WO1999019329A1 - A process for the preparation of aminocarbonyl derivatives of geneseroline having selective brain anticholinesterase activity - Google Patents
A process for the preparation of aminocarbonyl derivatives of geneseroline having selective brain anticholinesterase activity Download PDFInfo
- Publication number
- WO1999019329A1 WO1999019329A1 PCT/EP1998/006377 EP9806377W WO9919329A1 WO 1999019329 A1 WO1999019329 A1 WO 1999019329A1 EP 9806377 W EP9806377 W EP 9806377W WO 9919329 A1 WO9919329 A1 WO 9919329A1
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- Prior art keywords
- formula
- compounds
- geneseroline
- hydrolysis
- group
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- OPAXVHIAQIXNAM-OLZOCXBDSA-N C[C@]12c3cc(O)ccc3N(C)[C@@H]1ON(C)CC2 Chemical compound C[C@]12c3cc(O)ccc3N(C)[C@@H]1ON(C)CC2 OPAXVHIAQIXNAM-OLZOCXBDSA-N 0.000 description 1
- 0 C[C@]12c3cc(OC(*)=O)ccc3N(C)C1ON(C)CC2 Chemical compound C[C@]12c3cc(OC(*)=O)ccc3N(C)C1ON(C)CC2 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
-
- 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
- A61P25/28—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
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the present invention relates to a process for the preparation of structural analogues of geneseroline, in particular to aminocarbonyl derivatives of geneseroline of formula (I):
- R is C 2 -C 20 linear or branched alkyl, C 3 -C 7 cycloalkyi, phenyl or benzyl, which can optionally be substituted by C C 4 alkyl, halogen or C,-C 4 alkoxy group.
- Oxidation of eseroline derivatives to the corresponding geneseroline derivatives is carried out by using peracids or organic peroxides, such as m- chloroperbenzoic, monoperphthalic, peracetic acid, hydrogen peroxide, in inert solvents, such as halogenated hydrocarbons, aromatic hydrocarbons, dimethylformamide, dimethylsulfoxide.
- peracids or organic peroxides such as m- chloroperbenzoic, monoperphthalic, peracetic acid, hydrogen peroxide
- inert solvents such as halogenated hydrocarbons, aromatic hydrocarbons, dimethylformamide, dimethylsulfoxide.
- the compounds of formula (I) have been prepared starting from geneseroline through hydrolysis of the methylaminocarbonyloxy group, and subsequent acylation, carried out by always using N-alkylimidazoleurea.
- Geneseroline is a well-known compound (Yu Q.S. et al. Journal of Natural
- the compounds of formula (I) can be prepared starting from eserine, according the following reaction scheme n.1 , obtaining good yields, a good purity grade of the final product and improvement of reaction times.
- the above disclosed process comprising oxidation of eserine, followed by hydrolysis to geneseroline, without isolating the intermediate geneserine, allows a significant increase of the yields, maintaining a good purity of the final product.
- Acylation reaction is carried out by using isocyanates according to classical methods, with a suitable basic catalyst, selected among alkali alcoholates, carbonates or hydroxides, such as potassium tert-butylate or potassium carbonate, the latter being particularly preferred for the application to industrial productions.
- a suitable basic catalyst selected among alkali alcoholates, carbonates or hydroxides, such as potassium tert-butylate or potassium carbonate, the latter being particularly preferred for the application to industrial productions.
- the reaction may be carried out in the presence of small amounts of a phase transfer catalyst, such as tetrabutylammonium bromide, or using an ultrasound source.
- a phase transfer catalyst such as tetrabutylammonium bromide, or using an ultrasound source.
- R is a protective group for phenolic hydroxyl, which must be stable in a basic environment and under strong reducing reaction conditions and can be removed in acidic conditions without reducing the geneserine-like N- oxide group.
- R-, group are ethyl, tert-butyl, methoxymethyl, methoxyethoxy methyl, n-propyl, isopropyl, tetrahydropyranyl.
- said process comprises: a) oxidation of a compound of formula (II) with peracids or peroxides, preferably hydrogen peroxide, in an alcoholic solvent or in a water- alcohol mixture to give a compound of formula (III);
- said process comprises: a) hydrolysis with a mineral or an organic acid of a compound of formula
- Ri is a protective group for the phenolic hydroxyl, which must be stable in a basic environment and under strong reducing reaction conditions and can be removed in acidic conditions, such as for example ethyl, tert- butyl, methoxymethyl, methoxyethoxymethyl, n-propyl, isopropyl, tetrahydropyranyl; to give eseroline (Ha)
- Eseretole is one of the ethers that can be used in this invention and is commercially available at low cost and suitable quantities.
- Ri is tert-butyl, methoxymethyl, methoxyethoxymethyl, n-propyl, isopropyl, tetrahydropyranyl.
- ethers may be prepared according to methods available in the literature.
- Compounds (II) and (III) are within the scope of the present invention as intermediates in the process above disclosed.
- the embodiments of the present invention according to the reaction schemes 2 and 3 are characterised by the step comprising the hydrolysis of eseroline ethers of formula (II) or geneseroline ethers of formula (III) to eseroline or geneseroline, respectively.
- a particular aspect of the present invention relates to the use of a mineral or organic acid for the hydrolysis of alkyl ethers of indole derivatives, such as for example eseroline, geneseroline or physovenol.
- Suitable acids for the hydrolysis of compounds (II) or (III) are those having non-reducing properties, in particular with respect to compounds of formula (III), wherein the N-O group is sensitive to reducing agents.
- the acid is preferably selected from the group consisting of: sulfuric acid, phosphoric acid, hydrochloric acid, methanesulfonic acid, trifluoroacetic acid, acetic acid, a strongly acidic ion-exchange resin, such as Amberlyst ® Hydrolysis conditions will be selected according to the R group present in the molecule, in particular the choice will be made on the kind of acid, its concentration and hydrolysis temperature.
- Sulfuric acid can be used at different concentrations from 10 to 85%, preferably at a temperature ranging from 50 to 90°C.
- Phosphoric acid is generally used at the concentration of 85%, hot, preferably at a temperature of about 90°C.
- Methanesulfonic acid is used as such and is made to react hot, preferably at a temperature of about 90°C.
- Trifluoroacetic acid as such and 10% hydrochloric acid can be made to react warm at a temperature of about 40°C.
- the process according to the present invention allows for the first time and contrarily to the process disclosed in EP 0599890 to prepare in industrial scale compounds of formula (I), in particular wherein R is an aromatic group, preferably phenyl and benzyl, optionally substituted by d- C 4 alkyl, halogen or C ⁇ -C 4 alkoxy.
- European patent 0599890 relates to aminocarbonyl derivatives of geneseroline of formula (I):
- R is C 2 -C 2 o linear or branched alkyl, C 3 -C 7 cycloalkyi, phenyl or benzyl, which can optionally be substituted by C ⁇ -C 4 alkyl, halogen or C ⁇ -C 4 alkoxy group.
- n-heptylaminocarbonylgeneseroline named also CHF 2060
- CHF 2060 n-heptylaminocarbonylgeneseroline
- Symptomatic therapy of senile dementia associated to Alzheimer disease can be done with substances having anticholinesterase activity, with the purpose to raise acetylcholine brain levels and restore cholinergic neurons functionality.
- Tacrine was the first compound endowed with these properties to come into clinical practice (Cognex; Davis K.L. et al., N. Eng. J. Med., 327: 1253-1259, 1993).
- SDZ-ENA 713 (commercial name Exelon), described in Enz A. et al. Progress in Brain Res. 98, 431-438, 1993, can be considered one of the selective anticholinesterase substances. This compound has been used by the applicant as comparison in some studies. It has now been found that compounds of formula (la)
- R is phenyl or benzyl group, which can optionally be substituted by C ⁇ -C 4 alkyl, halogen or C ⁇ -C 4 alkoxy group are endowed with better pharmacological properties than the compounds of formula (I) wherein R is C 2 -C 2 o linear or branched alkyl, C 3 -C cycloalkyi, in particular n-heptyl. Accordingly, the present invention further relates to compounds of formula (la) as new compounds when used as medicaments.
- Still another object of the present invention is a pharmaceutical composition containing a therapeutically effective amount of at least a compound of formula (la).
- the use of said compounds as active ingredient for the manufacture of a medicament is also within the scope of the present invention.
- examples of phenyl or benzyl group substituted with C ⁇ -C 4 alkyl group are 2- methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methylbenzyl, 3- methylbenzyl, 4-methylbenzyl, 2-ethylphenyl, 3-ethyiphenyl, 4-ethylphenyl, 2-ethylbenzyl, 3-ethylbenzyl, 4-ethylbenzyl, 2-propylphenyl, 3-propylphenyl, 4-propylphenyl, 2-propylbenzyl, 3-propylbenzyl, 4-propylphenyl, 2-propylbenzyl, 3-propylbenzyl, 4-propylbenzyl, 2- butylphenyl, 3-butylphenyl, 4-butylphenyl, 2-butylbenzyl, 3-butylbenzyl, 4- butylbenzyl, being intended that the terms propyl and butyl comprise both linear and
- phenyl or benzyl group substituted with halogen atoms examples include 2-chlorophenyl, 3-chlorophenyl, 4- chlorophenyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2- bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-bromobenzyl, 3- bromobenzyl, 4-bromobenzyl, 2-iodiophenyl, 3-iodiophenyl, 4-iodiophenyl, 2- iodiobenzyl, 3-iodiobenzyl, 4-iodiobenzyl.
- phenyl or benzyl group substituted with C ⁇ -C 4 alkoxy group examples include 2-methoxyphenyl, 3- methoxyphenyl, 4-methoxyphenyl, 2-methoxybenz l, 3-methoxybenzyl, 4- methoxybenzyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 2- ethoxybenzyl, 3-ethoxybenzyl, 4-ethoxybenzyl, 2-propoxyphenyl, 3- propoxyphenyl, 4-propoxyphenyl, 2-propoxybenzyl, 3-propoxybenzyl, 4- propoxybenzyl, 2-butoxyphenyl, 3-butoxyphenyl, 4-butoxyphenyl, 2- butoxybenzyl, 3-butoxybenzyl, 4-butoxybenzyl, being intended that the terms propoxy and butoxy comprise both linear and branched isomers.
- Preferred compound according to the present invention are those in which R is selected from the group consisting of: 2-ethy
- aminocarbonyl derivatives of geneseroline of formula (la) show a higher inhibition potency for brain acetylcholinesterase (AChE) with respect to the derivatives substituted with an alkyl residue at the same position, such as disclosed in the above cited European patent and in particular to n-heptylgeneseroline.
- the potency increase observed occurs at the same efficacy of enzymatic inhibition.
- the compounds of formula (la) evidenced not only a higher potency, but also a higher selectivity of enzymatic inhibition.
- Methanol was evaporated at reduced pressure, warming at a maximum temperature of 35°C during about 10 min.
- the aqueous phase was extracted three times with 150 ml of chloroform and the organic phases were evaporated at reduced pressure giving the crude geneserine as a foaming oily residue.
- the crude residue was dissolved in 100 ml of 62 % (w/w) sulfuric acid and the solution was quickly heated to 85°C under a gentle flow of nitrogen. Heating was continued for 2 hours and an HPLC analysis showed a geneserine content lower than 1 %.
- the mixture was cooled at r.t. and poured into 100 g of ice.
- Ammonium hydroxide 30 % w/w in water, (120 ml) was added dropwise with stirring, while the reaction temperature was controlled below 20-25°C with a water bath. When pH was 4, then 250 ml of ethyl acetate were added. When the aqueous phase was almost neutral, a tar residue started to separate.
- the aqueous phase was further extracted twice with 200 ml of ethyl acetate, the organic phases were combined, washed with 20% w/v sodium chloride solution (200 ml), dried over sodium sulfate, filtered and evaporated at reduced pressure. The residue was triturated in hexane (200 ml), about 100 ml of solvent were evaporated at reduced pressure and the obtained suspension was cooled at 5°C and filtered.
- Eseretole (92.5 g, 0.377 mol) was dissolved in methanol (185 ml), then potassium bicarbonate (37.7 g, 0.377 mol) was added and the mixture was stirred for 10 minutes. Afterwards, during about 10 minutes, 40% w/v hydrogen peroxide (48 ml, 0.566 mol) and 5 ml of water were added, while cooling the flask in a water bath.
- the geneseretole conversion was followed through HPLC analysis and reaction was stopped after 3 hours when residual geneseretole content was about 3%.
- the mixture was cooled with an ice bath and poured into ice (800 g) under stirring.
- the aqueous phase was extracted with further ethyl acetate (500 + 500 ml) and the organic phases were joined, washed with 20% w/v sodium chloride solution (500 ml), dried over anhydrous sodium sulfate and filtered.
- the solution was concentrated in a rotary evaporator and when solid product began to precipitate, 600 ml of n-heptane were added in two successive portions and evaporation was continued until residual solvent volume was about 200 ml, in order to completely strip ethyl acetate.
- geneseroline ethers of formula (III) were subjected to hydrolysis.
- MOM methoxymethyl
- MEM methoxyethoxymethyl
- MES methanesulfonic acid
- TFA trifluoroacetic acid
- THP tetrahydropyranyl
- AcOH acetic acid
- eseroline ethers of formula (II) can be subjected to hydrolysis with similar procedures to give eseroline. Once eseroline is obtained, geneseroline derivatives of formula (I) can be obtained according to examples 1 and 6 of the European patent 0599890.
- heptylisocyanate 48 g was dropped quickly, in 3-5 minutes. A slight heat development was observed and temperature raised to 47°C.
- reaction mixture was stirred for 3 hours, then 1 g of tetrabutylammonium bromide was added; a further addition of heptylisocyanate (4.3 g) reduced geneseroline content below 2%.
- reaction mixture was cooled, filtered through a celite pad and the clear solution was evaporated at reduced pressure.
- n-heptylaminocarbonylgeneseroline was filtered, washed with hexane and dried at 50°C under vacuum obtaining 102.7 g of crude product.
- the crude was suspended in 820 ml of water at room temperature for 30 min. with vigorous stirring, then filtered, washed with hexane and dried at 60°C at reduced pressure to give 98.6 g (84.5%) of n- heptylaminocarbonylgeneseroline were obtained.
- N-heptylaminocarbonylgeneseroline hydrochloride N-heptylaminocarbonylgeneseroline (34.8 g, 0.093 mol) was dissolved in ethyl acetate (100 ml) at 40°C, then a solution of 22.5 ml of HCI 4.25 M in ethyl acetate diluted to 40 ml with the same solvent was dropped in. The solution was slowly cooled to 5°C, the product precipitated as a white solid that was filtered and dried at 60°C at reduced pressure yielding 33.0 g of crude product.
- n-(2-ethylphenyl)aminocarbonylgeneseroline hydrochloride can be obtained according to the method of the following example.
- compounds CHF 2819, CHF 2957, CHF 2822 were evaluated for their enzymatic inhibition potency and selectivity of action through a series of parameters in comparison with n-heptylaminocarbonylgeneseroline hydrochloride (CHF2060).
- mice Male SD rats weighing 150-200 g were split into groups of 8 animals each, depending on the treatment with the different substances, which were orally administered in distilled water, at a volume of 2 ml/kg. After 2 hours from the administration, the animals were sacrificed as to take their brains. Brain tissue was homogenized in a 11 % Triton 100 solution in 0J M phosphate buffer at pH 8. After 15 minutes centrifugation, at 4°C, the supernatant was separated and AChE was determined on it with the method described by Ellman G.L. et al. (Biochem Pharmacol. 7, 88-95, 1961 ). For each treatment enzyme inhibition percent was determined against controls (animals treated with distilled water only).
- CHF 2060, physostigmine and SDZ-ENA 713 are definitely more potent in inhibiting BuChE, rather than AChE.
- compound CHF 2819 resulted to be 115 times more selective on AChE.
- CHF 2957 has a good selectivity, whereas CHF
- BuChE is mainly distributed in the peripheral tissue and, to a less extent, in the brain at the level of microglia.
- the compounds of formula (la) are useful for the preparation of a medicament having inhibiting activity of acetylcholinesterase.
- CHF 2819 is characterised, with respect to the other compounds herein taken into consideration, for a favourable "in vitro" selectivity on AChE with respect to BuChE, a good duration of action and an "in vivo" selectivity in inhibiting brain AChE.
- said medicament is useful for the treatment of Alzheimer disease and other neurodegenerative pathologies.
- this medicament is devoid of peripheral side effects and this feature is claimed in the present invention.
- the medicament shall be formulated in forms and dosages that can be determined by the clinical expert in the field, depending on the kind of pathology, its severity and patient conditions.
- the present invention also provides pharmaceutical compositions comprising a therapeutically effective amount of active ingredient in admixture with carriers and excipients conventional in the pharmaceutical field.
- compositions can be prepared with well known techniques, for example as described in "Remington's Pharmaceutical Sciences Handbook", Mack Pub., New York, U.S.A.
- compositions are oral forms, solid or liquid, such as tablets, capsules, solutions, suspensions, syrups; injectable forms, such as solutions, suspensions , emulsions; controlled release formulations.
- the daily does of active ingredient to be administered with these compositions will range from 1 to 50 mg and preferably from 5 to 20 mg.
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Abstract
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Priority Applications (11)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US09/319,693 US6297237B1 (en) | 1997-10-10 | 1998-10-07 | Process for the preparation of aminocarbonyl derivatives of geneseroline having selective brain anticholinesterase activity |
HU0003747A HUP0003747A3 (en) | 1997-10-10 | 1998-10-07 | A process for the preparation of aminocarbonyl derivatives of geneseroline having selective brain anticholinesterase activity |
NZ503773A NZ503773A (en) | 1997-10-10 | 1998-10-07 | A process for the preparation of aminocarbonyl derivatives of geneseroline having selective brain anticholinesterase activity |
KR1020007003805A KR20010015714A (en) | 1997-10-10 | 1998-10-07 | A Process for the Preparation of Aminocarbonyl Derivatives of Geneseroline Having Selective Brain Anticholinesterase Activity |
SK503-2000A SK5032000A3 (en) | 1997-10-10 | 1998-10-07 | A process for the preparation of aminocarbonyl derivatives of geneseroline having selective brain anticholinesterase activity, pharmaceutical composition containing the same, use thereof and intermediates |
AU11516/99A AU750964B2 (en) | 1997-10-10 | 1998-10-07 | A process for the preparation of aminocarbonyl derivatives of geneseroline having selective brain anticholinesterase activity |
BR9815237-8A BR9815237A (en) | 1997-10-10 | 1998-10-07 | Process for preparing aminocarbonyl derivatives of geneseroline that have selective anticholinesterase activity in the brain |
CA002274658A CA2274658A1 (en) | 1997-10-10 | 1998-10-07 | A process for the preparation of aminocarbonyl derivatives of geneseroline having selective brain anticholinesterase activity |
EP98954370A EP1023297A1 (en) | 1997-10-10 | 1998-10-07 | A process for the preparation of aminocarbonyl derivatives of geneseroline having selective brain anticholinesterase activity |
EA200000300A EA003192B1 (en) | 1997-10-10 | 1998-10-07 | A process for the preparation of aminocarbonyl derivatives of geneseroline having selective brain anticholinesterase activity |
IL13539998A IL135399A0 (en) | 1997-10-10 | 1998-10-07 | A process for the preparation of aminocarbonyl derivatives of geneseroline having selective brain anticholinesterase activity |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IT002299 IT1295309B1 (en) | 1997-10-10 | 1997-10-10 | Preparation of new and known aminocarbonyl geneseroline derivatives - for use as acetylcholinesterase inhibitors |
ITMI97A02300 | 1997-10-10 | ||
ITMI97A002299 | 1997-10-10 | ||
IT002300 IT1295310B1 (en) | 1997-10-10 | 1997-10-10 | Preparation of new and known aminocarbonyl geneseroline derivatives - for use as acetylcholinesterase inhibitors |
Publications (1)
Publication Number | Publication Date |
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WO1999019329A1 true WO1999019329A1 (en) | 1999-04-22 |
Family
ID=26331547
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP1998/006377 WO1999019329A1 (en) | 1997-10-10 | 1998-10-07 | A process for the preparation of aminocarbonyl derivatives of geneseroline having selective brain anticholinesterase activity |
Country Status (17)
Country | Link |
---|---|
US (1) | US6297237B1 (en) |
EP (1) | EP1023297A1 (en) |
KR (1) | KR20010015714A (en) |
CN (1) | CN1278264A (en) |
AR (1) | AR018511A1 (en) |
AU (1) | AU750964B2 (en) |
BR (1) | BR9815237A (en) |
CA (1) | CA2274658A1 (en) |
EA (1) | EA003192B1 (en) |
HU (1) | HUP0003747A3 (en) |
IL (1) | IL135399A0 (en) |
NZ (1) | NZ503773A (en) |
PL (1) | PL339761A1 (en) |
SK (1) | SK5032000A3 (en) |
TR (1) | TR200000951T2 (en) |
TW (1) | TW490467B (en) |
WO (1) | WO1999019329A1 (en) |
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DE2839279A1 (en) * | 1977-09-20 | 1979-03-29 | Univ Firenze | DERIVATIVES OF 1,2,3,3A, 8,8A-HEXAHYDROPYRROLO SQUARE CLAMP ON 2,3-ANGLE BRACKET TO INDOLS, THE PROCESS FOR THEIR MANUFACTURING AND MEDICINAL PRODUCTS CONTAINED |
EP0253372A2 (en) * | 1986-07-16 | 1988-01-20 | Hoechst-Roussel Pharmaceuticals Incorporated | 1,2,3,3a,8,8a-Hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indoles, a process for their preparation and their use as medicaments |
WO1993003041A1 (en) * | 1991-08-09 | 1993-02-18 | Chiesi Farmaceutici S.P.A. | Geneserine derivatives as cholinesterase inhibitors |
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-
1998
- 1998-10-07 WO PCT/EP1998/006377 patent/WO1999019329A1/en not_active Application Discontinuation
- 1998-10-07 HU HU0003747A patent/HUP0003747A3/en unknown
- 1998-10-07 EP EP98954370A patent/EP1023297A1/en not_active Withdrawn
- 1998-10-07 BR BR9815237-8A patent/BR9815237A/en not_active IP Right Cessation
- 1998-10-07 KR KR1020007003805A patent/KR20010015714A/en not_active Application Discontinuation
- 1998-10-07 CA CA002274658A patent/CA2274658A1/en not_active Abandoned
- 1998-10-07 CN CN98810683A patent/CN1278264A/en active Pending
- 1998-10-07 SK SK503-2000A patent/SK5032000A3/en unknown
- 1998-10-07 AU AU11516/99A patent/AU750964B2/en not_active Ceased
- 1998-10-07 IL IL13539998A patent/IL135399A0/en unknown
- 1998-10-07 TR TR2000/00951T patent/TR200000951T2/en unknown
- 1998-10-07 US US09/319,693 patent/US6297237B1/en not_active Expired - Fee Related
- 1998-10-07 EA EA200000300A patent/EA003192B1/en not_active IP Right Cessation
- 1998-10-07 NZ NZ503773A patent/NZ503773A/en unknown
- 1998-10-07 PL PL98339761A patent/PL339761A1/en unknown
- 1998-10-09 AR ARP980105062A patent/AR018511A1/en unknown
- 1998-10-23 TW TW087117571A patent/TW490467B/en active
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HUP0003747A2 (en) | 2001-10-28 |
TR200000951T2 (en) | 2000-07-21 |
NZ503773A (en) | 2002-05-31 |
EA003192B1 (en) | 2003-02-27 |
AU750964B2 (en) | 2002-08-01 |
CN1278264A (en) | 2000-12-27 |
EA200000300A1 (en) | 2000-12-25 |
SK5032000A3 (en) | 2000-10-09 |
PL339761A1 (en) | 2001-01-02 |
IL135399A0 (en) | 2001-05-20 |
US6297237B1 (en) | 2001-10-02 |
EP1023297A1 (en) | 2000-08-02 |
BR9815237A (en) | 2000-10-31 |
CA2274658A1 (en) | 1999-04-22 |
AR018511A1 (en) | 2001-11-28 |
KR20010015714A (en) | 2001-02-26 |
AU1151699A (en) | 1999-05-03 |
HUP0003747A3 (en) | 2001-12-28 |
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