CN1061595A - Be used as new heterocyclics of excited amino acid receptor antagonists and its production and use - Google Patents
Be used as new heterocyclics of excited amino acid receptor antagonists and its production and use Download PDFInfo
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- CN1061595A CN1061595A CN91110925A CN91110925A CN1061595A CN 1061595 A CN1061595 A CN 1061595A CN 91110925 A CN91110925 A CN 91110925A CN 91110925 A CN91110925 A CN 91110925A CN 1061595 A CN1061595 A CN 1061595A
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- alkyl
- methylene radical
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- 102000015404 Amino Acid Receptors Human genes 0.000 title description 6
- 108010025177 Amino Acid Receptors Proteins 0.000 title description 6
- 239000002464 receptor antagonist Substances 0.000 title description 3
- 229940044551 receptor antagonist Drugs 0.000 title description 3
- 125000000623 heterocyclic group Chemical group 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 45
- 238000002360 preparation method Methods 0.000 claims abstract description 7
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- -1 imino- Chemical group 0.000 claims description 27
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- 150000003839 salts Chemical class 0.000 claims description 17
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical group [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 claims description 14
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- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 10
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- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 7
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- 230000008020 evaporation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 229910000765 intermetallic Inorganic materials 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- JGZKUKYUQJUUNE-UHFFFAOYSA-L magnesium;ethoxyethane;dibromide Chemical compound [Mg+2].[Br-].[Br-].CCOCC JGZKUKYUQJUUNE-UHFFFAOYSA-L 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- ODQZNBWVRPKMKN-UHFFFAOYSA-N methyl piperazine-2-carboxylate Chemical class COC(=O)C1CNCCN1 ODQZNBWVRPKMKN-UHFFFAOYSA-N 0.000 description 1
- YACKEPLHDIMKIO-UHFFFAOYSA-N methylphosphonic acid Chemical compound CP(O)(O)=O YACKEPLHDIMKIO-UHFFFAOYSA-N 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 210000001577 neostriatum Anatomy 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 230000007171 neuropathology Effects 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 150000003009 phosphonic acids Chemical class 0.000 description 1
- JSSXHAMIXJGYCS-UHFFFAOYSA-N piperazin-4-ium-2-carboxylate Chemical compound OC(=O)C1CNCCN1 JSSXHAMIXJGYCS-UHFFFAOYSA-N 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- NNOBHPBYUHDMQF-UHFFFAOYSA-N propylphosphine Chemical compound CCCP NNOBHPBYUHDMQF-UHFFFAOYSA-N 0.000 description 1
- 150000003233 pyrroles Chemical class 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 230000000979 retarding effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical group CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 238000005245 sintering Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000012439 solid excipient Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- MFPWEWYKQYMWRO-UHFFFAOYSA-N tert-butyl carboxy carbonate Chemical compound CC(C)(C)OC(=O)OC(O)=O MFPWEWYKQYMWRO-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- VXKWYPOMXBVZSJ-UHFFFAOYSA-N tetramethyltin Chemical compound C[Sn](C)(C)C VXKWYPOMXBVZSJ-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 125000005424 tosyloxy group Chemical group S(=O)(=O)(C1=CC=C(C)C=C1)O* 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 238000007738 vacuum evaporation Methods 0.000 description 1
- ZTWTYVWXUKTLCP-UHFFFAOYSA-N vinylphosphonic acid Chemical compound OP(O)(=O)C=C ZTWTYVWXUKTLCP-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
- C07F9/6509—Six-membered rings
- C07F9/650952—Six-membered rings having the nitrogen atoms in the positions 1 and 4
-
- 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
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- 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
- A61P25/20—Hypnotics; Sedatives
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/59—Hydrogenated pyridine rings
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pain & Pain Management (AREA)
- Anesthesiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The present invention relates to formula I compound and preparation method thereof, preparation and purposes, they are as pain killer, anticonvulsive agent and anti-ischaemic agent, and formula I is
Description
The present invention relates to new piperazine, piperidines and pyrrolidine compound and preparation method thereof, purposes and pharmaceutical preparation.These compounds are antagonists of N-methyl D-sky radon propylhomoserin salt (NMDA) acceptor and are used for the treatment of known imbalance to the excited amino acid receptor retarding reaction of NMDA, especially for treating as illnesss such as pain, anxiety and cerebral ischaemias.
The acceptor of excited amino acid (mainly being L-glutaminate and L-days radon propylhomoserin salt) is distributed widely in the vertebra central nervous system.These acidic amino acids of excessive release produce some neuropathologys to be changed, thereby is that effective receptor antagonist can be used as new therapeutical agent.In the animal model of human diseases, shown already that nmda antagonist had anti-convulsant activity, referring to for example Lehmannet al.J.Pharmacol.Exp.Therap.1988,246,65-75.This means that nmda antagonist can be used as the anti-epileptic medicament.Nmda antagonist also can prevent because of transition stimulate the nerve cell death cause (Boast et al.Brain Res, 1982,442,345-348), and can be used for the sick treatment of local asphyxia and anoxic conditions and nerve degeneration as the Alzheimer disease.By intrathecal injection, nmda antagonist has analgesic activity (Cahusac et al.Neuropharmacology 1984,23,719-724.These antagonists also are useful when secreting related disease in treatment migraine, anxiety with lutropin.Be the 2 piperidine carboxylic acid compounds that replaces of the phosphono alkyl of NMAD antagonist at United States Patent (USP) 4,746, narration in 653, cis-4-(phosphonomethyl)-2 piperidine carboxylic acid is mentioned as the example of this compounds.They are at J.Med.Chem.1989, and 32, narration is also arranged among the 827-833.
The present invention relates to the new nmda antagonist of a class by the definition of formula I:
In the formula, X is imino-, methylene radical, Ben Yajiaji, 1, the 1-acrol contains 1 of 2-7 carbon atom, the 1-alkylidene group, perhaps X is the D-E base, wherein, D is a nitrogen, as the part of ring, E is low alkyl group or the acyl group that contains the straight or branched of 1-7 carbon atom, aroyl, replacement or unsubstituted allyl group, benzyl or propargyl;
Y has hydroxyl or amino carbon atom, or carbonyl;
Z is by 1 to 4 group that methylene radical constitutes, or propenylene or 1, the inferior proyl of 3-;
W is P(O) (OR
1) (OR
2) base, wherein R
1And R
2Independent separately is hydrogen, C
1-C
16The C that alkyl, phenyl replace
1-C
2Alkyl, acyl-oxygen methyl or acyl-oxygen ethyl;
When X was nonnitrogenous in ring, n was 1 or 2, and when x was nitrogenous, n was 2; And carboxyl can be transformed into pharmaceutically acceptable ester or acid amides in each compound.
In this class heterocyclic amino acid of the present invention, comprise for example metal-salt of pharmacy acceptable salt and base addition salt, also comprise hydrate, also comprise various steric isomers.
Formula I compound particularly preferably is wherein:
X is an imino-, C
1-C
6Alkyl imino, methylene radical, 1,1-ethylidene or 1,1-propylidene;
Y is carbon atom or the carbonyl that has hydroxyl;
Z is by 1 to 3 group that methylene radical constitutes or propenylene or 1, the inferior proyl of 3-;
W is P(O) (OR
1) (OR
2) base, wherein R
1And R
2Independent separately is hydrogen, C
1-C
16The C that alkyl, phenyl replace
1-C
2Alkyl, acyl-oxygen methyl or acyl-oxygen ethyl;
When X was nonnitrogenous in ring, n was 1 or 2, and perhaps when x contained nitrogen, n was 2; And carboxyl can be transformed into pharmaceutically acceptable ester or acid amides in each compound.
In this class heterocyclic amino acid of the present invention, not only comprise for example metal-salt of pharmacy acceptable salt and base addition salt, also comprise hydrate, and steric isomer.
The The compounds of this invention that is more preferably is the compound shown in the formula II;
In the formula
X is an imino-, C
1-C
4Alkyl imino, methylene radical, 1,1-ethylidene or 1,1-propylidene;
Y is carbon atom or the carbonyl that has hydroxyl;
Z is by 1 to 3 group that methylene radical constitutes, or propenylene or 1, the inferior proyl of 3-;
W is P(O) (OR
1) (OR
2) group, wherein R
1And R
2Independent separately is hydrogen, C
1-C
16The C that alkyl, phenyl replace
1-C
2Alkyl, acyl-oxygen methyl or acyl-oxygen ethyl;
Also comprise for example metal-salt of its pharmacy acceptable salt and base addition salt at this class heterocyclic amino acid of the present invention, also comprise its hydrate and steric isomer.Some steric isomer is preferred.
More than used " aroyl " speech benzoyl for example 2 of being meant benzoyl or replacement, 6-dimethylbenzoyl or 4-benzoyl bromide, furans acyl group, thiophene acyl group or pyridine acyl.
Compound of the present invention can be by the known method preparation in present technique field.Can use following one or several method.
Method A: be included in inert solvent such as the tetrahydrofuran (THF), in-75 ℃ to room temperature, methane phosphonic acid dialkyl with α-metal replacement, the ethyl that β-metal replaces-or the vinyl phosphonic acid dialkyl ester, the propyl-phosphine acid dialkyl ester that γ-metal replaces, the allyl dialkyl alkylphosphonate that α-or γ-metal replaces, perhaps the 1-proyl dialkyl alkylphosphonate that replaces of metal adds in the unsaturated heterocycle dicarboxylic acid derivatives of formula III, and the formula III is:
In the formula, the definition of X and n is the same; R is alkoxyl group or the dialkyl amido that contains 10 carbon atoms of as many as; L is suitable leavings group such as chlorine, fluorine, alkoxyl group, the nucleophilic group that azido-or activating carboxy acid are used, or hydrogen; That A represents aromatics or the unsaturated ring of part.The ring of product is saturated with it with ordinary method such as catalytic hydrogenation then, and the protecting group of removing ester or amido, perhaps at first removes protecting group and then hydrogenation ring and obtains compound of the present invention.With well-known reductive agent such as sodium borohydride can with contain the ketone official can with intermediate be reduced into alcohol, the intermediate or the product that also can adopt standard technique to make to contain carbinol-functional to use are oxidized to ketone.
Method B: with above-mentioned general condition, the phosphonic acids that the metal described in the method A is replaced adds in the heterogeneous ring compound of formula IV:
In the formula, R, X, the definition of L and n is the same.Nuclear nitrogen can also be protected, for example protected with the form of carbamate.Pure and mild ketone can be changed mutually by method described in the method A.Remove the protecting group of ester or amido then and obtain The compounds of this invention.
Method C: the halogenated ketone of formula V and VI is reacted with trialkyl phosphite under the used condition of Arbuzov reaction, perhaps with phosphorous acid dialkyl group or trialkylsilkl ester (preferably trimethyl silyl ester), perhaps the dialkyl alkylphosphonate with the metal replacement reacts.
In the formula, the definition of X, n, R and A is the same, and Q represents leavings group such as chlorine, bromine, iodine or sulfonate group such as tosyloxy, and m is 1-3.Nuclear nitrogen can be protected with the form of carbamate.Ketone also can give temporary protection with the form of for example ketone acetal.Remove blocking group then and obtain The compounds of this invention.
Method D: phosphorous side chain is had the product that obtains among the method A of ketone and the B and the intermediate of part protection, under known conditions, react the introducing primary amino with ammonia or ammonia source (for example ammonium acetate).These conditions are commonly referred to the reductive amination condition and can react illustration in the presence of hydrogen and catalyzer (as palladium) or in the presence of hydrogen source such as sodium cyanoborohydride by in suitable solvent (as ethanol).
The initial compounds of formula III, IV, V and VI is known, can prepare with method known in those skilled in the art.The reduction of the ring of hetero-aromatic ring or fractional saturation can be by the known reduction of this specialty pyrroles, and the method for pyridine or pyrazine is carried out.For example, the reduction of pyridine ring is being carried out in acid solvent (for example acetate) in the presence of the Adams catalyzer with catalytic hydrogenation.When needs stop side reaction, can adopt blocking group, the type of described blocking group is known tertbutyloxycarbonyl that for example is used for amine or a carbobenzoxy of present technique field, is used for the C of carboxylic acid and phosphonate group
1-C
6The straight or branched alkyl, allyl group or benzyl ester, and the silyl or the ketone acetal type protecting group that are used for alcohols.
Some used in aforesaid method speech has following definitions.
" alkyl " is meant the straight chain that contains 1-8 carbon atom and the alkyl chain of side chain, and commonly used is ethyl, butyl or sec.-propyl." metal replaces " is meant by for example with carbonic acid or phosphonic dialkyl, it is the slightly acidic compound, with method such as highly basic (for example butyllithium, sodium hydride or LDA) reaction, perhaps by halogenide and metal (for example zinc-copper conjugates, magnesium, lithium or sodium) are reacted the organometallic reagent that forms in inertia and other The suitable solvent.So the reagent that forms can the further improvement by adding the inferior ketone of other metallic compound such as cyaniding.
Following examples are used to illustrate the present invention, and do not mean that restriction the present invention.With the trimethyl carbinol (δ=30.6ppm) be marked on D in the conduct
2Measure among the O
13C-NMR spectrum.
Embodiment 1: cis-3-(1-oxo-2-phosphonoethyl)-and 2 piperidine carboxylic acid
Method A
With 0.415g cis-1-(tertiary butyl oxygen carbonyl)-3-(2-dimethyl phosphine acyl group-1-oxoethyl)-mixture of 2 piperidine carboxylic acid isopropyl ester and 0.38ml trimethylammonium bromination silicomethane in the 3ml chloroform 60 ℃ stirred 3 hours down.Remove in a vacuum then and desolvate.Then resistates is dissolved in the water of 5ml and and handles with the 0.10g lithium hydroxide.At room temperature stir after 3 hours mixture water wash-out by Dowex post (50wx8H).Collect cut, vacuum is removed and is anhydrated, and obtains 3-(1-oxo-2-phosphonoethyl)-the cis/trans mixture (3: 2) of 2 piperidine carboxylic acid, crystallization from water/ethanol,
13C-NMR(PPm): 20.9,22.5,25.6,27.1,43.6,45.2,45.7,46.6,50.0,50.5,58.9,59.7,173.0,173.8,211.1,211.2; With trans-3-(1-oxo-2-phosphonoethyl)-2 piperidine carboxylic acid, crystallization from water/ethanol, m.p.184-186 ℃.
Feedstock production is as follows: with the mixture of 12.5ml butyllithium (1.54M hexane solution) and 2.1ml dimethyl methyl phosphonate [being dissolved in the 20ml tetrahydrofuran (THF) (THF)]-78 ℃ be added to 4.0g3-chloroformyl-piperidine carboxylic acid isopropyl ester (in 20ml THF) in.Stir the saturated ammonium chloride of interpolation after 15 minutes, heated mixt is to room temperature.After dried over sodium sulfate, solvent removed in vacuo.Resistates as the eluent silica gel column chromatography, obtains 3-(2-dimethyl phosphine acyl group-1-oxoethyl with ethyl acetate/acetone)-2 piperidine carboxylic acid isopropyl ester oily matter.
With 1.2g3-(2-dimethyl phosphine acyl group-1-oxoethyl)-mixture of 2 piperidine carboxylic acid isopropyl ester and 0.2g10% platinum/charcoal in 15ml acetate in room temperature, hydrogenation under the 300Kpa.Mixture filters and solvent removed in vacuo, and resistates is dissolved in the 10ml methylene dichloride and adds salt of wormwood.After 15 minutes; add 0.82ml two dimethyl dicarbonate butyl esters; mixture filtered and with ethyl acetate as eluent through silica gel column chromatography, obtain cis-1-(tertiary butyl oxygen carbonyl)-3-(2-dimethyl phosphine acyl group-1-oxoethyl)-2-carbonyl piperidine isopropyl propionate oily matter.
Method B
With 0.425g cis-3-(2-diethyl phosphonyl-1-oxoethyl)-1; the mixture of 2-piperidines dicarboxylic acid di-t-butyl ester and 0.95ml bromo trimethyl silyl stirred 3 hours in the chloroform of 5ml at 60 ℃; solvent removed in vacuo; resistates is dissolved in the water; and wash-out is by Dowex post (50wx8H); get cis-3-(1-oxo-2-phosphonoethyl)-2 piperidine carboxylic acid, crystallization from water/ethanol.
13C-NMR（ppm）：19.3，24.0，42.2，43.8，45.0，48.2，57.8，172.6，210.0，210.1.
Feedstock production is as follows: with the mixture of 19.6g3-carboxyl-2-Pyridinecarboxylic Acid tertiary butyl ester and 5g10% palladium/charcoal (in 250ml acetate) 300KPa hydrogenation 6 hours.Filtering mixture also, solvent removed in vacuo gets cis-3-carboxyl-2 piperidine carboxylic acid tert-butyl ester oily matter.
In the mixture of 7.7g cis-3-carboxyl-2 piperidine carboxylic acid tert-butyl ester, 5.2ml triethylamine, 100ml methyl alcohol and 50ml methylene dichloride, add 8.3g two dimethyl dicarbonate butyl esters.Mixture is at room temperature stirred a night, and solvent removed in vacuo obtains the oily product then.
With cis-1-(tertiary butyl oxygen carbonyl)-3-carboxyl-2 piperidine carboxylic acid tertiary butyl ester and 4.1g1, the mixture of 1-carbonyl dimidazoles (in the 50ml methylene dichloride) at room temperature stirs a night.Solvent removed in vacuo, resistates are dissolved in 250ml toluene and the 10ml methylene dichloride, and successively with the saturated citric acid solution of 75ml, 75ml water and the washing of 75ml saturated sodium bicarbonate liquid.After dried over sodium sulfate, solvent removed in vacuo obtains the oily product.
With 4.8ml butyllithium (in the 1.5M hexane) and 1,1ml methyl-phosphorous acid diethyl ester and 0, the mixture of 91g magnesium bromide etherate (in 10mlTHF) adds 1.3g cis-1-(tertiary butyl oxygen carbonyl in-78 ℃)-3-imidazolyl carbonyl-2 piperidine carboxylic acid tertiary butyl ester (in 10ml THF).Stir after 15 minutes, add saturated ammonium chloride solution, mixture is warming up to room temperature, after dried over sodium sulfate, solvent removed in vacuo.Resistates usefulness ethyl acetate/hexane (3: 2) through silica gel column chromatography, obtains cis-3-(2-diethyl phosphonyl-1-oxoethyl as eluent)-1,2-piperidines dicarboxylic acid di-t-butyl ester oily matter.
Embodiment 2
3-(1-oxo-3-phosphinylidyne propyl group)-2 piperidine carboxylic acid.
Prepared 3-(1-oxo-3-phosphoryl propyl group by aforesaid similar approach)-the cis/trans mixture (4: 1) of 2 piperidine carboxylic acid.
13C-NMR（ppm）：19.0，20.8，21.2，22.7，24.3，26.2，35.3，37.1，44.4，45.0，46.5，48.4，58.2，58.9，172.5，172.9，214.9，215.0.
Feedstock production is as follows, be about to 2.3g3-chloroformyl-2-Pyridinecarboxylic Acid isopropyl ester (in 10ml toluene) adds 1.5gZn-Cu, 10ml toluene, 2ml N,N-DIMETHYLACETAMIDE under the ultrasonic activation state, 5g diethyl phosphonic acids β-iodine ethyl ester is in the mixture of 100mg Palladous chloride and 170mg three neighbours-tolylphosphine.After 10 minutes, mixture cools off on ice bath and adds 50ml saturated sodium bicarbonate liquid.Mixture is filtered and uses ethyl acetate extraction.After the dried over sodium sulfate, solvent removed in vacuo.Resistates usefulness ethyl acetate/acetone through silica gel column chromatography, obtains cis-3-(3-diethyl-phosphoryl-1-oxopropyl as eluent)-2-Pyridinecarboxylic Acid isopropyl ester oily matter.
Embodiment 3
Cis-3-(1-oxo-2-phosphoryl ethyl)-2-piperidines-carboxylic acid isopropyl
With 0.2g cis-1-(tertiary butyl oxygen carbonyl)-3-(2-diethyl phosphonyl-1-oxoethyl)-mixture of 2 piperidine carboxylic acid isopropyl ester and 0.3ml trimethylammonium bromo silicomethane stirred 3 hours in the 3ml chloroform at 60 ℃.Solvent removed in vacuo then, resistates is dissolved in the 4ml water and stirred 5 hours.Mixture water wash-out obtains cis-3-(1-oxo-2-phosphonoethyl by Dowex post (50Wx8H))-the 2 piperidine carboxylic acid isopropyl esters,
13C-NMR（ppm）：20.9，23.1，23.2，25.6，43.3，44.9，46.7，50.2，58.7，75.2，171.1，211.1，211.2.
Embodiment 4
3-(1-oxo-2-phosphonoethyl)-2 piperidine carboxylic acid
With 0.20g3-(1-oxo-2-phosphonoethyl)-hydrogenation 1.5 hours under room temperature, 300Kpa of the mixture of 2-Pyridinecarboxylic Acid and 0.20g10% platinum/charcoal (in 10ml water).Mixture is filtered and solvent removed in vacuo.Resistates water wash-out obtains 3-(1-oxo-2-phosphonoethyl by Dowex post (50Wx8H))-2 piperidine carboxylic acid.
Embodiment 5
4-methyl-3-(1-oxo-2-phosphonoethyl)-2 piperidine carboxylic acid
With 0.08g3-(2-diethyl-phosphono-1-oxoethyl)-the 4-methyl isophthalic acid, the mixture of 2-piperidines dicarboxylic acid di-t-butyl ester and 0.2ml trimethylammonium bromo silicomethane (in the 1ml chloroform) heated 4 hours in 64 ℃ in the sealed glass bottle.Solvent removed in vacuo is also added 0.3ml water, and mixture was placed 1 hour.After the evaporation, resistates water wash-out is by cation exchange resin column (Dowex 50Wx8H).Product is a stereoisomer mixture, can identify wherein that main component is a title compound, and it has following feature:
1H-NMR signals（HDO at 4.74ppm as reference）：3.82（d，J 4Hz，H-2），3.72（t，H-3），1.14（d，3H，4-Me）.
Feedstock production is as follows: the 3-carboxyl-4-methyl-2-Pyridinecarboxylic Acid tertiary butyl ester (5.0g) that will be made by the corresponding acid anhydrides and the trimethyl carbinol, at 10%Pd-C(3g) in the presence of in 300Kpa hydrogenation in acetate.Filter and evaporating solvent after, almost be the resistates of pure 3-carboxyl-4-methyl piperidine-2-carboxylic acid tertiary butyl ester, it is handled with the triethylamine of equivalent in the mixture of methylene dichloride and methyl alcohol (3: 1) and the tert-Butyl dicarbonate of adding equivalent.After reacting 15 hours, solvent is fallen in vacuum-evaporation, and staying almost is pure 3-carboxyl-4-methyl piperidine-1,2-dicarboxylic acid di-t-butyl ester triethyl ammonium salt foam.This material (0.7g) is directly used oxalyl chloride (0.175ml) and 5 DMF(in 25ml toluene under cooling off) handle after 45 minutes, filter and evaporating solvent by the glass sintering strainer.On the other hand, use methylene chloride (98/2), but, handle the fluorochemical that converts it into acid with cyanuric fluoride then through the above-mentioned acid of silica gel column chromatography also purifying as eluent.The muriate of acid is dissolved among the THF,, stirs after 10 minutes, add saturated ammonium chloride solution, make mixture reach room temperature and use ethyl acetate extraction at-70 ℃ of THF solution that add the lithiumation methane phosphonic acid diethyl ester of appropriate amounts.Dried over sodium sulfate is also removed and is desolvated; obtain resistates; with ethyl acetate/hexane (3: 2) as eluent through silica gel column chromatography, obtain 3-(diethyl phosphonyl-1-oxoethyl)-4-methyl-piperidines-1,2-dicarboxylic acid di-t-butyl ester oily matter (90mg).
Embodiment 6
Cis-3-(1-hydroxyl-2-phosphonoethyl)-2 piperidine carboxylic acid.
With 0.35g cis-1-carbobenzoxy-(Cbz)-3-(1-hydroxyl-2-phosphonoethyl)-hydrogenation 2 hours under room temperature and 300Kpa of the mixture of 2 piperidine carboxylic acid ammonium salt and 0.30g palladium/charcoal (in 15ml water).Mixture filters and solvent removed in vacuo.Resistates is crystallization in water/ethanol, obtains cis-3-(1-hydroxyl-2-phosphonoethyl)-the 2 piperidine carboxylic acid ammonium salt.
13C-NMR（ppm）：20.6，22.6，34.1，35.8，38.5，38.6，44.9，63.3，70.4，174.8
Feedstock production is as follows: with the 22.6ml n-buli hexane solution (1.37M) and the mixture of 4.7g methyl-phosphorous acid diethyl ester (in 50ml THF) add the THF solution (50ml of 5.45g3-formyl radical-2-pyridine-3-carboxylic acid isopropyl ester to;-60 ℃) stir after 1 hour; add the 7g trimethyl ammonium chloride, mixture is warming up to room temperature.Solvent removed in vacuo, resistates usefulness acetone through silica gel column chromatography, obtains 3-(2-diethyl phosphoryl-1-hydroxyethyl as eluent)-the 2-Pyridinecarboxylic Acid lactone, oily matter.
With 1.0g3-(2-diethyl phosphonyl-1-hydroxyethyl)-hydrogenation 12 hours under room temperature 300KPa of the mixture of 2-Pyridinecarboxylic Acid lactone and 0.2g platinum oxide (in 20ml acetate).Mixture filters and solvent removed in vacuo.Resistates is dissolved in the 20ml methylene dichloride and adds saturated soda solution.Mixture stirs and adds the 0.61ml chloroformic acid benzyl ester down at 0 ℃.Stir after 3 hours under the room temperature, tell organic phase, dried over sodium sulfate is filtered solvent removed in vacuo.Resistates usefulness ethyl acetate through silica gel column chromatography, obtains 1-carbobenzoxy-(Cbz)-3-(2-diethyl phosphonyl-1-hydroxyethyl as eluent)-2 piperidine carboxylic acid lactone oily matter.With 0.38g1-carbobenzoxy-(Cbz)-3-(2-diethyl phosphonyl-1-hydroxyethyl)-mixture of 2 piperidine carboxylic acid lactone and 0.65ml trimethylammonium silyl bromide in the 4ml chloroform 60 ℃ stirred 3 hours down.Solvent removed in vacuo then, resistates are dissolved in the 3ml water and with the 0.10g lithium hydroxide and handle.Stir under the room temperature after 3 hours, mixture by Dowex post (50Wx8H), obtains cis-1-benzyloxycarbonyl-3-(1-hydroxyl-2-phosphonoethyl with 1M ammonia soln wash-out)-the 2 piperidine carboxylic acid ammonium salt.
Embodiment 7
3-(1-oxo-2-phosphonoethyl)-the 2-piperazine carboxylic acid
With 0.5g cis-1,4-two (tertiary butyl oxygen carbonyl)-3-(2-diethyl phosphonyl-1-oxoethyl)-mixture of 2-piperazine carboxylic acid methyl esters and 1.25ml trimethylammonium silyl bromide stirred 3 hours down at 60 ℃ in the 5ml chloroform.Solvent removed in vacuo then, resistates is handled with the 0.20g lithium hydroxide.Stir under the room temperature after 3 hours, mixture is used 1M ammoniacal liquor wash-out then by Dowex post (50Wx8H) beginning water, acquisition 3-(1-oxo-2-phosphonoethyl)-the cis/trans mixture (3: 2) of 2-piperazine carboxylic acid ammonium salt.
13C-NMR（ppm）：41.0，41.5，41.7，42.2，44.7，46.1，46.9，48.3，58.4，59.4，62.4，63.2，172.9，173.0，205.3，206.7.
Feedstock production is as follows: add the mixture of 4.7ml n-buli hexane solution (1.44M) and 1.0g methyl-phosphorous acid diethyl ester THF solution (10ml) to 2.0g cis-1,4-two (tertbutyloxycarbonyl)-2, in 3-piperazine dimethyl dicarboxylate's the THF solution (20ml ,-78 ℃).Stir after 30 minutes, add saturated ammonium chloride solvent, mixture is warming up to room temperature and uses chloroform extraction.After dried over sodium sulfate, solvent removed in vacuo.Resistates is made eluent through silica gel column chromatography with ethyl acetate/hexane, obtains cis-1,4-two (tert-butoxycarbonyl)-3-(2-diethyl phosphonyl-1-oxoethyl)-2-piperazine carboxylic acid methyl esters oily matter.
Pharmaceutical preparation
The medicament that contains formula I compound according to the known method preparation.When compound when the anodyne, with the present invention's compound dissolution in the liquid diluent that is suitable for injecting.Preferably with compound dissolution in isoosmotic sodium chloride solution.When being used for the treatment of convulsions, when anxiety and cerebral ischemia, they can be used with the form (for example tablet, capsule or suppository) of oral or rectal formulation.In order to produce the pharmaceutical preparation of the oral dosage unit form that contains formula 1 compound, the compound of selecting can mix with solid excipient (as lactose or derivatived cellulose), tackiness agent (as gelatin) and lubricant (for example magnesium stearate), is pressed into tablet then.
The dose unit that rectum is used can be solution or suspension, also can be prepared into suppository form.
The liquid preparation of oral application can be syrup or suspension form, for example contains about 0.2%-20%(weight) solution of active substance described herein.
The injection solution of parenterai administration can be made aqueous solution form with the pharmacy acceptable salt of active substance of the present invention.These solution can contain stablizer and/or buffer reagent, and provide easily with the ampoule form of various dose units.
The suitable oral dosage of The compounds of this invention is 10-200mg when being applied to the adult, is 0.1-100 μ g when using in the sheath.
Biological assessment
Compound exhibits of the present invention goes out the valuable pharmacological characteristic, for example blocks the excited amino acid receptor of Mammals NMDA.Thereby these compounds can be used for treating to responsive illness, particularly convulsions, anxiety, cerebral ischemia and the pain of this blocking-up.These act in external or the body and are confirmed in the test as mouse, rat, dog, monkey.Described compound can oral or parenterai administration.
To the restraining effect of the excited amino acid receptor of NMDA-type external be to cause by the NMDA that measures the rat brain striatum tissue
3The restraining effect that the H-acetylcholine discharges and determine (referring to Lehnamm and Scatton, Brain Reseach 1982,252,77-89 is described).By with control group relatively, when stimulating with 50 μ M NMDA
3The release percentage ratio of H-acetylcholine represents that in the line shape tissue slice NMDA causes
3The restraining effect that the H-acetylcholine discharges.Restraining effect to the excited amino acid receptor of NMDA type can also be passed through external test
3H-CGS 19755 determine with the restraining effect that cerebral tissue prepares bonding (mainly with reference to Lehman et al J.Pharmacol.Exptl.Therap.1988,246,65-75).
The anticonvulsant action of The compounds of this invention is by the restraining effect of measuring the convulsions that mouse electroshock or NMDA bring out definite (described in the documents of last narration) in vivo.
The analgesic effect of described compound to rat and mouse intrathecal injection and measure (mainly according to Cahusac et al.Neuropharmacology 1984,23,719-24.
Enforcement known today best method of the present invention is to adopt the compound of embodiment 1 or 6.
Claims (13)
1, the compound of formula I and hydrate thereof, pharmacy acceptable salt, base addition salt (as metal-salt) and various steric isomer, formula I is:
In the formula, X is imino-, methylene radical, Ben Yajiaji, 1, the 1-acrol, contain 1 of 2-7 carbon atom, the 1-alkylidene group, perhaps X is the D-E base, wherein, D is the part of ring, is nitrogen-atoms, and E is straight or branched alkyl or acyl group, aroyl, replacement or unsubstituted allyl group, benzyl or the propargyl that contains 1-7 carbon atom;
Y has hydroxyl or amino carbon atom, or carbonyl;
Z is by 1 to 4 group that methylene radical constitutes, or propenylene or 1, the inferior proyl of 3-;
W is P (O) (OR
1) (OR
2) base, wherein R
1And R
2Independently be hydrogen separately, C
1-C
16The C that alkyl, phenyl replace
1-C
2Alkyl, acyl-oxygen methyl or acyl-oxygen ethyl;
When X was nonnitrogenous in ring, n was 1 or 2, and perhaps when X was nitrogenous, n was 2; And the carboxyl in above-mentioned each compound can be transformed into pharmaceutically acceptable ester or acid amides.
2, according to the compound of claim 1 and hydrate, pharmacy acceptable salt and base addition salt (as metal-salt), various steric isomer, wherein:
X is an imino-, C
1-C
6Alkyl imino, acyl group imino-, methylene radical, 1,1-ethylidene or 1,1-propylidene;
Y is carbon atom or the carbonyl that has hydroxyl;
Z is by 1 to 3 group that methylene radical constitutes or propenylene or 1, the inferior proyl of 3-;
W is P(O) (OR
1) (OR
2) base, wherein R
1And R
2Independent separately is hydrogen, C
1-C
16The C that alkyl, phenyl replace
1-C
2Alkyl, acyl-oxygen methyl or acyl-oxygen ethyl;
When X was nonnitrogenous in ring, n was 1 or 2, and perhaps when x contained nitrogen, n was 2; And the carboxyl in each above-mentioned compound can be transformed into pharmaceutically acceptable ester or acid amides.
3, according to the formula II compound and the hydrate thereof of claim 1, pharmacy acceptable salt and base addition salt (as metal-salt) and various steric isomer,
Wherein:
X is an imino-, C
1-C
4Alkyl imino, acyl group imino-, methylene radical, 1,1-ethylidene or 1,1-propylidene;
Y is carbon atom or the carbonyl that has hydroxyl;
Z is by 1 to 3 group that methylene radical constitutes or propenylene or 1, the inferior proyl of 3-;
W is P(O) (OR
1) (OR
2) base, wherein R
1And R
2Independent separately is hydrogen, C
1-C
16The C that alkyl, phenyl replace
1-C
2Alkyl, acyl-oxygen methyl or acyl-oxygen ethyl;
4, according to the compound and the hydrate thereof of claim 1, pharmacy acceptable salt and base addition salt (as metal-salt), various steric isomer, wherein,
X is a methylene radical,
Y is a carbonyl,
Z is a methylene radical,
W is P(O) (OR
1) (OR
2) base, wherein R
1And R
2Both are hydrogen, and n is 2.
5, according to the compound of claim 1, wherein,
X is a methylene radical,
Y is the hydroxyl methylene radical,
Z is a methylene radical;
W is P(O) (OR
1) (OR
2) base, wherein R
1And R
2Both are hydrogen, and n is 2.
6, a kind of medicament that right requires 1 compound that contains with anticonvulsant action.
7, a kind of medicament that right requires 1 compound that contains with analgesic activity.
8, a kind of medicament that right requires 1 compound that contains with Chinese People's Anti-Japanese Military and Political College's cerebral ischaemia effect.
9, the compound of claim 1 is used to prepare the medicament with analgesic activity.
10, the compound of claim 1 is used to prepare the medicament with anti-ischemia effect.
11, the compound of claim 1 is used to prepare the medicament with brain anticonvulsant action.
12, the method for preparation and hydrate thereof, pharmacy acceptable salt, base addition salt and various steric isomers, the formula I is
Ⅰ
Identical in the definition of X, Y, Z, W and n and the claim 1 in the formula;
Described method comprises:
A) with the compound of formula III and the dialkyl alkylphosphonate reaction of metal replacement, the compound of generation reduces with ordinary method, removes protecting group then, and the formula III is
The definition of X and n is the same in the formula,
L is the leavings group that suits,
R is the alkoxyl group or the dialkyl amido of 10 carbon atoms of as many as,
That A represents aromatics or the unsaturated ring of part; Perhaps
(B) with the alkyl phosphonic acid reaction of IV compound and metal replacement, remove protecting group then, the formula IV is
X, L, R and n definition are the same in the formula; Perhaps
(C) with the halogenated ketone of formula V or VI and trialkyl phosphite or with the dialkyl alkylphosphonate reaction that metal replaces, remove protecting group then, formula V or VI are
X, R, A and n define ditto in the formula, and Q is a leavings group; Perhaps
(D) will contain the method A of ketone in the phosphorous side chain) or the intermediate of the part protection that one of B) obtains react with ammonia or ammonia source.
13, induce the method for pain relieving, treatment convulsions or cerebral ischemia, this method comprises that the Mammals to the needs treatment comprises that the people uses the compound of the claim 1 of significant quantity.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE9003652 | 1990-11-15 | ||
| SE9003652A SE9003652D0 (en) | 1990-11-15 | 1990-11-15 | NEW HETEROCYCLIC COMPOUNDS |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1061595A true CN1061595A (en) | 1992-06-03 |
Family
ID=20380925
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN91110925A Pending CN1061595A (en) | 1990-11-15 | 1991-11-05 | Be used as new heterocyclics of excited amino acid receptor antagonists and its production and use |
Country Status (17)
| Country | Link |
|---|---|
| EP (1) | EP0557375A1 (en) |
| JP (1) | JPH06502421A (en) |
| CN (1) | CN1061595A (en) |
| AU (1) | AU652399B2 (en) |
| CA (1) | CA2095224A1 (en) |
| CZ (1) | CZ80993A3 (en) |
| FI (1) | FI932206L (en) |
| HU (1) | HU9301417D0 (en) |
| IE (1) | IE913922A1 (en) |
| IS (1) | IS3782A7 (en) |
| LT (1) | LTIP1718A (en) |
| MX (1) | MX9101979A (en) |
| NO (1) | NO931679D0 (en) |
| PT (1) | PT99515A (en) |
| SE (1) | SE9003652D0 (en) |
| SK (1) | SK46993A3 (en) |
| WO (1) | WO1992008724A1 (en) |
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| US5194430A (en) * | 1990-05-17 | 1993-03-16 | Merrell Dow Pharmaceuticals Inc. | Heterocyclic-nmda antagonists |
| TW281670B (en) * | 1993-09-02 | 1996-07-21 | Hoffmann La Roche | |
| US5491241A (en) * | 1993-10-18 | 1996-02-13 | Eli Lilly And Company | Bicyclic intermediates for excitatory amino acid receptor antagonists |
| RS65984B1 (en) | 2016-02-04 | 2024-10-31 | Takeda Pharmaceuticals Co | Substituted piperidine compound as orexin type 2 agonist for the treatment of narcolepsy |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1248531A (en) * | 1984-04-17 | 1989-01-10 | Jeffrey C. Watkins | 4-substituted piperazine-2-carboxylic acids |
| JPS612519A (en) * | 1984-04-24 | 1986-01-08 | Aron Kasei Co Ltd | Method of injection molding |
| US4906621A (en) * | 1985-05-24 | 1990-03-06 | Ciba-Geigy Corporation | Certain 2-carboxypiperidyl-alkylene phosphonic acids and esters thereof useful for the treatment of disorders responsive to N-methyl-D-aspartate receptor blockade |
| US4740346A (en) * | 1986-02-26 | 1988-04-26 | The Budd Company | Perimeter resin feeding of composite structures |
| JPS63112129A (en) * | 1986-10-30 | 1988-05-17 | Toyoda Gosei Co Ltd | Multi-color resin molding die |
| EP0275820B1 (en) * | 1986-11-21 | 1991-02-06 | Ciba-Geigy Ag | Unsaturated phosphonic acids and derivatives |
-
1990
- 1990-11-15 SE SE9003652A patent/SE9003652D0/en unknown
-
1991
- 1991-11-05 CN CN91110925A patent/CN1061595A/en active Pending
- 1991-11-07 WO PCT/SE1991/000753 patent/WO1992008724A1/en not_active Application Discontinuation
- 1991-11-07 CZ CS93809A patent/CZ80993A3/en unknown
- 1991-11-07 CA CA002095224A patent/CA2095224A1/en not_active Abandoned
- 1991-11-07 AU AU89391/91A patent/AU652399B2/en not_active Ceased
- 1991-11-07 JP JP4500566A patent/JPH06502421A/en active Pending
- 1991-11-07 HU HU931417A patent/HU9301417D0/en unknown
- 1991-11-07 SK SK46993A patent/SK46993A3/en unknown
- 1991-11-07 EP EP91920264A patent/EP0557375A1/en not_active Withdrawn
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- 1991-11-12 IE IE392291A patent/IE913922A1/en unknown
- 1991-11-14 IS IS3782A patent/IS3782A7/en unknown
- 1991-11-14 PT PT99515A patent/PT99515A/en not_active Application Discontinuation
-
1993
- 1993-05-07 NO NO931679A patent/NO931679D0/en unknown
- 1993-05-14 FI FI932206A patent/FI932206L/en not_active Application Discontinuation
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Also Published As
| Publication number | Publication date |
|---|---|
| MX9101979A (en) | 1992-07-08 |
| AU8939191A (en) | 1992-06-11 |
| LTIP1718A (en) | 1995-07-25 |
| JPH06502421A (en) | 1994-03-17 |
| SE9003652D0 (en) | 1990-11-15 |
| AU652399B2 (en) | 1994-08-25 |
| NO931679L (en) | 1993-05-07 |
| FI932206A0 (en) | 1993-05-14 |
| WO1992008724A1 (en) | 1992-05-29 |
| IE913922A1 (en) | 1992-05-20 |
| SK46993A3 (en) | 1993-10-06 |
| HU9301417D0 (en) | 1993-09-28 |
| EP0557375A1 (en) | 1993-09-01 |
| CZ80993A3 (en) | 1994-02-16 |
| CA2095224A1 (en) | 1992-05-16 |
| NO931679D0 (en) | 1993-05-07 |
| FI932206L (en) | 1993-05-14 |
| IS3782A7 (en) | 1992-05-16 |
| PT99515A (en) | 1992-09-30 |
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