IE903420A1 - Novel CNS-active hexapeptides with an antiamnesic effect - Google Patents
Novel CNS-active hexapeptides with an antiamnesic effectInfo
- Publication number
- IE903420A1 IE903420A1 IE342090A IE342090A IE903420A1 IE 903420 A1 IE903420 A1 IE 903420A1 IE 342090 A IE342090 A IE 342090A IE 342090 A IE342090 A IE 342090A IE 903420 A1 IE903420 A1 IE 903420A1
- Authority
- IE
- Ireland
- Prior art keywords
- met
- hexapeptide
- formula
- phe
- alkanoyl
- Prior art date
Links
- 230000003496 anti-amnesic effect Effects 0.000 title description 4
- 239000002475 cognitive enhancer Substances 0.000 title description 4
- 238000000034 method Methods 0.000 claims abstract description 13
- KDXKERNSBIXSRK-RXMQYKEDSA-N D-lysine Chemical compound NCCCC[C@@H](N)C(O)=O KDXKERNSBIXSRK-RXMQYKEDSA-N 0.000 claims abstract description 7
- 239000003814 drug Substances 0.000 claims abstract description 6
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims abstract description 6
- QEFRNWWLZKMPFJ-YGVKFDHGSA-N L-methionine S-oxide Chemical compound CS(=O)CC[C@H](N)C(O)=O QEFRNWWLZKMPFJ-YGVKFDHGSA-N 0.000 claims abstract description 5
- 238000002360 preparation method Methods 0.000 claims abstract description 4
- RVLOMLVNNBWRSR-KNIFDHDWSA-N (2s)-2-aminopropanoic acid;(2s)-2,6-diaminohexanoic acid Chemical compound C[C@H](N)C(O)=O.NCCCC[C@H](N)C(O)=O RVLOMLVNNBWRSR-KNIFDHDWSA-N 0.000 claims abstract description 3
- WHUUTDBJXJRKMK-GSVOUGTGSA-N D-glutamic acid Chemical compound OC(=O)[C@H](N)CCC(O)=O WHUUTDBJXJRKMK-GSVOUGTGSA-N 0.000 claims abstract description 3
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- 238000006243 chemical reaction Methods 0.000 claims description 4
- 125000003277 amino group Chemical group 0.000 claims description 3
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
The present invention relates to hexapeptides of the general formula I R<1>-A<1>-A<2>-A<3>-A<4>-A<5>-A<6>-NH(CH2)n-NH2 (I> where R<1> denotes Z, formyl or (subst.) alkanoyl; A<1> denotes Met, Met(O) or Met(O2), all of which can be in the L or D form; A<2> denotes Glu, D-Glu, Ala or pyroglutamyl; A<3> denotes His, Ala, Phe or D-Lys; A<4> denotes the radical of a neutral aliphatic or aromatic alpha -amino acid; A<5> denotes Lys or D-Lys; A<6> denotes (subst.) Phe and n denotes an integer from 4 to 10. Processes for the preparation thereof, the use thereof as medicines, and pharmaceutical compositions containing these are described.
Description
HOECHST AKTIENGESELLSCHAFT HOE 89/F 316 Dr. Wl/rh Description Novel CNS-active hexapeptides with an antiamnesic effect CNS-active peptides with an antiamnesic effect or effect 5 on the cholinergic system have been disclosed in EP-A 179 332. However, the hexapeptides described therein have the disadvantage that they are easily transformed or decomposed, that is to say are relatively unstable. With a view to use as pharmaceuticals, this is a particular problem with regard to the production of pharmaceutical formulations and the shelf life thereof.
The object of the present invention is therefore to provide compounds which have an antiamnesic effect, are stable and thus can be handled without difficulty and can be used to produce pharmaceuticals with a long shelf life.
This object is surprisingly achieved by hexapeptides of the formula I ί^-Α^Α^Α^Α^-Α^Α^ΝΗ (CH2) n-NH2 (I) in which A1 is Met, D-Met, Met(O), D-Met(O), Met(02) or D-Met (O2), A2 is Glu, D-Glu, Ala or pyroglutamyl, A3 is His, Ala, Phe or D-Lys, A* is the residue of a neutral aliphatic or aromatic aamino acid, A5 is D-Lys or Lys, A6 is Phe, N-methylphenylalanine, 4-(Cx-C4) -alkoxyphenylalanine or l,2,3,4-tetrahydroisoquinoline-3carboxylic acid, R1 is benzyloxycarbonyl (Z), formyl, (C2-C6)-alkanoyl, (C6-C10) -aryl- (C2-C4) -alkanoyl, (C5-C7) -cycloalkyl- (Ci30 - 2 C2) -alkanoyl, (C2-C4) -alkanoyl-w-amino- (C3-C4) -nalkanoyl or methylsulfonyl-w-amino- (C3-CA) -n-alkanoyl and n is an integer from 4 to 10, and the physiologically tolerated salts thereof.
A1 is preferably Met(O) or Met(02). A2 is preferably Glu or Ala. A3 is preferably His or Ala. A* 10 is preferably Ala, Val, Leu, lie, Met, Ser-tCi-Cg)alkyl, Thr-(Cx-C6)-alkyl, Cys-(CX-C6)-alkyl, Phe, Phg (C-phenylglycin), Tyr-(C^-Cg)-alkyl, with Ala, Val, Leu, lie, Phe, Tyr(Me) and Tyr(Et) being particularly preferred. Phe is very particularly preferred. A5 is preferably D-Lys. 15 A6 is preferably Phe. R1 is preferably formyl or (C2-C6)-alkanoyl. Formyl, acetyl and propionyl are particularly preferred. n is preferably an integer from 6 to 10, with 8 being very particularly preferred.
A particularly preferred hexapeptide of the formula I is the compound of the formula Ac-Met (O2) -Glu-His-Phe-D-Lys-Phe-NH- (CH2) e-NH2.
Examples of physiologically tolerated salts of the compounds of the formula I are those formed between basic groups, that is to say the amino groups in particular, and inorganic or organic acids. Examples of such acids are hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid and p-toluenesulfonic acid.
A preferred acid is acetic acid.
The invention furthermore relates to a process for the preparation of compounds of the formula I, which comprises condensing a fragment with an N-terminal free amino group with a fragment with a C-terminal free carboxyl group, where in these fragments, when not involved in the reaction, primary and secondary amino groups are protected with urethane-type protective groups which can be eliminated with acid (such as, for example, Boc) and carboxyl groups are protected with ester-type protective groups which can be eliminated with acid (such as, for example, Bufc), eliminating with acid the protective groups introduced to protect amino and carboxyl groups in the compounds obtained in this way, and converting the compounds where appropriate into their physiologically tolerated salts.
Protective groups of the urethane type and ester type are described in Schroder, Liibke, Academic Press, The Peptides, vol. I, New York, London 1965, page 22 et seq., and page 52 et seq., and in A. Hubbuch, Kontakte Merck 3/79, pages 14-23.
The process is advantageously carried out in such a way that a) a compound of the formula Ila is condensed with a compound of the formula Ilia, R1-A1-OH (Ha) H-A2-A3-Aa-A5-A6-X (Ilia) b) a compound of the formula lib is condensed with a compound of the formula Illb, r'-a'-a^oh (lib) h-a!-a'-a!-a'-x (Illb) c) a compound of the formula lie is condensed with a compound of the formula IIIc, R1-A1-Az-A3-0H h-a*-a5-a6-x (lie) (Hie) d) a compound of the formula IId is condensed with a compound of the formula IIId, R1-A1-AZ-A3-A4-OH (lid) h-a5-a6-x (Hid) or d) a compound of the formula lie is condensed with a compound of the formula Ilie, r1-A1-A2-A3-A*-A5-OH (He) h-a6-x (Hie) where the radicals R1 and A1 to A6 are as defined above and X is protected -NH (CH2) n-NH2, but free primary and secondary amino groups, excepting the N-terminal groups of the compounds of the formulae Illa-e, are protected with urethane-type protective groups which can be eliminated with acid, and free carboxyl groups, excepting the C-terminal groups of the compounds of the formulae Ila-e, are protected with ester-type protective groups which can be eliminated with acid, subsequently protective groups introduced to protect amino and carboxyl groups in the compounds obtained according to a) - e) are eliminated with acid, and the resulting compounds are converted where appropriate into their physiologically tolerated salts. Reaction of compounds of the formula Ila with compounds of the formula Ilia is preferred.
The starting compounds of the formulae Ila-e and Illa-e are known or can be obtained in a manner known per se, for example by fragment condensation.
Suitable as N"— protective group is preferably the benzyloxycarbonyl or 9-fluorenylmethoxycarbonyl radical, and as carboxyl protective group is the tert.-butyl radical, in the synthesis of the peptides according to the invention.
The condensation in the process according to the invention is carried out by the general methods of peptide chemistry, for example by the mixed anhydride method, via active esters, azides or by the carbodiimide method, especially with the addition of substances which increase the reaction rate and prevent racemization, such as, for example, 1-hydroxybenzotriazole, N-hydroxysuccinimide, 3hydroxy-4-oxo-3,4-dihydro-l,2,3-benzotriazine, N-hydroxy5-norbornene-2,3-dicarboximide, and with the use of activated derivatives of 1-hydroxybenzotriazole or anhydrides of phosphoric, phosphonic and phosphinic acids.
Solvents are dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide, N-methylpyrrolidone or di20 methyl sulfoxide. It is also possible to employ solvents such as methylene chloride or chloroform where the solubility of the components permits it. The said methods are described, for example, in Meienhofer-Gross: The Peptides, Academic Press, vol. I, (1979).
The compounds according to the invention are, by reason of their pharmacological properties, suitable for the treatment of cognitive dysfunctions of a variety of etiologies, as occur, for example, in Alzheimer's disease or senile dementia. The improvement in cognitive func30 tions by the compounds according to the invention (nootropic effect) was tested in animal experiments on mice using the inhibitory (passive) avoidance test (stepthrough model) and on rats using the radial maze test (8arm radial maze). These are standard tests described in the literature for testing learning and memory functions in animal experiments. (Inhibitory avoidance: J. Bures, 0. Buresova and J. Huston in Techniques and Basic Experiments for the Study of Brain and Behavior", Elsevier Scientific Publishers, Amsterdam 1983; Radial Maze: U. StSubli, M. Baudry and G. Lynch, Behavioral and Neural Biology 40, 58-69 (1984).) In accordance with the statements in the said literature, a substance is said to have nootropic activity when it counteracts or is even able to abolish the increase in the rate of errors induced in the experimental animals by scopolamine, electric shock or inhibitors of protein synthesis in these tests.
The experiments were carried out by the test methods described above. The known nootropic 2-oxo-lpyrrolidinylacetamide (piracetam) was used as comparison compound. The distinct superiority of the compounds according to the invention was evident from the fact that the scopolamine-induced amnesia is abolished in the inhibitory-avoidance test with an MED (minimum effective dose) of 0.3 - 1 pg/kg s.c. and in the radial maze test with an MED of 10 s.c., while the comparison compound has an MED of 500 - 1000 mg/kg orally in these tests.
The peptides according to the invention have moodlightening, anti depressant and anxiolytic effects in humans. They increase awareness of the surroundings, improve learning and memory performance, have beneficial effects in resocialization processes and can be used for all diseases, post-traumatic and degenerative brain damage associated with reduced function of central acetylcholine metabolism, for example mild dementia as well as early forms of Alzheimer's disease etc. They also reduce hyperemotivity.
Hence the invention also relates to the use of compounds of the formula I as medicines and to pharmaceutical products which contain these compounds. - Ί For an adult of normal weight, intranasal administration is employed, preferably in a dosage of 0.1 ^g to 1 mg per dose, and 1 to 500, especially 5 to 200, μg per dose are particularly preferred. The pharmaceuticals according to the invention can be administered, for example, up to 6 times, preferably up to 3 times, per day. In many cases administration of one dose per day also suffices. The compounds according to the invention can also be administered subcutaneously with 0.001 to 10 μg/kg, prefer10 ably 0.01 to 5 pg/kg, especially 0.05 to 2 pg/kg. Their oral absorbability varies with the constitution. The dose range on oral administration is comparatively large and is between 0.1 and 50 mg a day, divided into several administrations.
The preferred single dose for the compounds with the most potent action is 0.1 to 10 mg.
Pharmaceutical products contain an effective amount of an active compound of the formula I together with an inorganic or organic pharmaceutically utilizable excipient.
Intranasal, intravenous, subcutaneous or oral use is possible.
For a form for oral use, the active compounds are mixed with the additives customary for this purpose, such as excipients, stabilizers or inert diluents, and converted by customary methods into suitable dosage forms such as tablets, coated tablets, hard gelatin capsules, aqueous, alcoholic or oily suspensions or aqueous or alcoholic solutions. Examples of inert vehicles which can be used are gum arabic, magnesium carbonate, potassium phosphate, lactose, glucose or starch, especially corn starch. This formulation can be carried out both as dry or wet granules . Examples of suitable oily excipients or solvents are vegetable and animal oils, such as sunflower oil or fish liver oil.
For subcutaneous or intravenous administration, the active compounds or the physiologically tolerated salts thereof are converted, if desired with the substances customary for this purpose, such as solubilizers, emulsifiers or other auxiliaries, into a solution, suspension or emulsion. Examples of suitable solvents for the novel active compounds and the corresponding physiologically tolerated salts are: water, physiological saline solutions or alcohols, for example ethanol, propane diol or glycerol, as well as sugar solutions such as glucose or mannitol solutions, or else a mixture of the various solvents mentioned.
Example 1 Ac-Met(O2)-Glu-His-Phe-D-Lys-Phe-NH-(CH2)8-NH2 . 2 CH3COOH a) Acetyl-L-methionine sulfone (Ac-Met (0,1-OH) .0 g of acetyl-L-methionine (Fluka) are dissolved in 50 ml of trif luoroacetic acid and, while stirring at -20°C, reacted with a mixture of 12.5 ml of 30 % strength hydrogen peroxide and 12.5 ml of water. After removal of the cooling, the mixture is stirred at room temperature, 1 g of palladium/carbon catalyst is added, and the mixture is stirred for 5 minutes and filtered with suction to remove catalysts. The filtrate is evaporated in vacuo, the oily residue is treated with 11 of diisopropyl ether, and the resulting solid substance is filtered off. The product is washed with diisopropyl ether and dried in vacuo.
Yield 10.31 g (88 % of theory) Melting point 141 - 146°C [aJD : +17.6* (C = 1 in methanol) +5.1* (C » 1 in water) b) Ac-Met (O?) -Glu(OtBu)-His-Phe-D-Lys(Boc)-Phe-NH(CH,) a-NH-Boc 32.1 g of H-Glu(OtBu)-His-Phe-D-Lys(Boc)-Phe-NH(CH2)8-NH-Boc · HTosOH (Example 11a of EP-A 179 332) are dissolved in 250 ml of dimethyl formamide, and .86 ml of N-ethylmorpholine, 3.44 g of 1-hydroxybenzotriazole and 5.7 g of Ac-Met(02)-OH are added and, after cooling to 0*C, 5.25 g of dicyclohexylcarbodiimide are added. The reaction mixture is stirred at room temperature for 15 hours, the precipitated dicyclohexylurea is filtered off and washed with dimethyl formamide, and the filtrate is evaporated in vacuo. The oily residue is dissolved in water-saturated n-butanol, and the solution is extracted successively with aqueous potassium bisulfate and sodium bicarbonate solution and water. The n-butanol phase is separated off and evaporated in vacuo, and the oily residue is dissolved in hot methanol. The solution is poured into 1 % strength aqueous sodium bicarbonate solution and, after stirring, the precipitated product is filtered off, washed with water and dried in vacuo.
The dried product is recrystallized five times in succession in a 416:45s413 mixture of n-heptane, n25 butanol and methanol using Dicalite as filtration aid. After the last filtration, methanol is added to the residue and, after stirring, the filtration aid is filtered off, the filtrate is distilled in vacuo, and the residue is stirred with water. The product is filtered off, washed with water and dried in vacuo.
Yield 14.5 g (44 % of theory). c) Ac-Met (0,)-Glu-His-Phe-D-Lvs-Phe-NH( CH,) a-NH,.
CH?COOH .2 g of Ac-Met(02)-Glu(OtBu)-His-Phe-D-Lys(Boc)Phe-NH-(CH2)8-Boc are dissolved in a mixture of 40.8 ml of trifluoroacetic acid and 4.5 ml of water.
The solution is stirred for 30 minutes and then distilled in vacuo. The oily residue is dissolved in water, applied to a column packed with Amberlite IRA 93 (acetate form) and eluted with water. The eluate is freeze-dried. yield 9.12 g (99.9 % of theory).
Comparison Example a) 200 mg of Ac-Met(O2)-Glu-His-Phe-D-Lys-Phe-NH(CH2)8NH2 · 2 CHgCOOH were dissolved in 20 ml of water and heated at 80°C for 8 days. Cooling was followed by freeze-drying. HPLC investigation revealed that no decomposition had taken place.
HPLC conditions: Column: Flow rate: Temperature: Detection: Mobile phase: acetonitrile/3H3P04 b) Repetition of a) with Phe-D-Lys-Phe-NH- (CH2) 8-NH2 179 332) reveals serious substrate.
Nucleosil 120 5μ C18 1.5 ml/min RT Absorption at 220 nm 800 water/100 TEA^pH 3.0 200 mg of H-Met(02)-Glu-His(Example 16 of EP-A decomposition of the
Claims (16)
1. Patent claims: 1A hexapeptide of the formula I R 1 -A 1 -A 2 -A 3 -A*-A 5 -A 6 -NH (CH 2 ) „-NH 2 (I) in which A 1 is Met, D-Met, Met(O), D-Met(O), Met(0 2 ) or D-Met (0 2 ), A 2 is Glu, D-Glu, Ala or pyroglutamyl, A 3 is His, Ala, Phe or D-Lys, A* is the residue of a neutral aliphatic or aromatic aamino acid, A 5 is D-Lys or Lys, A 6 is Phe, N-methylphenylalanine, 4-(Ci-CJ -alkoxyphenylalanine or l,2,3,4-tetrahydroisoguinoline-3carboxylic acid, R 1 is benzyloxycarbonyl, formyl, (C 2 -C 6 )-alkanoyl, (C 6 C 10 ) -aryl- (C 2 -C 4 ) -alkanoyl, (C 5 -C 7 ) -eye loalkyl- ((\-(: 2 ) alkanoyl, (C 2 -C 4 ) -alkanoyl-w-amino- (C 3 -C 4 ) -n-alkanoyl or methylsulfonyl-w-amino-(C 3 -C 4 )-n-alkanoyl and n is an integer from 4 to 10, and the physiologically tolerated salts thereof.
2. A hexapeptide as claimed in claim 1, wherein A 1 is Met(O) or Met(0 2 ) .
3. A hexapeptide as claimed in claim 1 and/or 2, wherein A* is Ala, Val, Leu, lie, Met, Ser-fCi-Cg)-alkyl, Thr-fCi-Ce)-alkyl, Cys-fCi-Cg)-alkyl, Phe, Phg or Tyr-fCiC 6 )-alkyl.
4. A hexapeptide as claimed in one or more of claims 1 to 3, wherein A 6 is Phe.
5. A hexapeptide as claimed in one or more of claims 1 to 4, wherein R 1 is formyl or (C 2 -C 6 )-alkanoyl.
6. Ac-Met (O 2 )-Glu-His-Phe-D-Lys-Phe-NH-(CH 2 ) 8 -NH 2 .
7. A process for the preparation of a hexapeptide of the formula I as claimed in any of claims 1 to 6, which comprises condensing a fragment with an N-terminal free amino group with a fragment with a C-terminal free carboxyl group, where in these fragments, when not involved in the reaction, primary and secondary amino groups are protected with urethane-type protective groups which can be eliminated with acid (such as, for example, Boc) and carboxyl groups are protected with ester-type protective groups which can be eliminated with acid (such as, for example, Bu 1 ), eliminating with acid the protective groups introduced to protect amino and carboxyl groups in the compounds obtained in this way, and converting the compounds where appropriate into their physiologically tolerated salts.
8. The use of a hexapeptide of the formula I as claimed in any of claims 1 to 6 as a medicine.
9. The use of a hexapeptide of the formula I as claimed in any of claims 1 to 6 for the treatment of cognitive dysfunctions.
10. A pharmaceutical agent containing a hexapeptide of the formula I as claimed in any of claims 1 to 6. -1311.
11.A hexapeptide of the formula (I) given and defined in claim 1, or a physiologically tolerated salt thereof, substantially as hereinbefore described and exemplified.
12. A process for the preparation of a hexapeptide of the formula (I) given and defined in claim 1, or a physiologically tolerated salt thereof, substantially as hereinbefore described and exemplified.
13. A hexapeptide of the formula (I) given and defined in claim 1, or a physiologically tolerated salt thereof, whenever prepared by a process claimed in a preceding claim.
14. Use according to claim 8, substantially as hereinbefore described.
15. Use according to claim 9, substantially as hereinbefore described.
16. A pharmaceutical agent according to claim 10, substantial ly as hereinbefore described.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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DE3931788A DE3931788A1 (en) | 1989-09-23 | 1989-09-23 | NEW CNS ACTIVE HEXAPEPTIDES WITH ANTIAMNESTIC EFFECT |
Publications (2)
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IE903420A1 true IE903420A1 (en) | 1991-04-10 |
IE66529B1 IE66529B1 (en) | 1996-01-17 |
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ID=6390039
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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IE342090A IE66529B1 (en) | 1989-09-23 | 1990-09-21 | Novel CNS-active hexapeptides with an antiamnesic effect |
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EP (1) | EP0424670B1 (en) |
JP (1) | JPH03120295A (en) |
AT (1) | ATE118786T1 (en) |
AU (1) | AU628653B2 (en) |
CA (1) | CA2025941A1 (en) |
DE (2) | DE3931788A1 (en) |
DK (1) | DK0424670T3 (en) |
ES (1) | ES2070229T3 (en) |
GR (1) | GR3015492T3 (en) |
IE (1) | IE66529B1 (en) |
PT (1) | PT95381B (en) |
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CN106608901B (en) * | 2015-10-22 | 2020-10-16 | 彭莉 | Dihydroxydimethyltetrahydroisoquinoline-3-formyl-Lys (Lys-Ala), and synthesis, activity and application thereof |
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BE758206A (en) * | 1969-10-31 | 1971-04-29 | Hoechst Ag | PEPTIDES WITH ADRENOCORTICOTROPIC ACTIVITY AND MEDICINAL PRODUCTS CONTAINING IT |
DE1965102A1 (en) * | 1969-12-27 | 1971-07-01 | Hoechst Ag | Tridecapeptides with adrenocorticotropic - activity |
US4623715A (en) * | 1984-10-22 | 1986-11-18 | Hoechst Aktiengeselleschaft | Novel peptides which are active on the central nervous system and have an action on the cholinergic system |
-
1989
- 1989-09-23 DE DE3931788A patent/DE3931788A1/en not_active Withdrawn
-
1990
- 1990-09-20 ES ES90118102T patent/ES2070229T3/en not_active Expired - Lifetime
- 1990-09-20 DE DE59008515T patent/DE59008515D1/en not_active Expired - Fee Related
- 1990-09-20 DK DK90118102.4T patent/DK0424670T3/en active
- 1990-09-20 AT AT90118102T patent/ATE118786T1/en not_active IP Right Cessation
- 1990-09-20 EP EP90118102A patent/EP0424670B1/en not_active Expired - Lifetime
- 1990-09-21 CA CA002025941A patent/CA2025941A1/en not_active Abandoned
- 1990-09-21 AU AU63064/90A patent/AU628653B2/en not_active Ceased
- 1990-09-21 PT PT95381A patent/PT95381B/en not_active IP Right Cessation
- 1990-09-21 IE IE342090A patent/IE66529B1/en not_active IP Right Cessation
- 1990-09-21 JP JP2250423A patent/JPH03120295A/en active Pending
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1995
- 1995-03-20 GR GR950400623T patent/GR3015492T3/en unknown
Also Published As
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JPH03120295A (en) | 1991-05-22 |
EP0424670B1 (en) | 1995-02-22 |
DE59008515D1 (en) | 1995-03-30 |
CA2025941A1 (en) | 1991-03-24 |
AU6306490A (en) | 1991-03-28 |
PT95381A (en) | 1991-05-22 |
ATE118786T1 (en) | 1995-03-15 |
GR3015492T3 (en) | 1995-06-30 |
PT95381B (en) | 1997-07-31 |
DK0424670T3 (en) | 1995-07-17 |
ES2070229T3 (en) | 1995-06-01 |
AU628653B2 (en) | 1992-09-17 |
DE3931788A1 (en) | 1991-04-04 |
IE66529B1 (en) | 1996-01-17 |
EP0424670A1 (en) | 1991-05-02 |
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