EP1000056A1 - 6-pyrrolidin-2-yl-pyridin derivate, ihre herstellung und therapeutische verwendung - Google Patents
6-pyrrolidin-2-yl-pyridin derivate, ihre herstellung und therapeutische verwendungInfo
- Publication number
- EP1000056A1 EP1000056A1 EP98936453A EP98936453A EP1000056A1 EP 1000056 A1 EP1000056 A1 EP 1000056A1 EP 98936453 A EP98936453 A EP 98936453A EP 98936453 A EP98936453 A EP 98936453A EP 1000056 A1 EP1000056 A1 EP 1000056A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- dihydro
- mixture
- pyrindine
- mmol
- pyrrolidin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- 6-pyrrolidin-2-ylpyrindine derivatives their preparation and their therapeutic use.
- R ⁇ represents a hydrogen atom, a (C- L -C ⁇ ) alkyl group or a phenyl (C 1 -C 4 ) alkyl group optionally substituted
- R 2 represents a hydrogen atom or a group (C 1 - C 4 ) alkyl
- R 3 , R 4 and R 5 each represent, independently of one another, a hydrogen or halogen atom or a trifluoromethyl, cyano, hydroxy, (C ⁇ -Cg) alkyl or (C 1 - C 6 ) alkoxy.
- R 2 represents a hydrogen atom
- the molecules of general formula (I) have two asymmetric carbon atoms, namely the carbon atom in position 6 and the carbon atom of the pyrrolidine ring to which it is linked; for the same combination of substituents R 1 # R 3 , R 4 and R 5 , the compounds of the invention can therefore exist in the form of 4 different isomers.
- the compounds of the invention may also exist in the form of bases or of addition salts with acids.
- the compounds of general formula (I) can be prepared according to a process illustrated by the scheme which follows.
- a derivative of general formula (II) is reacted, in which X represents a halogen atom and R 2 , R 3 , R and R 5 are as defined above, with diethyl propanedioate in basic medium to obtain , by bis-alkylation, a cyclized diester of general formula (III), which is saponified under acidic, or optionally basic, conditions to the acid of general formula (IV) in which Y represents a hydroxy group; this acid can be transformed into an ester of general formula (IV) in which Y represents an alkoxy group, or alternatively into an einreb amide of general formula (IV) in which Y represents a (N-alkoxy) alkylamino group.
- the derivative of general formula (IV) is then treated either according to the method described in Tetrah. Lett. (1984) 25 (46) 5271, or according to the method described in J. Med. Chem. (1997) 39 3235.
- the derivative of general formula (IV) is reacted with the organomagnesium derived from 3-bromopropanamine, the amino function of which is protected by a silylated function, then this function is hydrolyzed in an acid medium;
- the derivative of general formula (IV) is reacted with N-vinylpyrrolidin-2 - one under basic conditions to form an intermediate which is hydrolyzed in an acid medium.
- An imine of general formula (V) is obtained which is reduced to the derivative of general formula (VI) by an agent such as sodium borohydride or sodium cyanoborohydride in an appropriate solvent.
- the cis and trans stereoisomers formed during this step can be separated by chromatography into more polar isomers and less polar isomers.
- a cis or trans stereoisomer of general formula (VI) with a chiral substrate, for example an S-proline derivative under the coupling conditions.
- peptide for example in the presence of dicyclohexylcarbodiimide, to obtain a derivative of general formula (I), in which R ⁇ represents a prolinyl group, in the form of a mixture of diastereoisomers which can be separated by chromatography.
- the enantiomers are then obtained by treating each of the diastereoisomers in an acid medium.
- the nitrogen of the pyrrolidine ring is alkylated by any known method, for example a reductive methylation according to the Eschweiler-Clarck method (formaldehyde and formic acid), or by reductive amination in the presence of an aldehyde and sodium cyanoborohydride, or alternatively by acylation, to form an amide, which is reduced to amine, by means of an agent such as double hydride lithium and aluminum.
- R 2 , R 3 , R and R 5 cannot be present in the starting compound of general formula (II); depending on their nature, these substituents can be introduced into one and / or the other of the compounds of general formula (III), (IV), (V), (VI) and (I), in which R 2 , R 3 , R 4 and / or R 5 represent hydrogen atoms, according to all known methods, for example that described in J " . Het. Chem. (1996) 33 1051-1056, optionally after activation of nitrogen from the pyridine ring by formation of the corresponding Itf-oxide.
- Example 1 (Compounds No. 1 and 2). (2: 1) hydrochlorides of isomers of (+/-) -6-pyrrolidin-2-yl- 6,7-dihydro-5H-1-pyrindine.
- the medium is concentrated under reduced pressure and the residue is dried in the presence of phosphorus pentoxide. 5.1 g of product are thus obtained in the form of an amorphous solid.
- the hydrochloride (2: 1) is obtained by usual treatment of the base with hydrochloric acid in ethanol. Melting point: 204-205 ° C. 4.3 Isomers of (+/-) -6-pyrrolidin-2-yl-6, 7-dihydro-5H-1-pyrindine.
- the isomers obtained (A and B) are separated by chromatography on silica gel, eluting with a 90/10/1 mixture of chloroform, methanol and ammonia. This gives 6.6 g of the least polar isomer (isomer A) and 3.45 g of the most polar isomer (isomer B).
- the reaction medium is concentrated under reduced pressure, the residue is taken up in 200 ml of ice water and basified by adding a concentrated solution of aqueous sodium hydroxide. Chloroform is extracted, the chloroform extracts are dried and evaporated. The products are obtained as a mixture of diastereoisomers which are separated by chromatography on silica gel, eluting with a 90/10/1 mixture of chloroform, methanol and ammonia. 2.86 g of the least polar diastereoisomer are thus obtained in the form of a thick oil,
- the solution is cooled to room temperature and l alkalizes by adding a concentrated sodium hydroxide solution. Extraction with chloroform is dried and the extracts are evaporated under reduced pressure. The residue is purified by chromatography on silica gel, eluting with a 90/10/1 mixture of chloroform, methanol and ammonia. The purified product is treated with two equivalents of hydrochloric acid in ethanol. 1.8 g of product are thus obtained in the form of the hydrochloride.
- step 4.3 From the isomer B obtained in step 4.3, and operating according to the method described in step 4.4, the desired compounds are obtained.
- the product is salified with hydrobromic acid and the hydrobromide is recrystallized from a mixture of ethanol and propan-2-ol. 0.305 g of compound is obtained.
- the homogeneous biphasic mixture is stirred and 2.04 g (9.86 mmol) of ruthenium chloride is added.
- reaction is exothermic and causes the carbon tetra_chloride to reflux for more than one hour.
- the mixture is allowed to return to room temperature and allowed to stand overnight.
- the mixture is filtered on paper, the aqueous phase is separated by decantation, it is extracted several times with ethyl acetate and the organic phases are combined. After washing with water, drying over sodium sulfate and evaporation of the solvent under reduced pressure, 59.78 g of compound are isolated.
- Example 11 (Compound No. 17 and 18). (2: 1) hydrobromide (+/-) -2-methoxy-6-pyrrolidin-2-yl-6, 7-dihydro-5H-1-pyrindine.
- a saturated aqueous solution of sodium sulphate is added, cooling the mixture to 4 ° C. until the end of gas evolution, and stirring is continued cold for 1 h 30 min.
- the mixture is filtered by rinsing the solid with methanol, and the solvents are evaporated off under reduced pressure.
- the compounds of the invention have been the subject of tests which have demonstrated their therapeutic properties.
- the tissue is thawed slowly and suspended in 3 volumes of buffer. 150 ⁇ l of this membrane suspension are incubated at 4 ° C. for 120 min in the presence of 100 ⁇ l of [ 3 H] 1 nM cytisine in a final volume of 500 ⁇ l of buffer, in the presence or absence of the compound to be tested.
- the reaction is stopped by filtration through Whatman GF / B TM filters previously treated with polyethyleneimine, the filters are rinsed with twice 5 ml of buffer at 4 ° C., and the radioactivity retained on the filter is measured by liquid scintigraphy.
- the non-specific binding is determined in the presence of (-) -nicotine at 10 ⁇ M; non-specific binding represents 75 to 85% of the total binding recovered on the filter.
- the percentage of inhibition of the specific binding of [ 3 H] cytisine is determined, then the IC 50 , the concentration of compound which inhibits 50% of the specific binding, is calculated.
- the IC 50 values of the compounds of the invention are between 0.001 and 1 ⁇ M.
- the results of biological tests carried out on the compounds of the invention show that they are powerful and selective cholinergic ligands for nicotinic receptors.
- these disorders include cognitive alterations, more specifically memory impairment, but also attentional, linked to Alzheimer's disease, to pathological aging (Age Associated Memory Impairment, AAMI), to Parkinson's syndrome, to trisomy 21 ( Do n's syndrome), alcoholic Korsakoff syndrome, vascular dementia (multi-infarct dementia, MID).
- AAMI Alzheimer's disease
- AAMI pathological aging
- Parkinson's syndrome to trisomy 21
- Do n's syndrome alcoholic Korsakoff syndrome
- vascular dementia multi-infarct dementia
- MID multi-infarct dementia
- the compounds of the invention can also constitute a curative or symptomatic treatment of cerebrovascular accidents and cerebral hypoxic episodes. They can be used in cases of psychiatric pathologies: schizophrenia, depression, anxiety, panic attacks, compulsive and obsessive behaviors.
- the invention may be useful in the treatment of Crohn's disease, ulcerative colitis, irritable bowel syndrome and obesity.
- the compounds of the invention can be presented in any form of composition suitable for enteral, parenteral or transdermal administration, such as tablets, dragees, capsules, capsules, suspensions or oral or injectable solutions such as syrups or ampoules, transdermal patches ("patch"), etc., associated with suitable excipients, and dosed to allow daily administration of 0.01 to 20 mg / kg.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Psychiatry (AREA)
- Epidemiology (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Diabetes (AREA)
- Psychology (AREA)
- Addiction (AREA)
- Hospice & Palliative Care (AREA)
- Pain & Pain Management (AREA)
- Child & Adolescent Psychology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR9708706 | 1997-07-09 | ||
FR9708706A FR2765874B1 (fr) | 1997-07-09 | 1997-07-09 | Derives de 6-pyrrolidin-2-ylpyrindines, leur preparation et leur application en therapeutique |
PCT/FR1998/001446 WO1999002517A1 (fr) | 1997-07-09 | 1998-07-07 | Derives de 6-pyrrolidin-2-ylpyrindines, leur preparation et leur application en therapeutique |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1000056A1 true EP1000056A1 (de) | 2000-05-17 |
Family
ID=9509040
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP98936453A Withdrawn EP1000056A1 (de) | 1997-07-09 | 1998-07-07 | 6-pyrrolidin-2-yl-pyridin derivate, ihre herstellung und therapeutische verwendung |
Country Status (21)
Country | Link |
---|---|
US (1) | US6184229B1 (de) |
EP (1) | EP1000056A1 (de) |
JP (1) | JP2002508004A (de) |
KR (1) | KR20010021617A (de) |
CN (1) | CN1262680A (de) |
AR (1) | AR013192A1 (de) |
AU (1) | AU8544498A (de) |
BG (1) | BG104037A (de) |
BR (1) | BR9811672A (de) |
CA (1) | CA2295666A1 (de) |
CO (1) | CO4890850A1 (de) |
EE (1) | EE200000018A (de) |
FR (1) | FR2765874B1 (de) |
HU (1) | HUP0003856A2 (de) |
IL (1) | IL133536A0 (de) |
NO (1) | NO20000066L (de) |
PL (1) | PL338123A1 (de) |
SK (1) | SK212000A3 (de) |
TR (1) | TR200000057T2 (de) |
WO (1) | WO1999002517A1 (de) |
ZA (1) | ZA986047B (de) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2005126340A (ja) * | 2003-10-22 | 2005-05-19 | Kureha Chem Ind Co Ltd | 置換ピリドン類の製造法、その原料化合物及びその製造方法 |
WO2006031856A2 (en) | 2004-09-13 | 2006-03-23 | Chrono Therapeutics, Inc. | Biosynchronous transdermal drug delivery |
AU2008232453B8 (en) | 2007-04-02 | 2011-07-21 | Parkinson's Institute | Methods and compositions for reduction of side effects of therapeutic treatments |
WO2016123406A1 (en) | 2015-01-28 | 2016-08-04 | Chrono Therapeutics Inc. | Drug delivery methods and systems |
US11285306B2 (en) | 2017-01-06 | 2022-03-29 | Morningside Venture Investments Limited | Transdermal drug delivery devices and methods |
AU2019279884A1 (en) | 2018-05-29 | 2020-12-10 | Morningside Venture Investments Limited | Drug delivery methods and systems |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5227391A (en) * | 1992-04-10 | 1993-07-13 | R. J. Reynolds Tobacco Company | Method for treatment of neurodegenerative diseases |
US5232933A (en) * | 1992-05-21 | 1993-08-03 | R. J. Reynolds Tobacco Company | Method for treatment of neurodegenerative diseases |
-
1997
- 1997-07-09 FR FR9708706A patent/FR2765874B1/fr not_active Expired - Fee Related
-
1998
- 1998-07-07 IL IL13353698A patent/IL133536A0/xx unknown
- 1998-07-07 CN CN98807003A patent/CN1262680A/zh active Pending
- 1998-07-07 BR BR9811672-0A patent/BR9811672A/pt not_active IP Right Cessation
- 1998-07-07 WO PCT/FR1998/001446 patent/WO1999002517A1/fr not_active Application Discontinuation
- 1998-07-07 HU HU0003856A patent/HUP0003856A2/hu unknown
- 1998-07-07 EP EP98936453A patent/EP1000056A1/de not_active Withdrawn
- 1998-07-07 US US09/462,352 patent/US6184229B1/en not_active Expired - Fee Related
- 1998-07-07 KR KR1020007000175A patent/KR20010021617A/ko not_active Application Discontinuation
- 1998-07-07 EE EEP200000018A patent/EE200000018A/xx unknown
- 1998-07-07 SK SK21-2000A patent/SK212000A3/sk unknown
- 1998-07-07 PL PL98338123A patent/PL338123A1/xx unknown
- 1998-07-07 CA CA002295666A patent/CA2295666A1/en not_active Abandoned
- 1998-07-07 TR TR2000/00057T patent/TR200000057T2/xx unknown
- 1998-07-07 JP JP50824799A patent/JP2002508004A/ja active Pending
- 1998-07-07 AU AU85444/98A patent/AU8544498A/en not_active Abandoned
- 1998-07-08 CO CO98038696A patent/CO4890850A1/es unknown
- 1998-07-08 AR ARP980103305A patent/AR013192A1/es not_active Application Discontinuation
- 1998-07-08 ZA ZA986047A patent/ZA986047B/xx unknown
-
1999
- 1999-12-22 BG BG104037A patent/BG104037A/xx unknown
-
2000
- 2000-01-06 NO NO20000066A patent/NO20000066L/no not_active Application Discontinuation
Non-Patent Citations (1)
Title |
---|
See references of WO9902517A1 * |
Also Published As
Publication number | Publication date |
---|---|
CA2295666A1 (en) | 1999-01-21 |
ZA986047B (en) | 1999-02-01 |
CN1262680A (zh) | 2000-08-09 |
NO20000066D0 (no) | 2000-01-06 |
AR013192A1 (es) | 2000-12-13 |
WO1999002517A1 (fr) | 1999-01-21 |
US6184229B1 (en) | 2001-02-06 |
IL133536A0 (en) | 2001-04-30 |
FR2765874A1 (fr) | 1999-01-15 |
BG104037A (en) | 2001-04-30 |
HUP0003856A2 (hu) | 2001-10-28 |
PL338123A1 (en) | 2000-09-25 |
CO4890850A1 (es) | 2000-02-28 |
BR9811672A (pt) | 2000-09-19 |
AU8544498A (en) | 1999-02-08 |
EE200000018A (et) | 2000-08-15 |
KR20010021617A (ko) | 2001-03-15 |
TR200000057T2 (tr) | 2000-08-21 |
FR2765874B1 (fr) | 1999-08-13 |
SK212000A3 (en) | 2000-06-12 |
NO20000066L (no) | 2000-03-09 |
JP2002508004A (ja) | 2002-03-12 |
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Effective date: 20000209 |
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