CN101970431A - Substituted piperidines as therapeutic compounds - Google Patents
Substituted piperidines as therapeutic compounds Download PDFInfo
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Abstract
Described are compounds of the general formula (I), and pharmaceutically acceptable salt thereof, in which R1 has the definitions illustrated in detail in the description, as beta-secretase, cathepsin D, plasmepsin II and/or HIV protease inhibitors.
Description
Invention field
The present invention relates to the substituted piperidine class as beta-secretase, cathepsin D-, aspartate protease II (plasmepsin II)-and/or the purposes of HIV-proteinase inhibitor.
Background of invention
Beta-secretase, cathepsin D-, aspect aspartate protease II and/or the hiv protease restraining effect, still need highly effective activeconstituents.Under this background, the improvement of pharmacokinetics character is most important.The character relevant with better bioavailability be for example absorb, metabolic stability, solubleness or fat-soluble.
Alzheimer's disease aspartyl proteolytic enzyme: beta-secretase
Alzheimer's disease (AD) be brain carry out the sexual involution disease.The symptom of AD comprises the final forfeiture and the death of the carrying out property loss of memory, language problem and basic neuronal function.The biomarker of the central nervous system of AD comprises neurofibrillary tangles and activated microglia in amyloid plaque, the cell.As if apparent the going up of these three kinds of marks have contribution to the observed neuronal cell death and the loss of memory among the AD.
Amyloid beta protein is the defined property of AD, and it is believed that it is pathogenic precursor during disease takes place now.Amyloid plaques and blood vessel amyloid angiopathy also are trisomy 21 syndrome (mongolism), have hereditary cerebral hemorrhage to accompany the feature of the individual brain of Dutch type amyloidosis (HCHWA-D) and other neurological sexual dysfunctions.
The amyloid beta protein spot is mainly formed (A-β also is defined as β A4 sometimes) by amyloid beta.A-β peptide is the proteolysis development by beta-amyloyd precursor protein (APP).β-APP is handled by the enzymic activity of three obvious different order.A large amount of β-APP is processed with non-amyloid path by the alpha-secretase enzyme.β-the APP of small portion is in conjunction with C-terminal fragment C99 by the active cleaved produced film of beta-secretase.
Gamma-secretase pyrolysis c9 9 generates 39-42 amino acid whose amyloid A-β peptide.It is open that the aspartyl protease activity of beta-secretase has been used different terms, and these terms comprise BACE (β-site APP lyase), Asp and memapsin.
The meaning of committed step during the beta-secretase cracking of β-APP produces as AD, by β-APP beta-secretase cracking sublocus (swedish mutant) locate the human body sudden change cause increase that A-β generates and early the observations of the familial AD of outbreak can be understood.In addition, the mouse that knocks out of BACE-1 can not generate the A-beta polypeptides and be rendered as normal phenotype.When hybridizing, compare its offspring with control animal and show that A-β amount reduces in the big brain extract with the transgenic mice of overexpression APP.This evidence has supported active inhibition of beta-secretase and the sedimentary minimizing in brain of A-β peptide that the suggestion to AD and other amyloid beta treating dysfunction strategies is provided, people (2004) such as this therapeutic strategy such as Verdile are at Pharmcol.Res.50, described in the 397-409.
It can suppress the cracking of APP of beta-secretase mediation and the generation of A-β peptide for the compound of the effective inhibitor of beta-secretase.The pharmacology restraining effect that A-β peptide generates can reduce the amyloid-beta deposition, and the formation of patch.People such as Thompson (2005) are at Curr.Pharm.Res.11, and therefore the compound of the inhibition beta-secretase of discussing among the 3383-3404 is used to treat or prevents with amyloid-beta deposition or patch is the disease such as the AD of feature.
The invention still further relates to treatment the individual following disease of generation of individual or prevention of following disease or illness or the method for illness are arranged: this disease or illness are selected from AD, be used to help to prevent or postpone the outbreak of AD, be used to help to slow down the development of AD, be used for the treatment of the individuality that mild cognitive damage (MCI) is arranged, and prevention or postpone to develop into from MCI the outbreak of AD the individuality of AD at these, be used for the treatment of Down's syndrome, be used for the treatment of the people that HCHWAD is arranged, be used for the treatment of cerebral amyloid angiopathy and become, and be used for the treatment of the degeneration dementia.
Alzheimer's disease aspartyl proteolytic enzyme: cathepsin D
Tissue proteolytic enzyme D is an aspartyl peptase in the cell that is mainly seen in the lysosome.It has and manyly comprises degradation of cell and engulf proteic arrangement function.These enzymes may be related to the numerous disease state, comprise cancer and alzheimer's disease (AD).Clinical study display organization proteolytic enzyme D in breast cancer cell by overexpression, and as if with improve the cell growth due to the danger of transfer increase relevant.Cathepsin D also is considered to relate to the formation of beta amyloid peptide among the AD.Recently, several genetic correlation research with cathepsin D with follow amyloid pathology and alzheimer's disease to associate, as people such as Davidson, (2006) at J.Neurol.Neurosurg.Psychiatry 77,515-517 is described.The acquisition of selectivity and effective inhibitors will help further to define the effect of cathepsin D in disease, and may draw curative.
Malaria aspartyl proteolytic enzyme: aspartate protease I and II
Malaria is considered to one of the most serious in the world infectious diseases, influences about 500,000,000 people.This disease is propagated by the anopheles that great majority see the torrid areas.These species of plasmodium falciparum cause the relevant M ﹠ M of malaria more than 95%.Plasmodium falciparum becomes, and opposing more and more is existing treats, as chloroquine, Mefloquine hydrochloride and Sulphadoxine/Pyrimethamine hcl.Therefore be badly in need of new curative.
At the red corpuscle stage of parasite life cycle its host's of parasitic infestation red corpuscle, consume 80% the oxyphorase of g and D with nutrition.Hemoglobin degrading occurs in the parasitic acid vacuole, and many current antimalarial drugs show as the important vacuole function of destruction.The food vacuole comprises Aspartic Acid, halfcystine and metalloprotease, and these all are considered to work in the hemoglobin degrading process.In the plasmodium gene group, identified the gene of at least 10 kinds of coding aspartyl proteolytic enzyme.Four kinds of aspartyl proteolytic enzyme distribute and concentrate in the parasitic acidic food vacuole, i.e. aspartate protease I, II, IV and HAP, a kind of aspartyl proteolytic enzyme of organizing.The inhibitor of aspartate protease I and II has demonstrated effect in the cell of malaria and animal model, show that these enzymes may be the target of drug discovery, as people such as Coombs (2001) at Trends Parasitol 17, described in the 532-537.Really, the non-selective inhibitor of aspartyl proteolytic enzyme, pepstatin, vitro inhibition the growth of plasmodium falciparum.Analogue or immunodeficiency virus protease inhibitor with pepstatin have obtained analog result, the restraining effect that shows aspartyl proteolytic enzyme has been disturbed the life cycle of plasmodium falciparum, at Antimicrob.Agents Chemother 50, that is noticed among the 639-648 is such as people such as Andrews (2006).
The present invention relates to be used for the treatment of and/or the plasmodium falciparum proteolytic enzyme aspartate protease II of prevention of malaria or the lower molecular weight of other relevant aspartyl proteolytic enzyme, the evaluation of non-peptide inhibitor.
HIV aspartyl proteolytic enzyme: HIV-1 peptase
Acquired immune deficiency syndrome (AIDS) (AIDS) was at first reported among the patient in small number in 1981, now become world wide and infected the great pandemic that surpasses 3,008 million peoples, it is about 1,000,000 to be included in the U.S., in West Europe 580,000 and the Sub-Saharan Africa surpass 2,005 million peoples (
Http:// www.unaids.org).Since AIDS is identified at first clinically, science and therapeutic advance are outstanding.But it is out of control that AIDS remains, particularly in developing country.
Since the first AIDS report, obtained the AIDS patient's of current treatment the existing change completely of prognosis comprehensively.Today, the HIV-positive patient of receiving treatment lifetime intermediate value above 8 years.AIDS patient's life expectancy before AZT is introduced in 1987 were less than 1 year.This great variety is owing to the effectively exploitation of methods of treatment, the early detection of HIV-positive individuals, and to analysis and the ongoing effort of understanding virus resistance mechanism, and virus resistance can overcome by rational drug development and combined therapy.
Three steps of the curative target HIV life cycle of FDA approval: reverse transcription, proteoclastic maturation and fusion.Triple treatments often refer to high reactivity antiretroviral therapy (HAART), are standard treatment at present.It is by proteinase inhibitor or non-nucleoside reverse transcriptase inhibitor and two kinds of nucleoside reverse transcriptase inhibitor combinations and form.
The translation of human immunodeficiency virus's type-1 (HIV-1) geneome RNA causes generating two kinds of polyprotein precursors, Gag and Gag-Pol.55-kDa Gag precursor comprises structural protein, and the Gag-Pol polyprotein of 160-kDa comprises function viral enzyme proteolytic enzyme, reversed transcriptive enzyme and intergrase.Gag and Gag-Pol polyprotein are transported to plasma membrane, and the assembling of C-type retrovirus and slow virus generally takes place at plasma membrane.During particle assembling, virus protease is cracked into the required 26S Proteasome Structure and Function albumen of virus replication with Gag and Gag-Pol precursor.Allow the formation of virus particle at the intracytoplasmic protease activity of cells infected, these virus particle can discharge from cell in the final stage of budding.
Sophisticated HIV-proteolytic enzyme is the obligate dimer of identical 11-kDa subunit, in two catalysis Aspartic Acid residues of each contribution one.On the contrary, the aspartyl proteolytic enzyme family member of cell development has two monomeric enzymes that contain As β-Thr-Gly structural domain.The dimer structure of retroviral Protease uniqueness is mainly stablized by antiparallel β-fragment, and antiparallel β-fragment is each monomer by amino-and the staggered combination formation of beta chain of carboxyl-end.
The activation of HIV-1 proteolytic enzyme is that dimerization and the autocatalytically of Gag-Pol discharges, and is the committed step in the viral life cycle.Protease activated restraining effect causes major defect and the completely losing of viral infectivity of Gag polyprotein in handling.Like this, virus protease has become the target spot of HIV treatment, produces many hiv protease inhibitor that enter clinical trial, as people such as Pana (1999) at Pharmacotherapy 19, people such as 35-59 and Morse, (2006) are summarized among the 215-225 at Lancet Infect.Dis.6.Great majority are based on the inhibitor of substrate in these medicines, and the crystalline texture data of natural enzyme and enzyme inhibitor complex abundance have promoted the design of these inhibitor.In addition, current do not have to describe in detail be used for the catalyst mechanism that substrate selects and the physicochemical data widely of molecular basis.
Detailed Description Of The Invention
At first, the present invention relates to be used for the compound and the pharmacologically acceptable salt thereof of following general formula of the inhibitor of beta-secretase, cathepsin D, aspartate protease II and/or HIV-proteolytic enzyme
Wherein
R
1It is straight chain C
1-8-alkyloyl oxygen base, straight chain C
1-8-alkoxyl group, straight chain-C
1-8-alkoxyl group-straight chain-C
1-8-alkoxyl group, straight chain C
1-8-alkoxycarbonyl amino, straight chain-C
0-8-alkyl-carbonyl-amino, optional N-list or N, N-two-C
1-8-alkylation amino or hydroxyl or straight chain ω-hydroxyl-C
1-8-alkyl.
Straight chain also refers to straight chain (linear) or unbranched (un-branched's) sometimes in the literature.As used herein, straight chain C
1-8-alkyloyl oxygen base is a straight chain C
0-7-alkyl-carbonyl oxygen base such as methanoyl, acetoxyl group, propionyloxy and butyryl acyloxy.Straight chain C
1-8The example of-alkyl is respectively methyl, ethyl, n-propyl, normal-butyl, n-pentyl and n-hexyl.Straight chain ω-hydroxyl-C
1-8The example of-alkyl is respectively hydroxymethyl, 2-hydroxyl-ethyl, 3-hydroxyl-n-propyl, 4-hydroxyl-normal-butyl, 5-hydroxyl-just-amyl group and 6-hydroxyl-n-hexyl.Straight chain-C
1-8The example of-alkoxyl group is the group as methoxyl group, oxyethyl group, positive propoxy and n-butoxy.Straight chain C
0-C
8The example of-alkyl-carbonyl-amino is for example formyl radical amino (formamido), kharophen, propionamido and butyl carbonylamino.Optional N-list-or N, N-two-C
1-8That-alkylation amino is preferably optional N-is single-or N, N-two-straight chain-C
1-8-alkylation amino, and can be for example amino, methylamino, dimethylamino, ethylamino, methylethyl amino, n-propyl amino, normal-butyl amino, n-pentyl amino or n-hexyl amino.
The compound of formula (I) has three unsymmetrical carbons at least and can therefore exist with the mixture of optically pure diastereomer, diastereomer, the racemic modification of diastereomer, the mixture of diastereomer racemic modification or the form of meso compound.The present invention includes all these forms.
The mixture of the mixture of diastereomer, diastereomer raceme or diastereomer raceme can be separated by traditional method, for example by column chromatography, tlc, HPLC etc.
Salt mainly is the pharmaceutically useful or nontoxic salt of formula (I) compound.Term " pharmacologically acceptable salt " comprises and mineral acid or organic acid salt that described mineral acid or organic acid be hydrochloric acid, Hydrogen bromide, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, toxilic acid, acetate, succsinic acid, tartrate, methylsulfonic acid, tosic acid etc. for example.
Have salt forming group compound salt particularly acid salt, with the salt of alkali, in the presence of a plurality of salt forming groups, also be blended salt or inner salt in some cases perhaps.
This type of salt is formed by for example formula (I) compound and acidic-group; described acidic-group is carboxyl or alkylsulfonyl for example; and be the salt that for example forms with the alkali that is fit to; for example derived from the Ia of the periodic table of elements; Ib; the nontoxic metal-salt of the metal of IIa and IIb family; an alkali metal salt for example; lithium salts particularly; sodium salt or sylvite; alkaline earth salt; for example magnesium salts or calcium salt; and also can be zinc salt and ammonium salt; comprise the salt that those and organic amine form; the list that for example optional hydroxyl of described organic amine replaces-; two-or trialkylamine; particularly single-; two-or three (low alkyl group) amine; the perhaps salt that forms with quaternary ammonium hydroxide; described quaternary ammonium hydroxide for example methyl-; ethyl-; diethyl-or triethylamine; single-; two-or three (2-hydroxyl (low alkyl group)) amine; for example ethanol-; di-alcohol-or trolamine; three (hydroxymethyl) methylamine or 2-hydroxyl-tert-butylamine; N; N-two (low alkyl group)-N-(hydroxyl (low alkyl group)) amine; N for example; N-two-N-dimethyl-N-(2-hydroxyethyl) amine; or N-methyl D-glycosamine; perhaps quaternary ammonium hydroxide, for example tertiary butyl ammonium hydroxide.Have for example amino formula (I) compound of basic group and can form acid salt, for example form acid salt with the mineral acid that is fit to, described mineral acid is haloid acid for example, hydrochloric acid for example, Hydrogen bromide, sulfuric acid (replacing one or two proton), phosphoric acid (replaces one or more protons, for example ortho-phosphoric acid or metaphosphoric acid), tetra-sodium (replacing one or more protons), perhaps with organic carboxyl acid, the thionamic acid that sulfonic acid or phosphonic acids or N-replace forms acid salt, described acid is acetate for example, propionic acid, oxyacetic acid, succsinic acid, toxilic acid, hydroxymaleic acid, methyl-maleic acid, fumaric acid, oxysuccinic acid, tartrate, glyconic acid, saccharic acid, glucuronic acid, citric acid, phenylformic acid, styracin, amygdalic acid, Whitfield's ointment, the 4-aminosallcylic acid, the 2-phenoxy benzoic acid, the 2-acetoxy-benzoic acid, pamoic acid (embonic acid), nicotinic acid, the for example above-mentioned a-amino acid of Yi Yansuan and amino acid, it also can be methylsulfonic acid, ethyl sulfonic acid, the 2-ethylenehydrinsulfonic acid, second-1, the 2-disulfonic acid, Phenylsulfonic acid, the 4-toluene sulfonic acide, naphthalene-2-sulfonic acid, 2-or 3-phoshoglyceric acid, glucose 6-phosphoric acid, N-cyclohexyl thionamic acid (formation cyclamate), perhaps with other acidic organic compound for example xitix form acid salt.Formula (I) compound with acid and basic group can also form inner salt.
The salt that obtains can be converted into other salt with known method own, for example acid salt is by for example other sour sodium salt, barium salt or silver salt are handled in the solvent that is fit to and obtained with the metal-salt that is fit to, the inorganic salt that form in this solvent are insoluble, thereby it is separated from molecular balance, and alkali salt obtains by discharging free acid and forming salt again.
Formula (I) compound, the salt that comprises them can also or comprise the form that is used for the crystalline solvent with the form of hydrate and obtain.
For separating and purifying, also can use and be not suitable for medicinal salt.
The prodrug derivant of compound described herein is its derivative that discharges the primary compound when using in vivo by chemistry or physics method.When reaching physiological pH or, prodrug for example can being converted into the primary compound by enzymatic conversion.The possible example of prodrug derivant is the ester of free obtainable carboxylic acid, S-and O-acyl derivative, alcohol or the phenol of mercaptan, acyl group as defined herein.Preferred derivative is pharmaceutically acceptable ester derivative, it is that the primary carboxylic acid transforms by solvolysis in Physiological Medium, for example lower alkyl esters, cycloalkyl ester, low-grade alkenyl ester, benzyl ester, list-or for example rudimentary ω of dibasic lower alkyl esters-(amino, single-or dialkyl amido, carboxyl, elementary alkoxy carbonyl)-alkyl ester or for example rudimentary α-(alkyloyl oxygen base, alkoxy carbonyl or dialkyl amino carbonyl)-alkyl ester; Usually, use valeryl oxygen ylmethyl ester and similar ester.
Because the close relation of free cpds, prodrug derivant and salt compound, when may and be fit to, the specilization compound among the present invention also comprises its prodrug derivant and salt form.The definition of mentioning is applicable in the scope of the general principles of chemistry, as common atom valence state.
Formula (I) compound comprises that also wherein one or more atoms are by their stable, displaced those compounds of cold isotropic substance; For example hydrogen atom is replaced by deuterium.
The compound of the preferred group of formula (I) and pharmacologically acceptable salt thereof is such compound, wherein
R
1Be hydroxyl or straight chain ω-hydroxyl-C
1-8-Alkyl, more preferably hydroxyl or straight chain ω-hydroxyl-C
1-4-Alkyl.
The compound of the further preferred group of formula (I) and pharmacologically acceptable salt thereof is such compound, wherein
R
1It is straight chain C
1-8-Alkoxyl group or straight chain C
1-8-Alkoxyl group-straight chain C
1-8-Alkoxyl group more preferably is a straight chain C
1-4-Alkoxyl group or straight chain C
1-4-Alkoxyl group-straight chain C
1-4-Alkoxyl group.
The compound of the further preferred group of formula (I) and pharmacologically acceptable salt thereof is such compound, wherein
R
1It is straight chain C
1-8-Alkyloyl oxygen base is more preferably straight chain C
1-4-Alkyloyl oxygen base.
The compound of the further preferred group of formula (I) and pharmacologically acceptable salt thereof is such compound, wherein
R
1It is straight chain C
0-8-Alkyl-carbonyl-amino is more preferably straight chain C
0-3-Alkyl-carbonyl-amino.
The compound of the further preferred group of formula (I) and pharmacologically acceptable salt thereof is such compound, wherein
R
1Be optional N-single-or N, N-two-C
1-8-Alkylation amino, more preferably optional N-list-or N, N-two-C
1-4-Alkylation amino.
The compound of the further preferred group of formula (I) and pharmacologically acceptable salt thereof is such compound, wherein
R
1Be optional N-single-or N, N-two-straight chain-C
1-8-Alkylation amino, more preferably optional N-list-or N, N-two-straight chain-C
1-4-Alkylation amino.
R
1Be preferably hydroxyl, methoxyl group, 2-methoxyl group-oxyethyl group, acetoxyl group formamido group, methyl carbonylamino or ethyl carbonylamino very especially.
Compound group mentioned above is not considered as closing, and the suitable part of these compound groups can exchange each other or omit with the definition that above provides or with reasonable manner, for example replaces by definition more specifically is overall.Definition is according to the general principles of chemistry, for example common atom valence state is rational.
Formula (I) compound can document in disclosed preparation method's similar manner preparation.Similar preparation method for example describes in WO 97/09311 to some extent.The details of concrete preparation variant is found among the embodiment.
Formula (I) compound also can be with optically pure form preparation.Being separated into enantiomorph can be undertaken by known method itself, preferably synthetic early the stage by forming salt with optically active acid (for example (+)-or (-)-amygdalic acid) and by fraction Crystallization Separation diastereoisomeric salt; Perhaps preferably stage in evening relatively by carrying out derivatize and, subsequently bond cleavage solved the chirality assistant agent by chromatography and/or Crystallization Separation diastereomer product with chirality assistant agent structural unit (for example (+)-or (-)-camphane acyl chlorides).Pure diastereoisomeric salt and derivative can be analyzed determining the absolute configuration that piperidines exists, and for single crystal, X-ray spectrum method is particularly suitable method with the ordinary light spectrometry.
Formula (I) compound and pharmacologically acceptable salt thereof present the inhibition activity to beta-secretase, cathepsin D, aspartate protease II and/or HIV-proteolytic enzyme.
The activity of the inhibitor of beta-secretase, cathepsin D, aspartate protease II and/or HIV-proteolytic enzyme can be in order to analyzed in vitro test determination down.
The protease inhibiting activity of compound can use FRET (fluorescence resonance energy transfer) (FRET) analysis of technology test kit and the zymin of baculovirus expression of for example recombinating is tested.FRET is used to monitor the cracking of peptide substrates.Analysis principle is as follows, by measurable energy difference, depends on that the existence of peptide sequence is quantitative.Peptide substrates is with two terminal fluorophores, fluorescence donor and cancellation acceptor synthetic.Select distance between these two groups so that under optical excitation, donor fluorescence can shift significantly by the acceptor cancellation by resonance energy.By the cracking of proteolytic enzyme, fluorophore is separated by quenching group, recovers the fluorescence quantum yield of donor.Therefore weak fluorescence peptide substrates is by the enzymatic lysis height fluorescence that becomes; The increase of fluorescence and proteolysis speed are linear dependences.
FRET is determined in the white polysorp plate and carries out.Measuring damping fluid is made up of 50mM sodium-acetate pH5,392mM sodium-chlor, 12.5% glycerine and 0.1%BSA.Every hole Incubating Solution is dissolved in inhibitor, 10 μ l among the DMSO by 160 μ l damping fluids, 10 μ l and is dissolved in that peptide substrates among the DMSO and 20 μ l enzyme solution form.Inhibitor is tested in the concentration range of 1pM to 1mM.Fluorescent mark donor and acceptor peptide substrates generate by solid-phase peptide synthetic (Applied Biosystems).Beta-secretase peptide substrates Rh-Glu-Val-Asn-Leu-Asp-Ala-Glu-Phe-Lys-quencher is available from Invitrogen, Carlsbad, California, USA.Cathepsin D's peptide substrates of sequence D ABCYL-Pro-Thr-Glu-Phe-Phe-Arg-Leu-OXL, the aspartate protease peptide substrates of sequence D ABCYL-Glu-Arg-Nle-Phe-Leu-Ser-Phe-Pro-OXL and the hiv protease peptide substrates of sequence D ABCYL-His-Lys-Ala-Arg-Val-Leu-Tyr-Glu-Ala-Nle-Ser-EDANS are all available from AnaSpec Inc, San Jose, California, USA.Recombinant expressed zymin is added to the mensuration system of different amounts, is that 1 unit/ml is hatched volume as beta-secretase concentration, and cathepsin D's concentration is 100ng/ml, and hiv protease concentration is that 500ng/ml and aspartate protease II concentration are 50ng/ml.Reaction begins from adding enzyme solution.Hatch and occur in 37 ℃ of 30-120min, promptly particularly beta-secretase is hatched lasting 60min, and 120min is hatched in cathepsin D, and aspartate protease II is hatched 40min, and hiv protease is hatched 40min.Reaction stops by the 1.0M Tris alkaline solution that adds 20 μ l.Enzyme substrates is to estimate by the fluorometric assay under the 460nm wavelength to the conversion of product.
External enzyme inhibition activity
Compound of the present invention presents structure and relies on and the special inhibition activity of enzyme.Suppressing active measures with the IC50 value.Therefore beta-secretase is incubated field of activity between 1pM and 1mM; The numerical range of cathepsin D is between 1pM and 1mM, and aspartate protease II is between 1pM and 1mM, and HIV-proteolytic enzyme is between 1pM and 1mM.
Formula (I) compound and pharmacologically acceptable salt thereof can be used as medicine, for example with the form of pharmaceutical preparation.Pharmaceutical preparation can enteron aisle use for example oral, for example with the form of tablet, coated tablet, sweet tablet tablet, hard and Gelseal, solution, emulsion or suspensoid; Nose is used, for example with the form of nasal spray; Rectal administration is for example with the form of suppository; Or transdermal administration, for example with the form of ointment or patch.But, also can use non-enteron aisle and use, for example intramuscular or intravenously are for example with the form of injection solution agent.
Tablet, coated tablet, sweet tablet tablet and hard-gelatin capsules can be by being prepared formula (I) compound and pharmacologically acceptable salt thereof and pharmaceutically acceptable inert inorganic or organic excipients processing.For example can being used for, the vehicle of these types of tablet, sweet tablet tablet and hard-gelatin capsules is lactose, W-Gum or derivatives thereof, talcum powder, stearic acid or its salt etc.
The vehicle that is fit to Gelseal is for example vegetables oil, paraffin, fat, semisolid and liquid polyol etc.
The vehicle that is fit to preparation solution and syrup is for example water, polyvalent alcohol, sucrose, Nulomoline, glucose etc.
The vehicle that is fit to the injection solution agent is for example water, alcohol, polyvalent alcohol, glycerine, vegetables oil, cholic acid, Yelkin TTS etc.
The vehicle that is fit to suppository is for example natural and winterized stearin, paraffin, fat, semisolid or liquid polyol etc.
In addition, pharmaceutical preparation can also comprise material, stablizer, wetting agent, emulsifying agent, sweeting agent, tinting material, the perfume compound of sanitas, solubilizing agent, increase viscosity, salt, buffer reagent, Drug coating or the antioxidant of change osmotic pressure in addition.They can also comprise other material that therapeutic value is arranged.
Theme of the present invention still is that formula (I) compound and pharmacologically acceptable salt thereof are used to prevent, postpone to make progress or treat the purposes that alzheimer's disease, malaria or HIV infect.
Theme of the present invention still is that formula (I) compound and pharmacologically acceptable salt thereof are used to prepare prevention, postpone the purposes of the medicine of progress or treatment alzheimer's disease, malaria or HIV infection.
Theme of the present invention still prevents, postpones to make progress or treat the method that alzheimer's disease, malaria or HIV infect, and it is to use general formula (I) compound or pharmaceutically acceptable salt thereof of treatment effective dose.
Theme of the present invention also is to comprise general formula (I) compound or pharmaceutically acceptable salt thereof of the inhibition that is used for beta-secretase, kethepsin, aspartate protease and/or HIV-proteolytic enzyme and the pharmaceutical preparation of composition commonly used.
Theme of the present invention still is used to prevent, postpone to make progress or treat the pharmaceutical preparation that alzheimer's disease, malaria, HIV infect, and it comprises general formula (I) compound or pharmaceutically acceptable salt thereof and composition commonly used.
Dosage can change in wide limit and must be fit to separately situation certainly in every kind of independent situation.Usually, be fit to Orally administered per daily dose and should be the about 3mg of each grownup (70kg) to about 3g, preferred extremely about 1g, about 300mg for example of about 10mg, preferably be divided into 1-3 single dose, it is equal sizes for example, can be fit to, also can surpass the described upper limit, and children accept to be fit to the low dosage of their ages and body weight usually.
Embodiment
Following examples have been explained the present invention.All with a degree centigrade mark, pressure marks with millibar all temperature.Unless otherwise indicated, reaction all takes place at room temperature.Shortenings " Rf=xx (A) " for example refers to, and the Rf in solvent systems A is xx.The ratio of the amount between the solvent is represented with volume parts usually.The chemical name of final product and intermediate produces by AutoNom2000 (name automatically) program based on chemical structural formula.
At Hypersil BDS C-18 (5um); Post: the HPLC gradient on 4 * 125mm:
I 90% water */10% acetonitrile * to 0% water */100% acetonitrile *, 5 minutes+2.5 minutes (1.5ml/min)
Il 95% water */5% acetonitrile * to 0% water */100% acetonitrile *, 40 minutes (0.8ml/min)
* comprise 0.1% trifluoroacetic acid.
Used following shortenings:
The ratio of Rf distance of material and solvent front migration from the off in thin-layer chromatography
The retention time of Rt material in HPLC (in minute)
M.p. fusing point (temperature)
The thin-film chromatography elution system:
The dense ammonia of A methylene chloride-methanol-25%=200: 20: 1
The dense ammonia of B methylene chloride-methanol-25%=200: 10: 1
The dense ammonia of C methylene chloride-methanol-25%=200: 30: 1
The dense ammonia of D methylene chloride-methanol-25%=100: 10: 1
Universal method A:(N-Cbz-deprotection, N-(1-phenyl-ethyl)-deprotection or N-benzyl-deprotection)
Add 0.1mmol Pd/C 10% in " derivative of N-protected " solution in 15ml tetrahydrofuran (THF) (or methyl alcohol) of the 1mmol that stirs, reaction mixture is hydrogenation at room temperature.Filter reaction mixture and concentrating under reduced pressure.Residue flash chromatography (SiO
260F) purifying obtains title compound.
Universal method B:(N-Tos-deprotection)
In the solution of 0.09mmol " toluol sulfonamide " in 10ml methyl alcohol that stirs, add the sodium amalgam (10%Na) of 0.44mmol SODIUM PHOSPHATE, MONOBASIC and 0.90mmol under the room temperature.Stirred reaction mixture 2-18 hour, dilute with water, and with ethyl acetate extraction (3 *).Merge organic phase, use the salt water washing, and use dried over sodium sulfate.The concentrating under reduced pressure solvent, residue flash chromatography (SiO
260F) purifying obtains title compound.
Universal method C:(BH
3
-reduction)
In the solution in " lactan " tetrahydrofuran (THF) of the 1mmol that stirs, add the borine tetrahydrofuran (THF) (1M is in tetrahydrofuran (THF)) of 2-4mmol at 3ml, and be heated to 50 ℃ 2-8 hour.
Reaction mixture adds 10ml methyl alcohol termination reaction, and concentrating under reduced pressure.By flash chromatography (SiO
260F) obtain title compound from residue.
Universal method D:(O-alkylation I)
Under-10 ℃ of stirrings, the tetrabutylammonium iodide of the sodium hydride of 1.2mmol (60% disperses thing in oil) and 0.1mmol is added to 1mmol " alcohol " and 1.1mmol " benzyl halogenide " N at 2.0ml, in the solution of dinethylformamide.Reaction mixture stirred 1 hour down at-10 ℃, at room temperature stirred 18 hours.Mixture is inclined to the 1M sodium bicarbonate aqueous solution, and with t-butyl methyl ether extracts (2 *).Continuous water of organic phase and salt water washing, and with dried over sodium sulfate and the evaporation.By flash chromatography (SiO
2Method 60F) obtains title compound from residue.
Universal method E:(O-alkylation II)
Under-10 ℃ of stirrings, the sodium hydride of 1.1mmol is added to (60% disperses thing in oil) 1mmol " alcohol " and 1.0-2.0mmol " benzyl halogenide " N at 2.0ml, in the solution of dinethylformamide.Reaction mixture stirred 1 hour down at-10 ℃, at room temperature stirred 18 hours.Mixture is inclined to the 1M sodium bicarbonate aqueous solution, and with t-butyl methyl ether extracts (2 *).The continuous water of organic phase and the salt water washing that merge, and with dried over sodium sulfate and evaporation.By flash chromatography (SiO
2Method 60F) obtains title compound from residue.
Universal method F:(alcohol desiliconization alkylation)
" silyl ether " solution in the tetrahydrofuran (THF) of 5ml of 1mmol mixes with the tetrabutyl ammonium fluoride of 1.5-2.0mmol (solution of 1M in tetrahydrofuran (THF)), and at room temperature stirred solution 1-2 hour.Dilute with water reaction soln then, and extract with t-butyl methyl ether (2 *).The organic phase that merges is also evaporated with dried over sodium sulfate.By flash chromatography (SiO
260F) from residue, obtain title compound.
Embodiment 1
(3S, 4R, 5R)-4-[4-((S)-3-methoxyl group-2-methyl-propoxy-methyl)-phenyl]-5-[4-(the 3-methoxyl group-
Propyl group)-3,4-dihydro-2H-benzo [1,4] oxazine-6-ylmethoxy]-piperidines-3-yl }-methyl alcohol
According to universal method A, use (3S, 4R, 5R)-3-hydroxymethyl-4-[4-((S)-3-methoxyl group-2-methyl-propoxy-methyl)-phenyl]-5-[4-(3-methoxyl group-propyl group)-3,4-dihydro-2H-benzo [1,4] oxazine-6-ylmethoxy]-piperidines-1-formic acid benzyl ester obtains title compound.
Starting raw material is prepared as follows:
A)
(3S, 4R, 5R)-3-hydroxymethyl-4-[4-((S)-3-methoxyl group-2-methyl-propoxy-methyl)-benzene Base]-5-[4-(3-methoxyl group-propyl group)-3,4-dihydro-2H-benzo [1,4] oxazine-6-ylmethoxy]-piperidines-1- The formic acid benzyl ester
According to universal method C, use (3S, 4R, 5R)-3-hydroxymethyl-4-[4-((S)-3-methoxyl group-2-methyl-propoxy-methyl)-phenyl]-5-[4-(3-methoxyl group-propyl group)-3-oxo-3,4-=hydrogen-2H-benzo [1,4] oxazine-6-ylmethoxy]-piperidines-1-formic acid benzyl ester obtains muddy buttery title compound.
Rf=0.15 (EtOAc-heptane 2: 1); Rt=5.22 (gradient 1).
B)
(3S, 4R, 5R)-3-hydroxymethyl-4-[4-((S)-3-methoxyl group-2-methyl-propoxy-methyl)-benzene Base]-5-[4-(3-methoxyl group-propyl group)-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-6-ylmethoxy]- Piperidines-1-formic acid benzyl ester
8.526mmol (3R, 4R, 5S)-4-[4-((S)-3-methoxyl group-2-methyl-propoxy--methyl)-phenyl]-3-[4-(3-methoxyl group-propyl group)-3-oxo-3,4-=hydrogen-2H-benzo [1,4] oxazine-6-ylmethoxy]-5-trityl oxygen ylmethyl-piperidines-1-formic acid benzyl ester is handled with the toluene-4-sulfonic acid monohydrate of 12.789mmol at tetrahydrofuran (THF) and the solution in the 80ml methyl alcohol of 20ml.Stir after 15 hours, reaction mixture alkalizes with saturated sodium bicarbonate aqueous solution, and concentrating under reduced pressure is removed most of methyl alcohol and tetrahydrofuran (THF).Residue is with dichloromethane extraction (3 *)--the organic layer water and the salt solution continuous washing of merging, with dried over sodium sulfate and evaporation.By flash chromatography (SiO
2, 60F) obtain the title compound of yellow oily from residue.Rt=4.86 (gradient I).
C)
(3R, 4R, 5S)-4-[4-((S)-3-methoxyl group-2-methyl-propoxy-methyl)-phenyl]-3-[4-(the 3-methoxyl group- Propyl group)-and 3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-6-ylmethoxy]-5-trityl oxygen ylmethyl -piperidines-1-formic acid benzyl ester
According to universal method D, use (3R, 4R, 5S)-3-hydroxyl-4-[4-((S)-3-methoxyl group-2-methyl-propoxy-methyl)-phenyl]-[1,4] oxazine-3-ketone [857272-02-7] obtains the title compound of yellow oily for 5-trityl oxygen ylmethyl-piperidines-1-formic acid benzyl ester and 6-chloromethyl-4-(3-methoxyl group-propyl group)-4H-benzo.Rt=6.58 (gradient I).
D)
(3R, 4R, 5S)-3-hydroxyl-4-[4-((S)-3-methoxyl group-2-methyl-propoxy-methyl)-phenyl]-the 5-triphen Methyl oxygen ylmethyl-piperidines-1-formic acid benzyl ester
Under 0 ℃, the chloroformic acid benzyl ester of 8.478mmol is dropped to the (3R of 8.478mmol, 4R, 5S)-4-[4-((S)-3-methoxyl group-2-methyl-propoxy-methyl)-phenyl]-5-trityl oxygen ylmethyl-piperidines-3-alcohol (L)-(+) almond ester is in the mixture of the saturated sodium bicarbonate aqueous solution of the ethyl acetate of 150ml and 150ml.After 1 hour, reaction mixture is distributed between saturated aqueous sodium carbonate and ethyl acetate--organic layer water and salt solution continuous washing.The water layer that merges is stripped with ethyl acetate--and the organic layer of merging also evaporates with dried over sodium sulfate.Obtain the crude product title compound of white foam shape.Rt=6.14 (gradient I).
E)
(3R, 4R, 5S)-4-[4-((S)-3-methoxyl group-2-methyl-propoxy-methyl)-phenyl]-5-trityl oxygen Ylmethyl-piperidines-3-alcohol (L)-(+) almond ester
According to universal method A, use (3R, 4R, 5S)-1-benzyl-4-[4-((S)-3-methoxyl group-2-methyl-propoxy-methyl)-phenyl]-5-trityl oxygen ylmethyl-piperidines-3-alcohol (L)-(+) almond ester obtains the title compound of white foam.Rt=4.92 (gradient I).
F)
(3R, 4R, 5S)-1-benzyl-4-[4-((S)-3-methoxyl group-2-methyl-propoxy-methyl)-phenyl]-the 5-triphen Methyl oxygen ylmethyl-piperidines-3-alcohol (L)-(+) almond ester
Under 60 ℃ (oil bath temperatures), (L)-(+) amygdalic acid of 2.36mmol is added to (the racemization 3R of 5.90mmol, 4R, 5S)-1-benzyl-4-[4-((S)-3-methoxyl group-2-methyl-propoxy-methyl)-phenyl]-5-trityl oxygen ylmethyl-piperidines-3-alcohol is in the solution of the tetrahydrofuran (THF) of 36ml.At 60 ℃ of normal hexanes that slowly are added dropwise to 36ml.In 3 hours, mixture is slowly cooled to room temperature, after the of short duration processing of ultra sonic bath, be cooled to 0 ℃ again and continue 2 hours.Leach precipitation and obtain the title compound of white solid with tetrahydrofuran (THF)/normal hexane washing in 1: 4.Rt=5.36 (gradient I).
For analysis purposes, in a small amount salt is dissolved in the ethyl acetate and with saturated sodium carbonate solution washing (2 *).Organic phase salt water washing, dried over sodium sulfate, and evaporation obtains the title compound (white solid) of free alkali.Rt=12.81 (Raicel Chiralpak AD 0.46 * 25cm; 95% hexane/5% Virahol; 0.7ml/ minute continue 60 minutes).
G)
(racemization-3R, 4R, 5S)-1-benzyl-4-[4-((S)-3-methoxyl group-2-methyl-propoxy-methyl)-phenyl]-5- Trityl oxygen ylmethyl-piperidines-3-alcohol
Under the room temperature borine-tetrahydrofuran (THF) (1M/THF) drips of solution of 86.852mmol is added to 1-benzyl-4-[4-((S)-3-methoxyl group-2-methyl-propoxy-methyl)-phenyl of 43.426mmol]-3-(R, S)-trityl oxygen ylmethyl-1,2,3, in the solution of 6-tetrahydrochysene-pyridine in the 220ml tetrahydrofuran (THF).After stirring is spent the night, reaction mixture is cooled to 10 ℃, the solution of potassium hydroxide in 60ml water, the hydrogen peroxide of 86.852mmol (30%/water) that drip 251.871mmol are in succession handled.Reaction mixture slowly is warmed to 65 ℃, stirred 3 hours and then be cooled to room temperature.Reaction mixture is distributed in t-butyl methyl ether and frozen water--organic layer salt water washing.The water layer that merges is with t-butyl methyl ether extraction (2 *)--the organic layer of merging also evaporates with dried over sodium sulfate.Residue flash chromatography (SiO
260F) purifying obtains the title compound of yellow oily.Rf=0.15 (EtOAc-hexane 1: 1); Rt=5.36 (gradient I).
H)
1-benzyl-4-[4-((S)-3-methoxyl group-2-methyl-propoxy-methyl)-phenyl]-3-(R, S)-trityl Oxygen ylmethyl-1,2,3,6-tetrahydrochysene-pyridine
Under 0 ℃, the thionyl chloride of 102.636mmol is slowly added to 1-benzyl-4-[4-((S)-3-methoxyl group-2-methyl-propoxy-methyl)-phenyl of 85.53mmol]-3-(R, S)-trityl oxygen ylmethyl-piperidines-4-(R, S)-solution of alcohol in the pyridine of 250ml in.Notice that temperature inside keeps below 10 ℃.After 5 minutes, reaction mixture is by the 4N NaOH solution termination reaction of adding 50ml, and concentrating under reduced pressure.Residue is dissolved in the ethyl acetate, and use saturated sodium bicarbonate aqueous solution in succession, water and salt water washing, dried over sodium sulfate and evaporation.With residue flash chromatography (SiO
260F) purifying obtains the title compound of yellow oily.Rf=0.28 (the dense ammonia of EtOAc-heptane-25% 100: 200: 1); Rt=5.64 (gradient I).
I)
1-benzyl-4-[4-((S)-3-methoxyl group-2-methyl-propoxy-methyl)-phenyl]-3-(R, S)-trityl oxygen Ylmethyl-piperidines-4-(R, S)-alcohol
Glycol dibromide with 2.32mmol under the room temperature argon gas adds in the suspension of magnesium in the 20ml tetrahydrofuran (THF) of 156.518mmol.Reaction mixture is warmed to magnesium begins reaction, 1-bromo-4 ((S)-3-methoxyl group-2-methyl-propoxy-methyl)-solution of benzene in the tetrahydrofuran (THF) of 170ml that adds the 151.509mmol of 3ml then, then surplus solution is added, keep gentle backflow simultaneously.After 2 hours, reaction mixture is cooled to room temperature, slowly add the 1-benzyl-solution of 3-phenmethyl oxygen ylmethyl-piperidin-4-one-[234757-27-8] in the tetrahydrofuran (THF) of 170ml of 125.214mmol then, carefully keep internal reaction temperature below 40 ℃.Stirred overnight at room temperature is with reaction mixture saturated aqueous ammonium chloride termination reaction.Ethyl acetate is added in the reaction mixture--being separated--organic phase water and salt water washing in succession.The water that merges is stripped with ethyl acetate--and the organic phase of merging is also evaporated with dried over sodium sulfate.Residue flash chromatography purifying (SiO
260F) purifying obtains the title compound of yellow oily.Rf=0.30 (the dense ammonia of EtOAc-heptane-25% 100: 100: 1); Rt=5.43 (gradient I).
J)
1-bromo-4-((S)-3-methoxyl group-2-methyl-propoxy-methyl)-benzene
According to universal method E, use 1-bromo-4-chloromethyl-benzene [589-17-3] and (R)-3-methoxyl group-2-methyl-third-1-alcohol to obtain the title compound of yellow oily.Rf=0.44 (EtOAc-heptane 1: 6); Rt=5.29 (gradient I).
K)
(R)-3-methoxyl group-2-methyl-third-1-alcohol
According to universal method F, use triisopropyl-(3-methoxyl group-2 (S)-methyl propoxy-) silane to obtain the title compound of yellow oily.Rf=0.42 (methylene dichloride-Anaesthetie Ether 1: 1).
L)
Triisopropyl-((S)-3-methoxyl group-2-methyl propoxy-) silane
Under 0 ℃, the sodium hydride of 3.09g is added to (60% disperses thing, in oil) N of the methyl iodide of (the S)-2-methyl-3-sec.-propyl silicon alkoxypropan-1-alcohol [256643-28-4] of 9.55g and 7.3ml, in the solution in the dinethylformamide at 70ml.After the room temperature 60 hours, reaction mixture with t-butyl methyl ether dilution and water and salt water washing in succession, is also evaporated with dried over sodium sulfate.Residue flash chromatography (SiO
260F) purifying obtains the title compound of yellow oily.Rf=0.51 (EtOAc-heptane 1: 10).
Embodiment 2
N-{ (3S, 4R, 5R)-4-[4-((S)-3-methoxyl group-2-methyl-propoxy-methyl)-phenyl]-5-[4-(3-oxygen
Base-propyl group)-3,4-dihydro-2H-benzo [1,4] oxazine-6-ylmethoxy]-piperidines-3-ylmethyl }-ethanamide
According to universal method A; use (3R; 4R; 5R)-3-(acetylamino-methyl)-4-[4-((S)-3-methoxyl group-2-methyl-propoxy-methyl)-phenyl]-5-[4-(3-methoxyl group-propyl group)-3; 4-dihydro-2H-benzo [1,4] oxazine-6-ylmethoxy]-piperidines-1-formic acid benzyl ester obtains title compound.
Starting raw material is prepared as follows:
A)
(3R, 4R, 5R)-3-(acetylamino-methyl)-4-[4-((S)-3-methoxyl group-2-methyl-propoxy-first Base)-phenyl [5-[4-(3-methoxyl group-propyl group)-3,4-dihydro-2H-benzo [1,4] oxazine-6-ylmethoxy]-piperazine Pyridine-1-formic acid benzyl ester
Under 0 ℃ of argon gas, the Acetyl Chloride 98Min. of 5.936mmol is added to the (3R of 5.396mmol, 4R, 5R)-3-amino methyl-4-[4-((S)-3-methoxyl group-2-methyl-propoxy-methyl)-phenyl]-5-[4-(3-methoxyl group-propyl group)-3, in the solution of triethylamine in the methylene dichloride of 80ml of 4-dihydro-2H-benzo [1,4] oxazine-6-ylmethoxy]-piperidines-1-formic acid benzyl ester and 6.475mmol.After 30 minutes, reaction mixture saturated sodium bicarbonate aqueous solution termination reaction, and with t-butyl methyl ether extracts (2 *).Organic layer water and the salt water washing in succession that merges is with dried over sodium sulfate and evaporation.Residue flash chromatography (SiO
260F) purifying obtains the title compound of yellow oily.Rt=4.98 (gradient I).
B)
(3R, 4R, 5R)-3-amino methyl-4-[4-((S)-3-methoxyl group-2-methyl-propoxy-methyl)-benzene Base]-5-[4-(3-methoxyl group-propyl group)-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-6-ylmethoxy]- Piperidines-1-formic acid benzyl ester
The triphenylphosphine of 7.128mmol is at room temperature added to (the 3S of 5.940mmol, 4R, 5R)-3-azido-methyl-4-[4-((S)-3-methoxyl group-2-methyl-propoxy-methyl)-phenyl]-5-[4-(3-methoxyl group-propyl group)-3, in 4-dihydro-2H-benzo [1,4] oxazine-6-the ylmethoxy]-solution of piperidines-1-formic acid benzyl ester in the strong aqua (25%) of 20ml methyl alcohol, 20ml tetrahydrofuran (THF), 5ml water and 3.56ml.After stirring is spent the night, with reaction mixture in t-butyl methyl ether with in water/saturated sodium bicarbonate aqueous solution distribute at 5: 1.Water layer extracts with t-butyl methyl ether--the organic layer water and the salt water washing in succession of merging, and with dried over sodium sulfate and evaporation.Residue flash chromatography (SiO
2, 60F) purifying obtains the title compound of yellow oily.Rf=0.42 (the dense ammonia of methylene chloride-methanol-25% 200: 20: 1); Rt=4.64 (gradient I).
C)
(3S, 4R, 5R)-3-azido-methyl-4-[4-((S)-3-methoxyl group-2-methyl-propoxy-methyl)-benzene Base]-5-[4-(3-methoxyl group-propyl group)-3,4-dihydro-2H-benzo [1,4] oxazine-6-ylmethoxy]-piperidines-1- The formic acid benzyl ester
At 45 ℃ under argon gas; the sodiumazide of 31.625mmol is added to the (3R of 6.253mmol; 4R; 5S)-4-[4-((S)-3-methoxyl group-2-methyl-propoxy-methyl)-phenyl]-3-[4-(3-methoxyl group-propyl group)-3; 4-dihydro-2H-benzo [1; 4] oxazine-6-ylmethoxy]-5-(toluene-4-alkylsulfonyl oxygen ylmethyl)-piperidines-1-formic acid benzyl ester is at 1 of 50ml, the solution in 3-dimethyl-tetrahydropyrimidine-2-ketone (DMPU).After 5 hours, reaction mixture is cooled to room temperature, with t-butyl methyl ether dilution, water and salt water washing, with dried over sodium sulfate and evaporation.Obtain the crude product title compound of yellow oily.Rf=0.58 (EtOAc-heptane 2: 1); Rt=5.96 (gradient I).
D)
(3R, 4R, 5S)-4-[4-((S)-3-methoxyl group-2-methyl-propoxy-methyl)-phenyl]-3-[4-(3-first The oxygen base -propyl group)-3,4-dihydro-2H-benzo [1,4] oxazine-6-ylmethoxy]-5-(toluene-4-alkylsulfonyl oxygen Ji Jia Base)-piperidines-1-formic acid benzyl ester
At 0 ℃ of (3S that under argon gas, 4-methyl-benzene sulfonyl chloride of 7.077mmol is added to 6.583mmol, 4R, 5R)-3-hydroxymethyl-4-[4-((S)-3-methoxyl group-2-methyl-propoxy-methyl)-phenyl]-5-[4-(3-methoxyl group-propyl group)-3, in the triethylamine of 4-dihydro-2H-benzo [1,4] oxazine-6-ylmethoxy]-piperidines-1-formic acid benzyl ester (embodiment 1a), 9.875mmol and the solution of dimethyl-pyridin-4-yl-amine in the methylene dichloride of 65ml of 0.329mmol.After the stirred overnight at room temperature, reaction mixture is diluted with t-butyl methyl ether, use saturated sodium bicarbonate aqueous solution, water and salt water washing in succession, with dried over sodium sulfate and evaporation.Obtain the crude product title compound of yellow oily.Rf=0.44 (EtOAc-heptane 2: 1); Rt=5.94 (gradient I).
According to the method for describing among the embodiment 2, prepare following compound in a similar manner:
3
N-{ (3S, 4R, 5R)-4-[4-((S)-3-methoxyl group-2-methyl-propoxy-methyl)-phenyl]-5-[4-(3-first Oxygen base-propyl group)-3,4-dihydro-2H-benzo [1,4] oxazine-6-ylmethoxy]-piperidines-3-ylmethyl }-propionyl Amine
In step a, use propionyl chloride to substitute Acetyl Chloride 98Min..
7
N-{ (3S, 4R, 5R)-4-[4-((S)-3-methoxyl group-2-methyl-propoxy-methyl)-phenyl]-5-[4-(3-first Oxygen base-propyl group)-3,4-dihydro-2H-benzo [1,4] oxazine-6-ylmethoxy]-piperidines-3-ylmethyl }-formyl Amine
In order to descend method alternative steps a:
Under argon gas, the 4-nitrophenyl manthanoate of 1.4mmol is added to the (3R of 1mmol, 4R, 5R)-3-amino methyl-4-[4-((S)-3-methoxyl group-2-methyl-propoxy-methyl)-phenyl]-5-[4-(3-methoxyl group-propyl group)-3,4-dihydro-2H-benzo [1,4] oxazine-6-ylmethoxy]-piperidines-1-formic acid benzyl ester (embodiment 2b) in the 10ml methylene dichloride, add the triethylamine of 1mmol afterwards.After 60 minutes, evaporation reaction mixture.Residue flash chromatography (SiO
2, 60F) purifying obtains title compound, and it obtains identifying based on the Rf value.
Embodiment 4
6-{ (3R, 4R, 5S)-5-methoxymethyl-4-[4-((S)-3-methoxyl group-2-methyl-propoxy-methyl)-phenyl]-
Piperidines-3-base oxygen ylmethyl }-4-(3-methoxyl group-propyl group)-3,4-dihydro-2H-benzo [1,4] oxazine
According to universal method A, use (3S, 4R, 5R)-5-methoxymethyl-4-[4-((S)-3-methoxyl group-2-methyl-propoxy-methyl)-phenyl-5-[4-(3-methoxyl group-propyl group)-3,4-dihydro-2H-benzo [1,4] oxazine-6-ylmethoxy]-piperidines-1-formic acid benzyl ester obtains title compound.
Starting raw material is prepared as follows:
A)
(3S, 4R, 5R)-3-methoxymethyl-4-[4-((S)-3-methoxyl group-2-methyl-propoxy-methyl)-phenyl -5-[4-(3-methoxyl group-propyl group)-3,4-dihydro-2H-benzo [1,4] oxazine-6-ylmethoxy]-piperidines-1-formic acid Benzyl ester
At 0 ℃ of (3S that under argon gas, the methyl iodide of 2.568mmol is added to 0.642mmol, 4R, 5R)-3-hydroxymethyl-4-[4-((S)-3-methoxyl group-2-methyl-propoxy-methyl)-phenyl]-5-[4-(3-methoxyl group-propyl group)-3,4-dihydro-2H-benzo [1,4] oxazine-6-ylmethoxy]-suspension of the sodium hydride (60% disperses thing, in oil) of piperidines-1-formic acid benzyl ester (embodiment 1a) and 0.963mmol in.0 ℃ stir 1 hour after, stirring at room 1 hour, reaction mixture is distributed between t-butyl methyl ether and saturated sodium bicarbonate aqueous solution.Water layer is with t-butyl methyl ether extraction (2 *)--the organic layer water and the salt water washing in succession of merging, with dried over sodium sulfate and evaporation.Residue flash chromatography (SiO
260F) purifying obtains the title compound (EtOAc-heptane 1: 1) of yellow oily; Rt=5.87 (gradient I).
According to the method for describing among the embodiment 4, prepare following compound in a similar manner:
6
6-{ (3R, 4R, 5S)-5-(2-methoxyl group-second methyl)-4-[4-((S)-3-methoxyl group-2-methyl-third oxygen Ylmethyl)-phenyl]-piperidines-3-base oxygen ylmethyl }-4-(3-methoxyl group-propyl group)-3,4-dihydro-2H-benzo [1,4] oxazine
In step a, use 1-bromo-2-methoxyl group-ethane (substituting methyl iodide) and 1 normal tetrabutylammonium iodide.
Embodiment 5
Acetate (3S, 4R, 5R)-4-[4-((S}-3-methoxyl group-2-methyl-propoxy-methyl)-phenyl]-5-[4-(3-methoxy
Base-propyl group)-3,4-dihydro-2H-benzo [1,4] oxazine-6-ylmethoxy]-piperidines-3-ylmethyl ester
According to universal method A, use (3S, 4R, 5R)-3-acetoxy-methyl-4-[4-((S)-3-methoxyl group-2-methyl-propoxy-methyl)-phenyl]-5-[4-(3-methoxyl group-propyl group)-3,4-dihydro-2H-benzo [1,4] oxazine-6-ylmethoxy]-piperidines-1-formic acid benzyl ester obtains title compound.
Starting raw material is prepared as follows:
A)
(3S, 4R, 5R)-3-acetoxy-methyl-4-[4-((S)-3-methoxyl group-2-methyl-propoxy-methyl)-benzene Base]-5-[4-(3-methoxyl group-propyl group)-3,4-dihydro-2H-benzo [1,4] oxazine-6-ylmethoxy]-piperidines-1- The formic acid benzyl ester
Similar to embodiment 2a, use (3S, 4R, 5R)-3-hydroxymethyl-4-[4-((S)-3-methoxyl group-2-methyl-propoxy-methyl)-phenyl]-5-[4-(3-methoxyl group-propyl group)-3,4-dihydro-2H-benzo [1,4] oxazine-6-ylmethoxy]-piperidines-1-formic acid benzyl ester (embodiment 1a) and Acetyl Chloride 98Min. obtain the title compound of colorless oil.Rf=0.20 (EtOAc-heptane 1: 1); Rt=5.69 (gradient I).
Claims (8)
1. be used to suppress following formula: compound or its pharmacologically acceptable salt of beta-secretase, cathepsin D, aspartate protease II and/or HIV-proteolytic enzyme, wherein
R
1It is straight chain C
1-8-alkyloyl oxygen base, straight chain C
1-8-alkoxyl group, straight chain C
1-8-alkoxyl group-straight chain C
1-8-alkoxyl group, straight chain C
1-8-alkoxycarbonyl amino, straight chain C
0-8-alkyl-carbonyl-amino, optional N-list-or N, N-two-C
1-8-alkylation amino or hydroxyl or straight chain ω-hydroxyl-C
1-8-alkyl.
2. according to the compound of claim 1, wherein
R
1Be hydroxyl or straight chain ω-hydroxyl-C
1-8-alkyl.
3. according to the compound of claim 1, wherein
R
1It is straight chain C
1-8-alkyloyl oxygen base.
4. according to the compound of claim 1, wherein
R
1Be or straight chain C
0-8-alkyl-carbonyl-amino.
5. according to the compound of claim 1, wherein
R
1Randomly be N-single-or N, N-two-straight chain C
1-8-alkylation amino.
6. according to the compound of claim 1, wherein
R
1Be hydroxyl, methoxyl group, 2-methoxyl group-oxyethyl group, acetoxyl group, formamido-, methyl carbonylamino or ethyl carbonylamino.
7. be used to prevent, postpone to make progress or treat any one general formula (I) compound or pharmaceutically acceptable salt thereof that alzheimer's disease, malaria or HIV infect according to claim 1 to 6.
8. be used to prevent, postpone to make progress or treat the pharmaceutical preparation that alzheimer's disease, malaria or HIV infect, its described preparation comprises any one general formula (I) compound or pharmaceutically acceptable salt thereof according to claim 1 to 6, and usual excipients.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP08153929.8 | 2008-04-02 | ||
| EP08153929 | 2008-04-02 | ||
| PCT/EP2009/053898 WO2009121914A1 (en) | 2008-04-02 | 2009-04-01 | Substituted piperidines as therapeutic compounds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101970431A true CN101970431A (en) | 2011-02-09 |
Family
ID=40627638
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2009801083136A Pending CN101970431A (en) | 2008-04-02 | 2009-04-01 | Substituted piperidines as therapeutic compounds |
Country Status (10)
| Country | Link |
|---|---|
| EP (1) | EP2271644A1 (en) |
| JP (1) | JP2011516453A (en) |
| KR (1) | KR20110002459A (en) |
| CN (1) | CN101970431A (en) |
| AU (1) | AU2009232012A1 (en) |
| BR (1) | BRPI0910991A2 (en) |
| CA (1) | CA2719070A1 (en) |
| EA (1) | EA201001517A1 (en) |
| MX (1) | MX2010010876A (en) |
| WO (1) | WO2009121914A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105001300A (en) * | 2014-04-17 | 2015-10-28 | 复旦大学 | Cathepsin D inhibitor, preparation method, pharmaceutical composition and applications thereof |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011057160A2 (en) * | 2009-11-06 | 2011-05-12 | The Regents Of The Uiversity Of California | Method to improve the immunogenicity of vaccine antigens by modification of cleavage sites in hiv-1 gp 120 |
| CN104945382B (en) | 2009-10-14 | 2020-02-07 | 默沙东公司 | Substituted piperidines that increase p53 activity and uses thereof |
| GB201008209D0 (en) * | 2010-05-17 | 2010-06-30 | Senexis Ltd | Compounds |
| WO2013062923A1 (en) | 2011-10-28 | 2013-05-02 | Merck Sharp & Dohme Corp. | MACROCYCLES THAT INCREASE p53 ACTIVITY AND THE USES THEREOF |
| CA2895504A1 (en) | 2012-12-20 | 2014-06-26 | Merck Sharp & Dohme Corp. | Substituted imidazopyridines as hdm2 inhibitors |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1816122A3 (en) * | 2006-01-19 | 2007-09-19 | Speedel Experimenta AG | 3,4,5-substituted piperidines as therapeutic compounds |
| EP1908761A1 (en) * | 2006-10-04 | 2008-04-09 | Speedel Experimenta AG | Organic compounds |
| EP1911758A1 (en) * | 2006-10-04 | 2008-04-16 | Speedel Experimenta AG | Phenyl piperidine derivatives for use as renin inhibitors |
-
2009
- 2009-04-01 MX MX2010010876A patent/MX2010010876A/en not_active Application Discontinuation
- 2009-04-01 CA CA2719070A patent/CA2719070A1/en not_active Abandoned
- 2009-04-01 JP JP2011502382A patent/JP2011516453A/en active Pending
- 2009-04-01 AU AU2009232012A patent/AU2009232012A1/en not_active Abandoned
- 2009-04-01 BR BRPI0910991A patent/BRPI0910991A2/en not_active Application Discontinuation
- 2009-04-01 KR KR1020107022007A patent/KR20110002459A/en not_active Application Discontinuation
- 2009-04-01 CN CN2009801083136A patent/CN101970431A/en active Pending
- 2009-04-01 EA EA201001517A patent/EA201001517A1/en unknown
- 2009-04-01 EP EP09728288A patent/EP2271644A1/en not_active Withdrawn
- 2009-04-01 WO PCT/EP2009/053898 patent/WO2009121914A1/en active Application Filing
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105001300A (en) * | 2014-04-17 | 2015-10-28 | 复旦大学 | Cathepsin D inhibitor, preparation method, pharmaceutical composition and applications thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| EP2271644A1 (en) | 2011-01-12 |
| JP2011516453A (en) | 2011-05-26 |
| WO2009121914A1 (en) | 2009-10-08 |
| KR20110002459A (en) | 2011-01-07 |
| CA2719070A1 (en) | 2009-10-08 |
| EA201001517A1 (en) | 2011-04-29 |
| AU2009232012A1 (en) | 2009-10-08 |
| MX2010010876A (en) | 2010-10-26 |
| BRPI0910991A2 (en) | 2016-01-19 |
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Open date: 20110209 |