WO2008125008A1 - Composés de cyclohepta[b]pyridine, leur procédé de préparation et leur usage ainsi que compositions pharmaceutiques contenant les composés - Google Patents

Composés de cyclohepta[b]pyridine, leur procédé de préparation et leur usage ainsi que compositions pharmaceutiques contenant les composés Download PDF

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Publication number
WO2008125008A1
WO2008125008A1 PCT/CN2008/000722 CN2008000722W WO2008125008A1 WO 2008125008 A1 WO2008125008 A1 WO 2008125008A1 CN 2008000722 W CN2008000722 W CN 2008000722W WO 2008125008 A1 WO2008125008 A1 WO 2008125008A1
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WIPO (PCT)
Prior art keywords
cyano
thio
group
pentahydrocycloheptapyridine
acetamide
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PCT/CN2008/000722
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English (en)
Chinese (zh)
Inventor
Hualiang Jiang
Xu Shen
Hong Liu
Zhiyi Yao
Chenjing Li
Yu Zhou
Kaixian Chen
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Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences
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Publication of WO2008125008A1 publication Critical patent/WO2008125008A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring 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
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to the field of medicinal chemistry and pharmacotherapeutics, and in particular to novel cyclohepta pyridine compounds, processes for their preparation, uses and pharmaceutical compositions comprising such compounds.
  • AD Alzheimer's Disease
  • It is a degenerative disease of the brain, mostly with brain atrophy, especially the shrinkage of the frontal cortex. The average male is 65 years old and the female is 55 years old.
  • AD Alzheimer's disease
  • AD patients The cause of dementia in AD patients is due to the death of neuronal cells in certain areas of the human brain due to high levels of "senile plaques” and “neurofiber disorders.” "Abnormal production and deposition of ⁇ -amyloid ( ⁇ )” is considered to be one of the main causes of neuronal damage and loss.
  • ⁇ is formed by the hydrolysis of ⁇ and ⁇ -secretase by Amyloid precursor protein.
  • a ⁇ contains 39-42 amino acid residues. The results show that the production of A ⁇ is the most critical factor in the early stage of AD. In early onset AD, excess production ⁇ 42 will directly lead to the pathological laminated, and excess ⁇ 42 is difficult to be cleared, so ⁇ 42 will be deposited under the effect of a number of aggregation factors. In theory, as long as the expression of sputum is blocked, the formation of ⁇ can be avoided and the purpose of treating AD can be achieved.
  • ⁇ -secretase pathway Under normal conditions ( ⁇ -secretase pathway), ⁇ is catalytically hydrolyzed by ⁇ -secretase into the soluble ⁇ fragment ⁇ -APPs and C83 peptides within the ⁇ sequence, which prevents the formation of ⁇ ; under abnormal conditions ( ⁇ - Secretase pathway), ⁇ is catalyzed by ⁇ -secretase in the ⁇ -terminal cleavage of ⁇ to form soluble ⁇ fragments ⁇ -APPs and C99 peptides, which are cleavage of ⁇ -secretase at the C-terminus of ⁇ to Complete ⁇ .
  • ⁇ -secretase is the rate-limiting enzyme that produces ⁇ , which is the catalytic hydrolysis of ruthenium. Prerequisites for ⁇ .
  • AD Alzheimer's disease
  • ⁇ peptide insoluble ⁇ -amyloid
  • ⁇ peptide insoluble ⁇ -amyloid
  • the 39-43 amino acid polypeptide produced by the cleavage of the precursor ( ⁇ ) has the main forms of ⁇ 40 and ⁇ 42.
  • the ⁇ -secretase enzyme cleavage site is located between the 16th lysine- 17th leucine of ⁇ . Hydrolysis of peptide bonds at this site produces soluble polypeptides that reduce the formation of a ⁇ peptides.
  • ⁇ -secretase is a transmembrane aspartic protease that plays an important role in the production of ⁇ -amyloid peptides. The ⁇ -secretase hydrolyzes ⁇ with ⁇ -secretase to form ⁇ peptide, which causes Alzheimer's disease and its related complications.
  • ⁇ -secretase is beneficial for preventing the formation of ⁇ peptide.
  • the ⁇ -secretase produces ⁇ peptide under the combined action of ⁇ -secretase. Therefore, activation of ⁇ -secretase or/and inhibition of ⁇ -secretase or/and ⁇ -secretase activity can effectively prevent the production of A ⁇ peptide, thereby preventing the occurrence of Alzheimer's disease. Therefore, 01, ⁇ , and ⁇ -secretase can be selected as single or common targets for drug research on Alzheimer's disease and related complications.
  • the present inventors designed various agonists/multiple agonists and inhibitors/multiple inhibitors based on the three-dimensional structure of ⁇ , ⁇ , ⁇ -secretase, which directly act on secretase and participate in the regulation of ⁇ amyloid production.
  • step the level of ⁇ amyloid in the brain is lowered to exert a pharmacodynamic effect.
  • Another object of the present invention is to provide a process for the preparation of the cycloheptapyridine compound.
  • a further object of the invention is to provide the use of said compounds as single or multiple agonists or inhibitors of alpha, beta, gamma-secretase.
  • a further object of the invention is to provide the use of said compounds as experimental model tools for single or multiple agonists or inhibitors of alpha, beta, gamma-secretase.
  • Still another object of the present invention is to provide the use of the compound for the preparation of a medicament for the treatment and prevention of Alzheimer's disease, childhood mental retardation, amnesia and other cardiovascular and cerebrovascular diseases.
  • the present invention provides a compound having the following formula I: among them:
  • X is 0, S or ⁇
  • ⁇ is 0, S, NH or CH 2 ;
  • Z is 0 or S
  • n are each an integer of 0-3;
  • Ri and R 2 are each independently selected from hydrogen, a straight or branched saturated or unsaturated CC 6 hydrocarbon group, a cyano group, a nitro group, an amino group, an amino group, a decyl group, an amino acyl group, a hydroxyl group, a hydroxy group, Trifluoromethyl, trifluoromethoxy, J ⁇ , d-C4 alkoxy, fluorenyl, -C4 acyl, C 3 -C 7 cycloalkyl, benzyl, aryl or 5-7 membered heterocyclic;
  • R 3 and R 4 are each independently selected from the group consisting of phenyl, substituted phenyl, naphthyl, biphenyl, 5-7 membered heterocyclic ring, wherein the substituted phenyl group includes 1 to 4 selected from halogen, dC 6 straight a chain or branched hydrocarbon group, a cyano group, a nitro group, an amino group, a hydroxyl group, a hydroxymethyl group, a trifluoromethyl group, a trifluoromethoxy group, a carboxyl group, a dC 4 alkoxy group, a fluorenyl group, and a CC 4 acyl substituent; Ri, R 2 and R 4 may be the same or different, but at least one of them is a non-hydrogen atom;
  • the aryl group described in Ri ⁇ R 4 is a phenyl group, a substituted phenyl group, a naphthyl group or a biphenyl group, a 5-7 membered aromatic heterocyclic ring; wherein the substituted phenyl group is composed of 1 to 4 selected from halogen, CC 6 a straight-chain or branched-chain hydrocarbon group, a cyano group, a nitro group, an amino group, a hydroxyl group, a hydroxyl group Yue, Yue trifluoromethyl group, trifluoromethoxy group Yue, carboxy, C r C 4 alkoxy group, a mercapto group, and a substituted acyl group -C4 ;
  • the 5-7 membered heterocyclic group contains 1-3 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, and contains one or more selected from the group consisting of halogen, Cr C 6 straight or branched chain hydrocarbon, cyano group, a substituent of a nitro group, a hydroxyl group, a hydroxymethyl group, a trifluoromethyl group, a trifluoromethoxy group, a carboxyl group, a C r C 4 alkoxy group, a decyl group, a C r C 4 acyl group, and an aryl group, said 5-
  • the 7-membered heterocyclic group can be combined with the phenyl group in the mother nucleus.
  • R 3 is thiophen-2-yl or pyrrol-2-yl; definitions of X, Y, Z, m, n, R 1 3 ⁇ 4 R 2 and R 4 Same as compound I above.
  • R 3 is thiophen-2-yl; X is S or 0;
  • Z, Y, m, n, R 2 and R 4 are as defined above for compound I.
  • R 3 is thiophen-2-yl; X is S; Z is 0; Y is 0 or NH;
  • n, R 2 and R 4 are as defined above for the compound I.
  • R 3 is thiophen-2-yl; X is NH; Z is 0; Y is 0 or NH;
  • n, R 2 and R 4 are as defined above for the compound I.
  • R 3 is pyrrol-2-yl; X is S; Y is 0 or NH;
  • R 3 is pyrrol-2-yl; X is 0; Z is 0; Y is 0, NH or S; m, n, RR 2 and R 4 are as defined above for the compound I.
  • R 3 is pyrrol-2-yl; X is 0 or NH; Y is 0 or NH;
  • R 3 is phenyl or substituted phenyl; X is S; Y is 0 or NH;
  • R 3 is phenyl or substituted phenyl; X is 0; Z is 0; Y is 0, NH or S;
  • R 3 is phenyl or substituted phenyl; X is 0 or NH; Y is 0 or NH;
  • R 3 is an aromatic heterocyclic group
  • X, Y, Z, m, n, R 2 and R 4 are as defined above for the compound I.
  • the compound of the formula I provided by the invention can be combined with organic acids and aspartic acid, such as propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, etc.
  • organic acids and aspartic acid such as propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, etc.
  • the invention also provides a process for the preparation of a compound of formula I, Wherein X, Y, Z, m, n, R 2 , R 3 and R 4 are
  • the method includes the following steps:
  • the above step (1) and (2) used in the solvent is selected from THF, Et 2 0, DMF, Yue glycol dimethyl ether, ethylene glycol diethyl ether, and dioxane, including the base used is selected from pyridine, Triethylamine, 4-diguanylidenepyridine (DMAP), an organic base of diisopropylethylamine, and an inorganic base comprising sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide; used in the step (3)
  • the solvent is selected from the group consisting of ethanol, decyl alcohol, ethyl acetate and tetrahydrofuran.
  • the products obtained in the step (1), the step (2) and the step (3) can be separately purified to obtain a pure product, followed by the next reaction.
  • the method of purification is selected from the group consisting of column chromatography and recrystallization.
  • the invention still further provides a pharmaceutical composition for the treatment and prevention of Alzheimer's disease, childhood mental retardation, amnesia and other cardiovascular diseases, comprising a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable thereof A salt and a pharmaceutically acceptable carrier, diluent or excipient.
  • the pharmaceutically acceptable carrier means a pharmaceutical carrier conventionally used in the pharmaceutical field, for example, a diluent, an excipient such as water, etc.; a filler such as starch sucrose or the like; a binder such as a cellulose derivative, an alginate, Gelatin and polyvinylpyrrolidone; disintegrating agents such as agar calcium carbonate, sodium hydrogencarbonate and the like.
  • the pharmaceutical compositions provided by the present invention may be present in various dosage forms such as tablets, capsules, powders, syrups, solutions, suspensions and aerosols, and may be present in a suitable solid or liquid carrier or diluent. And a suitable sterilizing device for injection or drip.
  • the pharmaceutical composition may also contain a flavoring agent, a flavoring agent, and the like.
  • a desirable ratio of the compound of the formula I to a pharmaceutically acceptable carrier, diluent or excipient is that the compound of the formula I is active ingredient in an amount of from 1 to 99%, preferably from 1 to 60%, more preferably the total weight of the composition. It is 1-20%, preferably 1-10%; the remainder is a pharmaceutically acceptable carrier, diluent or excipient.
  • a unit dosage of the formulation may comprise from 0.05 mg to 200 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, preferably from 0.1 mg to 100 mg of a compound of formula I or a pharmaceutically acceptable compound thereof .
  • the compounds of formula I as described above can be administered to mammals clinically, including humans and animals, and can be administered orally, nasally, dermally, pulmonaryly, or parenterally.
  • the most preferred is oral.
  • the daily dose is from 0.01 to 200 mg/kg body weight, administered once, or in divided doses.
  • the optimal dosage for an individual should be based on the particular treatment. It is usually starting with a small dose and gradually increasing the dose until the most suitable dose is found.
  • the invention further provides the use of a compound of formula I as a single or multiple agonist or inhibitor of alpha, beta, gamma-secretase.
  • the invention still further provides the use of a compound of formula I for the manufacture of a medicament for the treatment and prevention of Alzheimer's disease, childhood mental retardation, amnesia and other cardiovascular diseases.
  • Figure 1 shows the molecular level of the compound ⁇ 37
  • Figure 2 is the ⁇ -secretase activity activation curve of the compound ⁇ 37 cell level
  • Figure 3 is the compound ⁇ 37 agonistic ⁇ 1-40 production curve.
  • the analytical data of the sample was determined by the following instruments: The melting point was measured by a ⁇ -4 type melting point apparatus manufactured by Shanghai Precision Scientific Instrument Co., Ltd., and the temperature was not corrected; the nuclear magnetic resonance was performed by GEMINI-300 type, Bmker AMX-400 type and INVOA-600 type.
  • the NMR was determined by TNMR as the internal standard, the chemical shift unit was ppm, and the unit of the constant was Hz.
  • the mass was determined by Finnigan MAT-711, MAT-95 and LCQ-DECA mass spectrometer.
  • Example 8 Using 4-hydroxyaniline instead of 2-hydroxyaniline, the remaining starting materials, reagents and preparation methods were the same as those in Example 1 and Example 8, to obtain the target compound 2- ⁇ [3-cyano-4-(thiophen-2-yl). -5,6,7,8,9-pentahydrocycloheptapyridine-2-yl]thio- ⁇ -N-(4-hydroxyphenyl)acetamide, a total yield of 1.3%.
  • the aniline was replaced by 2,5-diethoxyaniline, and the other desired starting materials, reagents and preparation methods were the same as in Example 1, to obtain the target compound 2- ⁇ [3-cyano-4-(thiophen-2-yl)-5. 6,7,8,9-Pentahydrocycloheptapyridin-2-yl]thio- ⁇ -N-(2,5-diethoxyphenyl)acetamide, total yield 12.6%.
  • 2-pyrrolidinoic acid was used in place of 2-thiophenefurfural, and the remaining starting materials, reagents and preparation methods were the same as in Example 1, to obtain the target compound 2- ⁇ [3-cyano-4-(2-pyrrolyl)-5. 6,7,8,9-Pentahydrocycloheptapyridin-2-yl]thio- ⁇ -N-(2,6-diethylphenyl)acetamide, total yield 11.5%.
  • 2-pyrrolidinoic acid was used instead of 2-thiophenefurfural, 4-fluoroaniline was substituted for 2,6-diethylaniline, and the remaining materials, reagents and preparation methods were the same as in Example 1, to obtain the target compound 2- ⁇ [3-cyanide 4-(pyrrole- 2 -yl)-5,6,7,8,9-pentahydrocycloheptapyridine- 2 -yl]thio- ⁇ -N-( 4 -fluorophenyl)acetamide .
  • Oxalyl chloride (0.31 g, 2.4 mmol) was dissolved in 5 mL of dichloromethane, and added dropwise to 8 mL of dichlorobenzene (R)-2-bromo-3-indolylbutyric acid (0.2 g, 1.1 mmol) The mixture was reacted for 48 hours in decane, and the solvent was evaporated to dryness to give (D)-2-bromo-3-decyl tert-butyryl chloride 0.2 g (92.0%).
  • Example 29 L-valine was used instead of D-valine, and the remaining starting materials, reagents and preparation methods were the same as in Example 27 to obtain the target compound (R)-2- ⁇ [3-cyano-4-(thiophen-2- -5,6,7,8,9-pentahydrocycloheptapyridine-2-yl]thio- ⁇ -N-phenyl-3-indolylbutanamide.
  • Example 29
  • Example 30 The aniline was replaced by 2,6-diethylaniline, and the remaining starting materials, reagents and preparation methods were the same as those in Example 27 to obtain the target compound (S)-2- ⁇ [3-cyano-4-(thiophen-2-yl) -5,6,7,8,9-pentahydrocycloheptapyridine-2-yl]thio- ⁇ -N-(2,6-diethylphenyl)-3-indolylbutanamide.
  • Example 30 Example 30
  • Example 32 The aniline was replaced by 4-hydroxyaniline, and the remaining starting materials, reagents and preparation methods were the same as those in Example 27 to obtain the target compound (S)-2- ⁇ [3-cyano-4-(thiophen-2-yl)-5. 6,7,8,9-Pentahydrocycloheptapyridin-2-yl]thio- ⁇ -N-(4-hydroxyphenyl)-3-indolylbutanamide.
  • Example 32
  • Example 34 The aniline was replaced by 2-hydroxyaniline, and the remaining starting materials, reagents and preparation methods were the same as those in Example 27 to obtain the target compound (S)-2- ⁇ [3-cyano-4-(thiophen-2-yl)-5. 6,7,8,9-Pentahydrocycloheptapyridine- 2 -yl]thio- ⁇ -N-( 2 -hydroxyphenyl)-3-mercaptobutyramide.
  • Example 34
  • FRET fluorescence resonance energy transfer
  • kits B ACE 1 ( ⁇ -secretase) FRET Assay Kit, Red purchased from Invitrogen.
  • the kit includes:
  • BACE1 stored in 50 mM Tris (H 7.5), 10% glycerol; ⁇ -secretase substrate 75 ⁇ : Rh-EVNLDAEFK-Quencher, stored in 50 mM ammonium bicarbonate;
  • Rh-EVNL stored in 50 mM ammonium bicarbonate; black 384-well plate (purchased from BMG);
  • Microplate reader (Genios, purchased from TECAN).
  • the ⁇ -secretase (192 units/ml) in the kit was diluted with the reaction buffer to a final concentration of 1.0 unit/ml.
  • the ⁇ -secretase substrate (75 ⁇ M) in the kit was diluted with the reaction buffer to a final concentration of 750 nM.
  • Enzyme reaction 3 ⁇ -secretase, 3 ⁇ -secretase substrate (750 ⁇ ) and ⁇ -secretase reaction buffer each ⁇ , mix, wait for 60min reaction at room temperature, add ⁇ -secretase reaction to terminate The liquid terminates the reaction.
  • DMSO control reaction 3 ⁇ -secretase, 3 ⁇ -secretase substrate (750 ⁇ ) and dilution
  • the DMSO-containing ⁇ -secretase reaction buffer (the DMSO concentration is the same as the DMSO concentration in the 3 X test compound buffer) is ⁇ , mixed, and after reacting at room temperature for 60 min, ⁇ -secretase is added.
  • the reaction stop solution terminates the reaction.
  • the compounds to be tested were diluted to different concentrations and reacted according to 2.1. All experiments were performed with duplicate wells.
  • the compounds to be tested in the patent were screened, and the compound ZY37 was screened to have a good agonistic effect on ⁇ -secretase, and its EC 5 .
  • CH02B7 cells (which have been stabilized to APP695wt) were used. After inoculation for 24 hours, the compounds were incubated with a compound concentration of 10 - 4 M to ⁇ - ⁇ , using 1%. DMS0 is used as a negative control. The sample was collected 24 hours after the administration, and the cells were lysed by freezing and thawing for 6 times, and then the concentration of the cell lysate was measured, and the ⁇ -secretase activity of the cell lysate was measured by the aforementioned ⁇ -secretase assay.
  • CH02B7 cells stably transfected been APP695wt
  • 24 hours after seeding was added compound incubation, compound concentration of 10- 6 M to ⁇ - ⁇ ⁇ , 1%.
  • DMS0 is used as a blank control.
  • Samples were taken 24 hours after dosing, and the content of secreted A ⁇ 1-40 was analyzed.
  • the ⁇ 1-40 content determination kit of Biosource was purchased using the ELISA principle to quantify the detection of ⁇ 1-40.
  • the cyclohepta pyridine compound of the present invention exhibits an activating/inhibiting enzyme activity in a computer virtual screening and a ⁇ -secretase binding experiment, and can effectively treat and prevent Alzheimer's disease, children with mental retardation, amnesia and other cardiovascular diseases.
  • Pyridine compound on the model and the ⁇ - -secretase cycloheptane interaction in Biacore 3000 biosensor technology development of the invention all the compounds was observed in this model are 10- 7 -10- 5 ⁇ concentration range effect.
  • the compounds of the invention are very toxic.
  • the compound of the present invention can be used for the preparation of a medicament for treating and preventing a disease caused by a secreted enzyme regulating disorder, and also as a tool for measuring single or multiple agonistic/inhibitory enzyme activities of ⁇ , ⁇ , ⁇ -secretase.

Abstract

L'invention porte sur un composé de cyclohepta[b]pyridine décrit comme formule I et sur des sels pharmaceutiquement acceptables de ce composé. L'invention porte également sur le procédé de préparation de ces composés de cyclohepta[b]pyridine ainsi que sur l'utilisation de ces composés de cyclohepta[b]pyridine et des compositions de ceux-ci dans la préparation de médicaments pour le traitement et la prophylaxie de la maladie d'Alzheimer, du retard mental chez l'enfant, de l'amnésie et autres maladies cardiovasculaires et cérébrovasculaires. Les composés de la présente invention peuvent être utilisés comme agoniste et/ou inhibiteur des α, β, Ϝ-sécrétases. Les composés empêchent la production d'amyloïde par activité d'activation ou d'inhibition d'enzymes et permettent de traiter et/ou de prévenir de façon efficace la maladie d'Alzheimer, le retard mental chez l'enfant, l'amnésie et autres maladies cardiovasculaires et cérébrovasculaires.
PCT/CN2008/000722 2007-04-12 2008-04-09 Composés de cyclohepta[b]pyridine, leur procédé de préparation et leur usage ainsi que compositions pharmaceutiques contenant les composés WO2008125008A1 (fr)

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CN200710039447XA CN101284828B (zh) 2007-04-12 2007-04-12 环庚烷并吡啶类化合物、其制备方法、用途及包含此类化合物的药物组合物
CN200710039447.X 2007-04-12

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CN113214234B (zh) * 2021-05-12 2022-11-25 南开大学 一种含噻吩基吡啶和硫基团的乙酰芳胺衍生物及其制备方法和用途

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999067220A1 (fr) * 1998-06-22 1999-12-29 Elan Pharmaceuticals, Inc. Composes permettant d'inhiber la liberation et/ou la synthese de peptide beta-amyloide
CN1242007A (zh) * 1996-12-23 2000-01-19 伊兰药品公司 环烷基、内酰胺、内酯和相关化合物、包括这些化合物的药用组合物以及用这些化合抑制β淀粉样肽释放和/或其合成的方法
WO2001060826A2 (fr) * 2000-02-17 2001-08-23 Bristol-Myers Squibb Pharma Company CARBOCYCLES ET HETEROCYCLES SUCCINOYLAMINO UTILISES EN TANT QU'INHIBITEURS DE LA PRODUCTION DE LA PROTEINE A$g(b)

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1242007A (zh) * 1996-12-23 2000-01-19 伊兰药品公司 环烷基、内酰胺、内酯和相关化合物、包括这些化合物的药用组合物以及用这些化合抑制β淀粉样肽释放和/或其合成的方法
WO1999067220A1 (fr) * 1998-06-22 1999-12-29 Elan Pharmaceuticals, Inc. Composes permettant d'inhiber la liberation et/ou la synthese de peptide beta-amyloide
WO2001060826A2 (fr) * 2000-02-17 2001-08-23 Bristol-Myers Squibb Pharma Company CARBOCYCLES ET HETEROCYCLES SUCCINOYLAMINO UTILISES EN TANT QU'INHIBITEURS DE LA PRODUCTION DE LA PROTEINE A$g(b)

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