WO2002008220A1 - Derives d'acide 2-thenoique (thiophene) presentant une activite d'antagoniste de recepteurs de glutamate - Google Patents

Derives d'acide 2-thenoique (thiophene) presentant une activite d'antagoniste de recepteurs de glutamate Download PDF

Info

Publication number
WO2002008220A1
WO2002008220A1 PCT/IB2001/001295 IB0101295W WO0208220A1 WO 2002008220 A1 WO2002008220 A1 WO 2002008220A1 IB 0101295 W IB0101295 W IB 0101295W WO 0208220 A1 WO0208220 A1 WO 0208220A1
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
receptors
carboxy
compound
mmol
Prior art date
Application number
PCT/IB2001/001295
Other languages
English (en)
Inventor
Roberto Pellicciari
Flavio Moroni
Christian Noe
Original Assignee
Glaxosmithkline S.P.A.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Glaxosmithkline S.P.A. filed Critical Glaxosmithkline S.P.A.
Priority to AU2001275767A priority Critical patent/AU2001275767A1/en
Publication of WO2002008220A1 publication Critical patent/WO2002008220A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the present invention relates to derivatives of 5 2-thenoic acid with antagonist activity on glutamate receptors.
  • Glutamate can activate both channel receptors and receptors associated .with G proteins.
  • the first are
  • ionotropic receptors 10 commonly called ionotropic receptors (iGlu) whereas the second are called metabotropic receptors (mGlu) .
  • mGlu metabotropic receptors
  • the mGlu receptors are selectively stimulated by 1-amino- cyclopentane-1, 3-dicarboxylic acid (1S,3R-ACPD) and their structure is similar to that of other members of
  • 2nd) mGlu receptors that inhibit adenylate cyclase and are stimulated preferentially by DCG-IV and by CCG1 (mGlu2, mGlu3) .
  • the order of potency of the agonists is as follows: L-CCG1 > 1S,3R-ACPD > QUIS »»> L-AP4. Good antagonists for this subgroup are also available now (see Pellicciari et al . , J. Med. Chem. 39: 2259- 2269; 1996 and Cozzi et al . , Eur. J. Neurosci. 9: 1350- 1355; 1997) .
  • L-AP4 mGlu4, mGlu ⁇ , mGlu7, mGlu8
  • Their . distribution in the CNS is now well characterized and it is known that several receptor subtypes can be expressed by the same neuron. The end effects of their activation depend on the types of receptors present and therefore, when they come into contact with the agonist, there may be both inhibitory effects and excitatory effects.
  • stimulation of Glul leads to activation of calcium-dependent potassium channels (production of IP3 causes an increase in the intracellular concentration of calcium) and hence to hyperpolarization; it also leads to phosphorylation of the NR2C subunit of the NMDA receptor and to diminished functioning of this channel receptor; at the level of the hippocampus, activation of the mGlu 1 receptors increases neuronal excitability through inhibition of the potassium channels operated by the voltage and in other structures of the central nervous system, such as the spinal cord, activation of the mGlu receptors of the first group causes a notable amplification of the synaptic responses mediated both by the NMDA and AMPA receptors.
  • mGlu receptors localized at presynaptic level that are able to regulate the release of transmitter with particularly interesting mechanisms.
  • the stimulation of mGlu4 or mGlu7 can reduce the ingress of Ca 2+ into the nerve terminals, directly inhibiting the voltage-dependent channels and thus reducing the synaptic release of transmitter.
  • a similar result can be obtained by stimulating the mGlu2 receptors that may even be located at quite a distance from the active site of the synapse, but which, having a high affinity for glutamate, seem to be able to be activated, even tonically, by the amino acid present in the extracellular spaces.
  • These receptors inhibit the formation of cAMP and in some way reduce the effects of depolarization on the release of transmitter.
  • the stimulation of other subtypes of mGlu receptors (perhaps mGlul) amplifies the depolarization- transmitter release coupling.
  • Ri is hydrogen, methyl, cyclopropyl or a group of formula
  • R 2 is hydrogen, methyl, methoxy, hydroxy, halogen, cyano; R 3 is carboxy.
  • the invention also relates to the salts of compounds (I) with pharmaceutically acceptable acids or bases, and physiologically equivalent derivatives such as esters or amides and the individual enantiomers of compounds (I) .
  • Ri is hydrogen and R 2 is hydrogen or methyl.
  • Ri is a group of formula
  • X is sulphur or oxygen
  • R 2 is hydrogen or methyl
  • R 3 is carboxy
  • X is oxygen
  • the configuration of the asymmetric carbon atom is preferably R.
  • the compounds of formula (I) in which Ri is hydrogen can be prepared by reaction of a compound of formula (II)
  • R' 3 is a protected carboxy group, for example such as alkyl ester, with alpha-phenylglycinol, preferably with
  • N-substituted alpha-amino-nitriles obtained, for example by means of lead tetra-acetate and removal of any protective groups on the carboxyl.
  • reaction with alpha-phenylglycinol is stereoselective and is carried out in the presence of anhydrous polar solvents such as alcohols, ethers, esters, or ketones at temperatures between -10 and +10°C.
  • anhydrous polar solvents such as alcohols, ethers, esters, or ketones at temperatures between -10 and +10°C.
  • Hydrolysis with lead tetra-acetate is normally carried out in the presence of anhydrous solvents, for example alcohols, ketones, esters, halogenated hydrocarbons or their mixtures at a temperature of approx. 0°C.
  • anhydrous solvents for example alcohols, ketones, esters, halogenated hydrocarbons or their mixtures at a temperature of approx. 0°C.
  • Final hydrolysis in acids gives the desired compounds.
  • R 2 and R' 3 are as defined above and Ri ' is methyl or cyclopropyl, by reaction with alkaline cyanides in the presence of ammonium carbonate in the conditions of the Buchere-Berg reaction, followed by hydrolysis with alkaline hydroxides.
  • 2-formyl-thiophenes can be converted to the corresponding protected imidazolidine derivatives by reaction with N,N- dimethylethylenediamine and then submitted to reactions of carboxylation in position 5 (in the presence of strong bases and C0 2 ) , or halogenation followed by carboxylation .
  • the compounds of formula (I) have antagonist activity on the glutamate receptors and can be used both for scientific purposes (for the characterization of glutamate receptors) and for therapeutic purposes for the treatment of diseases in which there is excessive stimulation of the mGlu receptors.
  • stroke focal cerebral ischaemia
  • global ischaemia cardiac arrest ' or fibrillation
  • CNS traumas cerebral and subarachnoid haemorrhage
  • Parkinson's disease Alzheimer's disease
  • Huntington's chorea amyotrophic lateral sclerosis
  • dementia in the course of AIDS, convulsive disorders, pain and hyperalgesic syndromes, muscle spasms and myoclonus
  • schizophrenia, psychiatric syndromes of anxiety and depression, drug dependence, vomiting for the therapeutic uses envisaged, compounds (I) will be formulated in suitable pharmaceutical compositions, employing conventional techniques and excipients .
  • Compounds (I) can be administered by the oral, parenteral, rectal or transdermal route, at dosages that will depend on several factors (weight, sex, age of the patient, seriousness and type of pathology) and on the pharmacokinetic and toxicological characteristics of each individual compound.
  • a pharmaceutical composition of the invention which can be prepared by mixing, conveniently at room temperature and at atmospheric pressure, is generally suitable for oral, parenteral, rectal or transdermal administration and, as such, can be in the form of tablets, capsules, liquid oral preparations, powders, granules, pastilles, powders that can be reconstituted, solutions or suspensions that are injectable or can be administered by infusion, or suppositories.
  • the tablets and the capsules for oral administration can be in the form of a unit dose, and can contain conventional excipients, such as acceptable binders, fillers, lubricants for tableting, disintegrating agents and wetting agents.
  • the tablets can be coated according to methods that are well known in usual pharmaceutical practice.
  • the liquid oral preparations can be in the form of, for example, suspensions in water or oil, solutions, emulsions, syrups or elixirs, or in the form of a dry product for reconstituting with water or some other suitable vehicle before use. It will be possible for these liquid preparations to contain conventional additives such as suspending agents, emulsifiers, non- aqueous vehicles (which can include food-grade oils) , preservatives and, if desired, conventional flavourings and colouring matter.
  • fluid forms of unit dose are prepared using a compound of the invention or one of its pharmaceutically acceptable salts and a sterile vehicle. The compound, depending on the vehicle and on the concentration employed, can be suspended or dissolved in a vehicle.
  • the compound can be dissolved for injection and submitted to sterile filtration prior to distribution in suitable vials or ampoules, and sealing.
  • adjuvants such as local anaesthetics, preservatives and buffering agents are dissolved in the vehicle.
  • the composition can be frozen and the water eliminated under vacuum.
  • the parenteral suspensions are prepared substantially in the same way, except that the compound is suspended in the vehicle instead of being dissolved, and sterilization cannot be effected by filtration.
  • the compound can be sterilized by treatment with ethylene oxide prior to suspension in a sterile vehicle.
  • the composition includes a surfactant or wetting agent to facilitate uniform distribution of the compound.
  • composition may contain from 0.1% to 99% by weight, preferably from 10 to 60% by weight, of the active ingredient, depending on the method of administration.
  • formulations include capsules, tablets, vials, granules containing single doses from 10 to 500 mg of compounds (I) . These unit doses can be administered once or more per day, for example two or three times per day, and the therapy can be spread over many weeks or months. The following examples illustrate the invention in greater detail.
  • Example 1 a) 1,3-Dime hyl-2- (3-methyl-2- thienyl) imidazolidine (2) Add N, ' -dimethylethylenediamine (17.5 g, 198.5 mmol) to a solution of 3-methyl-2-thiophene- carboxaldehyde (1) (25 g, 198.1 mmol) in anhydrous benzene (280 ml) , with magnetic stirring, in an inert atmosphere. The mixture obtained is reacted under reflux for 12 hours, from time to time removing the water that is formed by the reaction, using Dean-Stark apparatus.
  • ester 4 (7.1 g, 38.6 mmol, yield 80%) as a white solid (end point 75-77°C), which is used "as is" for the subsequent reaction.
  • Example 3 Methoxycarbonyl-2-thiophenecarboxylic acid (9) Jones reagent 8N was added to a solution of (8) (4.5 g, 26.5 mmol) in acetone (225 ml) cooled with ice, under magnetic stirring, until a persistent orange colour was obtained. The reaction mixture was stirred at room temperature for 1 hour. 2-Propanol (5 ml) was then added, and after 10 min the mixture was filtered on Celite, washing with methanol. The solvent was eliminated under vacuum and the residue was absorbed in ethyl acetate, dried (Na 2 S0 4 ) and concentrated to reduced volume (approx. 10 ml) . The precipitated compound was filtered to give (9) (3.76 g, 76.4%).
  • n-BuLi (19 ml of a 1.6 M solution in hexane) was added dropwise to a solution of monoethyl malonate (1.93 g, 14.6 mmol) and 2, 2 ' -bipyridyl (5 mg) in anhydrous THF (35 ml) cooled to -78 °C, stirred mechanically in an argon atmosphere until a pink colour persisted for several minutes, while the internal temperature was allowed to rise to approx. -10 °C.
  • the reaction mixture was cooled again to -65 °C and a solution of raw acyl chloride (1.50 g, 7.30 mmol) in anhydrous THF (10 ml) was added dropwise in 10 min.
  • reaction mixture was poured into a separating funnel containing 130 ml of diethyl ether and 80 ml of cold IN HCl.
  • the organic phase was separated and washed with saturated NaHC0 3 (2 x 40 ml) , water (2 x 40 ml) , and dried (Na 2 S0 4 ) .
  • the solvents were eliminated under vacuum to give (10) (1.30 g, 68%) .
  • the molecules that are active on the mGlus of the 1st group were then tested for potentiation of transmitter release from thin slices of rat cortex and the molecules that are active on the mGlus of the 2nd group were tested for inhibition of the release of transmitter from thin slices of striatum. All the molecules investigated were also tested on mouse cortex preparations (cortical wedges: see Mannaioni et al . , Br. J. Pharmacol. 118: 1530-1536; 1996) to evaluate their possible selectivity and their action on ionotropic receptors. The methods employed for the above experiments are described in: Lombardi et al., British J. Pharmacol . 110: 1407-1412; 1993; and Lombardi et al . , British J. Pharmacol . Ill : 189-195, 1996 and Moroni et al . , Eur. J. Pharmacol. 347: 189- 195; 1998.
  • the compound of Example 2 (ATIDA) antagonizes the effect of 1S,3R-ACPD (300 ⁇ M) on the formation of inositol phosphates in slices of rat cortex with an IC 50 of 70 ⁇ M. It has no agonistic or antagonistic effect (up to 300 ⁇ M) , in cortical or cerebral slices, on the cAMP accumulation test effected by forskolin. Moreover, it did not reduce the responses induced by NMDA (10 ⁇ M) or AMPA (5 ⁇ M) in cortical preparations ("cortical wedges" ) .
  • Example 3 also antagonizes the effect of 1S,3R-ACPD (300 ⁇ M) on the formation of inositol phosphates in slices of rat cortex with an IC 50 of 20 ⁇ M.
  • Stroke model The middle cerebral artery was occluded in anaesthetized Sprague-Dawley rats by inserting a silicone-coated nylon filament (0.28 mm) into the internal carotid artery as far as the Willis circle. Forty-eight hours after the procedure, the rats were anaesthetized again, the thorax was opened and a solution containing 2, 3, 5-triphenyltetrazolium chloride in physiological solution was slowly injected into the left cardiac ventricle in order to reveal necrotic tissue. The brain was removed, frontal ("coronal") sections were prepared, with thickness of 1 mm, the infarcted areas were measured and the volume of the infarct was calculated by the methods described previously. Results

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Neurosurgery (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Psychiatry (AREA)
  • Hospice & Palliative Care (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne des dérivés d'acide 2-thénoïque de la formule (I), les composés selon l'invention présentant une activité d'antagoniste de récepteurs de glutamate.
PCT/IB2001/001295 2000-07-21 2001-07-20 Derives d'acide 2-thenoique (thiophene) presentant une activite d'antagoniste de recepteurs de glutamate WO2002008220A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2001275767A AU2001275767A1 (en) 2000-07-21 2001-07-20 2-thenoic acid (thiophene) derivatives having glutamate receptor antagonistic activity

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITMI2000A001667 2000-07-21
IT2000MI001667A IT1318636B1 (it) 2000-07-21 2000-07-21 Derivati dell'acido 2- o 3- tenoico ad attivita' antagonista deirecettori del glutammato.

Publications (1)

Publication Number Publication Date
WO2002008220A1 true WO2002008220A1 (fr) 2002-01-31

Family

ID=11445531

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2001/001295 WO2002008220A1 (fr) 2000-07-21 2001-07-20 Derives d'acide 2-thenoique (thiophene) presentant une activite d'antagoniste de recepteurs de glutamate

Country Status (3)

Country Link
AU (1) AU2001275767A1 (fr)
IT (1) IT1318636B1 (fr)
WO (1) WO2002008220A1 (fr)

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995012587A1 (fr) * 1993-11-03 1995-05-11 H. Lundbeck A/S Composes d'acide 2-aminocarboxylique substitue par 5-arylisoxazol-4-yle
WO1998014447A1 (fr) * 1996-10-01 1998-04-09 Neurosearch A/S Nouveaux derives d'indol-2,3-dion-3-oxime
EP0849263A2 (fr) * 1996-12-17 1998-06-24 Eli Lilly And Company Limited Dérivés substitués d'acide propanoique utiles en pharmacie
WO1998045256A1 (fr) * 1997-04-04 1998-10-15 Guilford Pharmaceuticals Inc. Derives d'acide hydroxamique
WO2000006149A1 (fr) * 1998-07-31 2000-02-10 Eli Lilly And Company Sulfamides
WO2000006156A1 (fr) * 1998-07-31 2000-02-10 Eli Lilly And Company Derives d'amide, de carbamate et d'uree
WO2000063166A1 (fr) * 1999-04-20 2000-10-26 F. Hoffmann-La Roche Ag Derives d'acide carbamique et leur utilisation comme ligands du recepteur de glutamate metabotropique

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995012587A1 (fr) * 1993-11-03 1995-05-11 H. Lundbeck A/S Composes d'acide 2-aminocarboxylique substitue par 5-arylisoxazol-4-yle
WO1998014447A1 (fr) * 1996-10-01 1998-04-09 Neurosearch A/S Nouveaux derives d'indol-2,3-dion-3-oxime
EP0849263A2 (fr) * 1996-12-17 1998-06-24 Eli Lilly And Company Limited Dérivés substitués d'acide propanoique utiles en pharmacie
WO1998045256A1 (fr) * 1997-04-04 1998-10-15 Guilford Pharmaceuticals Inc. Derives d'acide hydroxamique
WO2000006149A1 (fr) * 1998-07-31 2000-02-10 Eli Lilly And Company Sulfamides
WO2000006156A1 (fr) * 1998-07-31 2000-02-10 Eli Lilly And Company Derives d'amide, de carbamate et d'uree
WO2000063166A1 (fr) * 1999-04-20 2000-10-26 F. Hoffmann-La Roche Ag Derives d'acide carbamique et leur utilisation comme ligands du recepteur de glutamate metabotropique

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
BRÄUNER-OSBORNE,H. ET AL.: "Ligands for Glutamate Receptors: Design and Therapeutic Prospects", J.MED.CHEM., vol. 43, no. 14, 13 July 2000 (2000-07-13), WASHINGTON, pages 2609 - 2645, XP002182209 *
KNOEPFEL T ET AL: "METABOTROPIC GLUTAMATE RECEPTORS: NOVEL TARGETS FOR DRUG DEVELOPMENT", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 38, no. 9, 28 April 1995 (1995-04-28), pages 1417 - 1426, XP000611483, ISSN: 0022-2623 *
KULAGOWSKI J J ET AL: "3'-(ARYLMETHYL)-AND 3'-(ARYLOXY)-3-PHENYL-4-HYDROXYQUINOLIN- 2(1H)-ONES: ORALLY ACTIVE ANTAGONISTS OF THE GLYCINE SITE ON THE NMDA RECEPTOR", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 37, no. 10, 13 March 1994 (1994-03-13), pages 1402 - 1405, XP000561217, ISSN: 0022-2623 *

Also Published As

Publication number Publication date
ITMI20001667A1 (it) 2002-01-21
IT1318636B1 (it) 2003-08-27
ITMI20001667A0 (it) 2000-07-21
AU2001275767A1 (en) 2002-02-05

Similar Documents

Publication Publication Date Title
KR101818096B1 (ko) 비시클릭 아릴 스핑고신 1-포스페이트 유사체
JP5917555B2 (ja) ケモカイン受容体調節因子としてのリン酸誘導体
EP0934326A1 (fr) Acides aminoalcanophosphoniques substitues
JP2001515483A (ja) 抗てんかん誘発剤
JPH11509846A (ja) ヘテロ環式化合物、それらの調製及び使用
NZ522674A (en) Novel spiro[2.4]heptane amino carboxy compounds and derivatives thereof
JPH0641475B2 (ja) 置換アルファアミノ酸、その製法および医薬
WO1996015100A1 (fr) Composes heterocycliques, preparation et utilisation
CA2841983A1 (fr) Derives polycycliques de pyrrolidine-2,5-dione en tant que modulateurs du recepteur fprl-1 (recepteur de n-formyl peptide de type 1)
JPH08169884A (ja) シクロプロパクロメンカルボン酸誘導体
EP0569333B1 (fr) Nouveaux acides N-aralkyl et N-hétéroaralkylamino alcane phosphoniques
EP2814815A1 (fr) Dérivés d'imidazolidine-2,4-dione en tant que modulateurs du récepteur des peptides n-formylés 2
JP2016529235A (ja) ホルミルペプチド受容体モジュレーターとしてのｎ−尿素置換アミノ酸の誘導体
JP2002512214A (ja) 代謝生成物産生グルタミン酸レセプターアンタゴニストとしてのキュバン誘導体およびそれらの調製プロセス
JP2002509934A (ja) ホスフィン酸誘導体
CN103857655B (zh) 用于抑制11β-羟基类固醇脱氢酶1的化合物及包含该化合物的药物组合物
JP2002519408A (ja) 医薬化合物及び組成物として有用なＮＡＡＬＡＤａｓｅ阻害剤
EP0733036A1 (fr) Alpha-aminoacides alpha quaternaires utilises comme agents influant sur le snc (systeme nerveux central)
JPH09500644A (ja) エンドセリン拮抗剤
WO1997019049A1 (fr) Derives de la glycine
US20040171835A1 (en) Tetrahydroquinoline derivative compound and drug containing the compound as active ingredient
DE10164564A1 (de) Tetrahydrocarbazolderivate als Liganden für G-Protein gekoppelte Rezeptoren (GPCR)
WO2002008220A1 (fr) Derives d'acide 2-thenoique (thiophene) presentant une activite d'antagoniste de recepteurs de glutamate
JP7032323B2 (ja) Ｎ－ホルミルペプチド受容体モジュレーターとしてのフェニル尿素誘導体
WO2001068655A2 (fr) Derives de caprolactam et leurs utilisations

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP