was discharged. pH in the aqueous phase was adjusted to 2 with 0.1 N aqueous HCI and the aqueous phase was extracted with diethyl ether (3 x 100 mL). 5
• the combined organic phases were dried (Na 2 S ⁇ 4 ) and evaporated in vacuo.
• the residue was dissolved in diethyl ether (40 mL) and a saturated solution of HCI in diethyl ether was added. The resulting mixture was stirred for 20 h at 20 °C.
• the precipitate was collected by filtration and dried.
• the crystals were dissolved in water (5 mL) and pH was adjusted to 3.
• the precipitate was collected by filtration
• the title compound was prepared in analogy with the method described by Christensen, IT. et al, Drug Design and Delivery 1989, 5, 57-71 , with the following modifications 1 ) Ethyl benzoylacetate was used as starting material. 2) The isoxazole ring in the intermediate 5-phenyl-4-(2-propenyl)-3-isoxazolol was prepared according to the method of Sato, K. et al, Agric. Biol. Chem. 1986, 50, 1831 -1837. 3) The zwitterion of the title compound 3a, was obtained by adjusting pH in the aqueous phase to 3.5 with 0.1 N aqueous NaOH. Mp.
• the ⁇ -keto ester, ethyl 3-oxo-3-(4-fluorophenyl)propionate was prepared in analogy with the method described in Example 1 using 4-fluorobenzonitrile (25.0 g; 0.21 mol), ethyl 2-bromacetate (51.7 g; 0.31 mol), activated zinc (20.3 g; 0.31 mol), CuBr2 (0,2 g; 0.9 mmol) and benzene (500 ml).
• Ethyl 3-[5-(4-fluorophenyl)-3-hydroxyisoxazol-4-yl]propionate was prepared in analogy with the the method described in Example 1 with the following modifica ⁇ tions: 1 ) Ethyl 4-ethoxycarbonyl-5-(4-fluorophenyl)-5-oxopentanoate (27.5 g; 89 mmol) was used as starting material. 2) After evaporation of the methanol from the methanol/water solution, the aqeous phase was extracted with diethyl ether. The combined organic phases were dried (MgS ⁇ 4 ) and evaporated in vacuo.
• Ethyl 3-[3-ethoxy-5-(4-fluorophenyl)isoxazol-4-yl]propionate was prepared as described in Example 1 with the following modifications: 1 ) Ethyl 3-[5-(4-fluoro- phenyl)-3-hydroxyisoxazol-4-yl]propionate (5.5 g; 20 mmol) was used as starting material. 2) Instead of two equivalents, only one equivalent of ethylbromide was added.
• the aqueous phase was acidified using 2 M HCI to pH 2.5 and was left at 5 °C for 18 h.
• the formed crystals were collected by filtration and washed with water, acetone and diethyl ether. The crystals were dried in vacuo to give the title compound, 6a, (906 mg, 87 %).
• Mp. 248-50 °C (dec). CHN; Calcd: 50.39; 3.75; 13.57, Found: 50.66; 3.72; 13.55.
• Ethyl 2-acetylamino-2-ethoxycarbonyl-3-[3-ethoxycarbonyl-5-(2-thienyl)isoxazol-4- yljproionate was prepared from ethyl [4-bromomethyl-5-(2-thienyl)isoxazol-3- yljcarboxylate in analogy with the method described in Example 7.
• the crystals were dissolved in 47 % HBr and the solution was extracted with diethyl ether which was discharged. The aqueous solution was evaporated in vacuo and diethyl ether was added. The reaction mixture was stirred at 22 °C for 16 h and the crystals were collected by decantation of the diethyl ether. The crystals were dried in vacuo and aqueous NaOH (0.1 M) was added dropwise to pH 2.5. The formed crystals were collected by filtration and suspended in water (15 mL). The reaction mixture was stirred at 22 °C for 48 h and the resulting crystals were collected by filtration to give the title compound, 9a (270 mg; 43 %). Mp. 227-28 °C (dec). CHN; Calcd: 46.07; 3.69; 9.77, Found: 46.15; 3.68; 9.74.
• [4-Bromomethyl-5-(2-thienyl)isoxazol-3-yl]carbonitrile was prepared from [4-methyl- 5-(2-thienyl)isoxazol-3-yl]carbonitrile in analogy with the method described in Example 7.
• Ethyl 2-acetylamino-2-ethoxycarbonyl-3-[3-cyano-5-(2-thienyl)isoxazol-4-yl]propio- nate was prepared from 4-[bromomethyl-5-(2-thienyl)isoxazol-3-yl]carbonitrile in analogy with the method described in Example 7.
• 3-Hydroxy-4,5-dimethylisoxazole was prepared by the method as described by Jacquier, R. et al., Bull. Soc. Chim. Fr., 1970, 2685-90 as modified by Sato, K. et al., Agric. Biol. Chem., 1986, 50(7), 1831-1837. 0
• a suspension of 3-hydroxy-4,5-dimethylisoxazol (68.5 g, 0.6 mol) and K 2 CO 3 (125.6 g, 0.9 mmol) in acetone (1000 mL) was heated to reflux temperature.
• a solution of ethylbromide (99.1 g, 0.9 mol) in acetone was added dropwise to the boiling reaction mixture.
• reaction mixture was evaporated in vacuo, dissolved in CH 2 CI 2 (100 mL) and added dropwise to a cooled (5 °C) mixture of aminoacetaldehydedimethyl- acetale (3.5 mL, 3.2 mmol) and K 2 C0 3 (6.0 g; 4.4 mmol) in CH 2 CI 2 (100 mL).
• the resulting solution was stirred for 4 h at 22 °C. Water was added and the phases were separated.
• Ethyl 2-acetylamino-2-ethoxycarbonyl-3-[3-benzenesulfonyloxy-5-(2-oxazolyl)isoxa- zol-4-yl]propionate 120 mg; 22%) was prepared from 3-benzenesulfonyloxy-4- bromomethyI-5-(2-oxazolyl)isoxazoI (440 mg) in analogy with the method described in Example 7.
• the aqueous phase was evaporated in vacuo and 1 M aqueous HCI (10 mL) was added. The reaction mixture was boiled under reflux for 3 h. The reaction mixture was evaporated in vacuo and ether (10 mL) was added. The resulting crystals were collected by filtration and dried in vacuo. The crystals were dissolved in 1 M aqueous HCI and the aqueous phase was washed with diethyl ether. The aqueous phase was evaporated in vacuo and the residue was dissolved in water. The aqueous phase was passed through a column containing an ion exchange resin 5 [Amberiite IRA 400, (CI, 150 mL] using acetic acid (1 M) as an eluent. Evaporation of the solvent gave the title compound, 11a, (15 mg; 27 %).
• Ethyl 2-acetylamino-2-ethoxycarbonyl-3-[3-ethoxy-5-(2-thiazolyl)isoxazol-4-yl]pro- pionate (320 mg; 41%) was prepared from 4-bromomethyl-3-ethoxy-5-(2-thia- zolyl)isoxazol (540 mg) in analogy with the method described in Example 7.
• the yield of the first eluted isomer (Isomer 1) was 10.4 g (60 %) and the yield of the second eluted isomer (Isomer 2) was 9.0 g (51 %).
• Isomer 1 (10.4 g; 18.2 mmol) was dissolved in methanol (600 mL). ⁇ aOH (0.8 g; 20.0 mmol) in methanol (20 mL) was added and the resulting reaction mixture was stirred at 22 °C for 10 min. Water (5000 mL) was added to the reaction mixture and pH in the aqueous solution was adjusted to 1 with cone aqueous HCI. The aqueous solution was extracted with diethyl ether and CH 2 CI 2 .
• Test results of the receptor binding tests are shown in Table 1
• test results of the electophysiological rat cortial wedge preparation are shown in Table 2.
• the test was carried out in accordance with a modified version of the method of Honore, T. and Nielsen, M., Neurosci. Lett. 1985, 54, 27-32.
• the test was carried out in the presence of KSCN. This means that only the [3H]AMPA high affinity binding sites were labelled.
• the membrane preparations used were obtained in accordance with the method of Ransom, R.W. and Stec, J.Neurochem. 1988, 57, 830-836.
• the test was performed according to the method described by Murphy, D.E., et al. J.Pharm.Exp.Ther. 1987, 240, 778-784.
• the membrane preparations used were prepared as described above.
• the Cortical wedge model is a test in which slices of rat brain is examined in vitro in order to quantify the effect of ligands at the Glu-receptors and evaluate the pharmacological profile of the ligands (i.e. agonist/antagonist properties).
• the test was performed as described by Harrison, N.L. and Simmonds, M.A. Br.J. Pharmacol. 1985, 84, 381 -391 as modified according to Wheatley, P.L. Br.J. Phar ⁇ macol. 1986, 87, 159P.
• the compounds of the invention were found to be agonists or partial agonists whereas others were found to be antago ⁇ nists. Accordingly the invention comprise compounds having different agonist/anta ⁇ gonist profiles at the glutamic acid receptors with activities in the low micromolar concentrations.
• the pharmaceutical formulations of the invention may be prepared by conventional methods in the art.
• Tablets may be prepared by mixing the active ingredient with ordinary adjuvants and/or diluents and subsequently compressing the mixture in a conven ⁇ tional tabletting machine.
• adjuvants or diluents comprise: corn starch, lactose, talcum, magnesium stearate, gelatine, lactose, gums, and the like. Any other adjuvant or additive colourings, aroma, preservatives etc. may be used provided that they are compatible with the active ingredients.
• Solutions for injections may be prepared by solving the active ingredient and possible additives in a part of the vehicle, preferably sterile water, adjusting the solution to the desired volume, sterilization of the solution and filling in suitable ampules or vials. Any suitable additive conventionally used in the art may be added, such as tonicity agents, preservatives, antioxidants, etc.
• Typical examples of recipes for the formulations of the invention are as follows: 1 ) Tablets containing 5 milligrams of Compound 1 a: Compound 1a 5.0 mg Lactose 60 mg Maize starch 30 mg Hydroxypropylcellulose 2.4 mg Microcrystalline cellulose 19.2 mg Croscarmellose Sodium Type A 2.4 mg Magnesium stearate 0.84 mg

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Life Sciences & Earth Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Animal Behavior & Ethology (AREA)
• General Chemical & Material Sciences (AREA)
• Neurosurgery (AREA)
• Neurology (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Biomedical Technology (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Psychiatry (AREA)
• Pain & Pain Management (AREA)
• Vascular Medicine (AREA)
• Urology & Nephrology (AREA)
• Heart & Thoracic Surgery (AREA)
• Psychology (AREA)
• Hospice & Palliative Care (AREA)
• Cardiology (AREA)
• Epidemiology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
• Polyurethanes Or Polyureas (AREA)
• Plural Heterocyclic Compounds (AREA)

Priority Applications (1)

Applications Claiming Priority (3)

Related Child Applications (1)

Publications (1)

Family

ID=8102626

Family Applications (2)

Family Applications Before (1)

Country Status (17)

Families Citing this family (8)

Family Cites Families (2)

• 1993
  • 1993-11-03 DK DK931243A patent/DK124393D0/da not_active Application Discontinuation
• 1994
  • 1994-11-02 RU RU96112168A patent/RU2138488C1/ru active
  • 1994-11-02 WO PCT/DK1994/000411 patent/WO1995012587A1/en not_active Application Discontinuation
  • 1994-11-02 JP JP7512970A patent/JPH09504531A/ja active Pending
  • 1994-11-02 EP EP99125828A patent/EP0994107A1/en not_active Withdrawn
  • 1994-11-02 NZ NZ275088A patent/NZ275088A/xx unknown
  • 1994-11-02 CA CA002175685A patent/CA2175685A1/en not_active Abandoned
  • 1994-11-02 CN CN94194388A patent/CN1056837C/zh not_active Expired - Fee Related
  • 1994-11-02 AU AU80579/94A patent/AU680062B2/en not_active Ceased
  • 1994-11-02 EP EP94931523A patent/EP0726896A1/en not_active Withdrawn
  • 1994-11-02 ZA ZA948631A patent/ZA948631B/xx unknown
  • 1994-11-02 CZ CZ961272A patent/CZ127296A3/cs unknown
  • 1994-11-02 SK SK564-96A patent/SK56496A3/sk unknown
  • 1994-11-02 KR KR1019960702307A patent/KR960705797A/ko not_active Application Discontinuation
  • 1994-11-02 PL PL94314182A patent/PL314182A1/xx unknown
  • 1994-11-02 HU HU9601167A patent/HUT74692A/hu unknown
• 1996
  • 1996-05-02 NO NO961783A patent/NO306159B1/no not_active IP Right Cessation
  • 1996-05-02 FI FI961872A patent/FI961872A/fi unknown

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events