CN101328117B - 1-phenylalkanecarboxylic acid derivatives for the treatment of neurodegenerative diseases - Google Patents
1-phenylalkanecarboxylic acid derivatives for the treatment of neurodegenerative diseases Download PDFInfo
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- CN101328117B CN101328117B CN200810100704.0A CN200810100704A CN101328117B CN 101328117 B CN101328117 B CN 101328117B CN 200810100704 A CN200810100704 A CN 200810100704A CN 101328117 B CN101328117 B CN 101328117B
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Abstract
The invention relates to 1-Phenylalkanecarboxylic acid derivatives shown as a formula (I), pro-drug and organism isostere on the carboxylic acid thereof, the processes for the preparation thereof and the use thereof in the treatment and/or prevention of neurodegenerative diseases such as Alzheimer's disease. The compound of the invention can inhibit the release of A beta 42, thus regulating gamma-secreting enzyme activity and not influencing other important metabolic processes.
Description
The present invention relates to 1-octadecyloxy phenyl carboxylic-acid, the prodrug in its carboxylic moiety and bioisoster.The invention still further relates to their preparation method and the application in prevention or treatment neurodegenerative disease, particularly alzheimer's disease thereof.
Foreword
Alzheimer's disease is a kind of neurodegenerative disease, it is characterized in that a large amount of disappearances of pallium atrophy and cortical neuron and basal nuclei cholinergic project to cortex.From histopathologic point, there is the interior neurofibrillary tangles of born of the same parents in extracellular and blood vessel peripheral nerve spot and brain essence in patients with Alzheimer disease dispersivity.
Neuritic plaque is mainly by forming with the protein aggregate that is called amyloid beta (β A) of 39-43 amino acids residue and with the difference of amino acid quantity, described protein is A β
39, A β
40, A β
42with A β
43.
Except these histopathology infringements, also lack some neurotransmitter, particularly vagusstoff, serotonin, norepinephrine, Dopamine HCL, L-glutamic acid and Substance P.In any case the pharmacology means that object is mainly to increase vagusstoff cerebral levels by acetylcholinesterase depressant are poor or can not obtain the effect that significantly prevents that this disease from developing from the effect of clinical point acquisition.Due to this reason, the attention in recent years has concentrated in the mechanism that in brain in patients, main pathological lesion forms, i.e. neuritic plaque and neurofibrillary tangles, and sought more efficiently treatment means.
Prior art
Epidemiological study confirms to give for a long time non-steroidal anti-inflammatory drug (NSAIDs) and significantly reduced in the crowd who regularly takes these medicines the outbreak of alzheimer's disease.The mechanism of this class NSAID prophylactic effect is illustrated not yet completely, but obviously relevant to the ability of its inhibition cyclo-oxygenase (COX).
The new pharmacotoxicological effect of some non-steroidal anti-inflammatory drug (NSAIDs) has been described recently: indomethacin, sulindac, Ibuprofen BP/EP and flurbiprofen can optionally reduce most of neurotoxicity isotype of beta-amyloid peptide in cell culture and produce, and contain 42 amino acid whose form (A β
42), be conducive to thus a small amount of harmful isotype A β
38discharge (Weggen etc., < < nature > > (Nature) 2001; 414 (6860): 212-6).But, under high concentration, observed A β in vitro
42generation is suppressed, and this can be owing to the interaction of these medicines and gamma-secretase (having macromole/polyprotein enzyme complex of aspartyl protease activity).Being equivalent to the blood plasma of dosage used in experiment in vitro and brain concentration can significantly increase the harm of treated patient typical case COX inhibitor side effect, such as gastrointestinal hemorrhage and perforated ulcer.
Claimed prevention in WO01/78721, delay or reverse the method for alzheimer's disease development, by A β
38level increases and A β
42under the condition that level remains unchanged, reduce A β
42promoting agent carry out.In addition disclose for the identification of reducing A β with research and development,
42the method of promoting agent and material and for the identification of the method for promoting agent that increases alzheimer's disease development or fast-developing harm.Reported the embodiment that relates to indomethacin and Flufenamic Acid derivative, but without the embodiment that relates to flurbiprofen derivative.
Jantzen etc. are at < < Journal of Neuroscience > > (J Neurosci) 2002; The flurbiprofen derivative that can discharge nitrogen oxide has been described in 22:2246-2254.This file described in general manner flurbiprofen derivative obviously than NSAIDs remove aspect amyloid beta settling more effective, but to any reduction A β
42selection activity all do not relate to.
The problem that may exist in this treatment plan and according to conventional NSAID s, to peptide A β
42have more selectivity and have and more effectively suppress active and lower or do not have inhibiting novel derivative can become object to be completely to prevent Alzheimer onste and/or to delay to represent the obvious improvement in the therapy that the cognitive ability of early stage disease stage declines to the inhibition degree of cyclo-oxygenase.
At GB 1,198,212, in US 3,978,071, US 757,136, GB 1,352,723, JP49100089 and JP 50046669 by 1-phenyl-2 that replace, 2-dialkyl carboxylic acid derivatives is described as antiphlogiston, anodyne and febrifuge.
JP-4, in 7047,375 and FR-2,012,285 by 3-halo-4-alkyl-or the 1-benzyl ring alkyl-carboxylic acid derivatives of cycloalkyl-replacement be described as having the material of identical activity.
From (Takeda Kenkyushoho 1975 in relating to the file of Kuzuna S etc. of structure-activity research of a series of phenylacetic acid derivatives, 34,467-473) described in general manner and on alpha-carbon atom position, introduced cyclopropane base and reduced anti-inflammatory and analgesic activity.
In WO 99/41224, the claimed numerous disease that is used for the treatment of, comprises that new two aryl-acetic acids derivatives with anti-inflammatory activity of alzheimer's disease are as cyclooxygenase-2 inhibitor
Summary of the invention
The present invention relates to 1-octadecyloxy phenyl carboxylic-acid, the prodrug in its carboxylic moiety and bioisoster, its preparation method, the pharmaceutical composition that contains them and the application in prevention or treatment neurodegenerative disease, particularly alzheimer's disease thereof.
Compound of the present invention suppresses A β
42peptide discharges, and can regulate thus gamma-secretase active and do not affect other important metabolic process.
Detailed Description Of The Invention
The present invention relates to compound, its pharmaceutically acceptable salt and other ester class of general formula (I):
Wherein:
R and R
1identical and be selected from straight or branched C
1-C
4alkyl; Or together with their carbon atoms of connecting with them, form the ring of 3-6 carbon atom;
G is:
-COOR " group, wherein R " is H, straight or branched C
1-C
4alkyl, C
3-C
6cycloalkyl or ascorbigen (ascorbyl);
-CONH
2or CONHSO
2r " ' group, wherein R " ' is straight or branched C
1-C
4alkyl or C
3-C
6cycloalkyl;
-tetrazolium residue;
R
2for H, CF
3, OCF
3or be selected from the halogen of the group of F, Cl, Br, I, preferably fluorine;
Ar is following general formula:
Wherein R
3represent one or more groups independently selected from following groups:
-halogen defined above;
-CF
3；
-optionally by one or more C
1-C
4the C that alkyl and/or oxo base replace
3-C
8cycloalkyl;
-CH＝CH
2；
-CN；
-CH
2OH；
-methylene-dioxy or ethylenedioxy;
-NO
2；
-optionally by the phenyl of one or more following groups replacements: halogen; CF
3; OCF
3; OH; Straight or branched C
1-C
4alkyl; Contain at least 4 carbon atoms and at least 1 heteroatomic saturated heterocyclic; Optional successively by the C of the one or more replacements in following groups
3-C
8cycloalkyl: straight or branched C
1-C
4alkyl, CF
3or OH; OR
4or NHCOR
4, wherein R
4for CF
3, straight or branched C
2-C
6alkenyl or alkynyl; Benzyl; Optionally by the phenyl of the one or more replacements in following group: halogen, CF
3, OCF
3, OH, straight or branched C
1-C
4alkyl; Contain at least 4 carbon atoms and at least 1 heteroatomic saturated heterocyclic; Optional successively by the C of the one or more replacements in following groups
3-C
8cycloalkyl: straight or branched C
1-C
4alkyl, CF
3or OH;
-SR
5, SO
2r
5or COR
5, wherein R
5for straight or branched C
1-C
6alkyl;
Or Ar is the heterocycle that is selected from following group: thiophene, thionaphthene, dibenzothiophene, thianthrene, pyrroles, pyrazoles, furans, cumarone, diphenylene-oxide, indoles, isoindole, cumarone, imidazoles, benzoglyoxaline, oxazole, isoxazole, benzoxazole, thiazole, pyridine, pyrimidine, pyrazine, pyridazine, quinoline, isoquinoline 99.9, quinazoline, quinoxaline, cinnolines, pyrazoles, pyrans, chromene, pyrrolizine, 2, 3-naphthyridine, 1, 5-naphthyridine, 1, 3-dioxole, 1, 3-benzo dioxole, they are optionally by one or more R as defined above
3group replaces.
First group of preferred compound be, wherein:
R and R
1together with the carbon atom connecting with them, form the ring of 3 carbon atoms;
R
2for fluorine;
G is COOR, and " group, wherein R " is H, straight or branched C
1-C
4alkyl, C
3-C
6cycloalkyl or ascorbigen;
Ar is as above-mentioned defined phenyl.
Second group of preferred compound be, wherein:
R and R
1together with the carbon atom connecting with them, form the ring of 3 carbon atoms;
R
2for fluorine;
G is CONH
2or CONHSO
2r " ', wherein R " ' be straight or branched C
1-C
4alkyl or C
3-C
6cycloalkyl;
Ar is as above-mentioned defined phenyl.
The 3rd group of preferred compound be, wherein:
R and R
1be methyl;
R
2for fluorine;
G is COOR ", wherein R " defines as above-mentioned;
Ar is as above-mentioned defined phenyl.
The 4th group of preferred compound be, wherein:
R and R
1be methyl;
R
2for fluorine;
G is CONH
2or CONHSO
2r " ', wherein R " ' as above-mentioned, define;
Ar is as above-mentioned defined phenyl.
The 5th group of preferred compound be, wherein:
R and R
1together with the carbon atom connecting with them, form the ring of 3 carbon atoms;
R
2for fluorine;
G is COOR ", wherein R " defines as above-mentioned;
Ar is as above-mentioned defined heterocycle.
The 6th group of preferred compound be, wherein:
R and R
1be methyl;
R
2for fluorine;
G is COOR ", wherein R " defines as above-mentioned;
Ar is as above-mentioned defined heterocycle.
Particularly preferably following compound:
2-methyl-2 (the fluoro-4 '-trifluoromethyl-biphenyl-4-yl of 2-) propionic acid (CHF 4810);
2-methyl-2 (2-fluoro-4 ' cyclohexyl biphenyl-4-yl) propionic acid (CHF 4961);
1-(the fluoro-4 '-trifluoromethyl-biphenyl-4-yl of 2-) cyclopropane-carboxylic acid (CHF 5022);
1-(4 '-cyclohexyl-2-fluorine biphenyl-4-yl) cyclopropane-carboxylic acid (CHF 5023);
1-(4 '-benzyloxy-2-fluorine biphenyl-4-yl) cyclopropane-carboxylic acid (CHF 5042);
1-(the fluoro-4 '-isopropoxy of 2-biphenyl-4-yl) cyclopropane-carboxylic acid (CHF 5044);
1-(the fluoro-3 '-trifluoromethoxy of 2-biphenyl-4-yl) cyclopropane-carboxylic acid (CHF 5045);
1-(the fluoro-4 '-trifluoromethoxy of 2-biphenyl-4-yl) cyclopropane-carboxylic acid (CHF 5046);
1-(the fluoro-3 '-trifluoromethyl-biphenyl-4-yl of 2-) cyclopropane-carboxylic acid (CHF 5058);
1-(4 '-cyclopentyl-2-fluorine biphenyl-4-yl) cyclopropane-carboxylic acid (CHF 5059);
1-(4 '-suberyl-2-fluorine biphenyl-4-yl) cyclopropane-carboxylic acid (CHF5060);
1-(2 '-cyclohexyl-2-fluorine biphenyl-4-yl) cyclopropane-carboxylic acid (CHF 5061);
1-(the fluoro-4 '-xenol-4-yl of 2-) cyclopropane-carboxylic acid (CHF 5070);
Fluoro-4 '-(the tetrahydropyran-4-base oxygen base) biphenyl-4-yl of 1-[2-]-cyclopropane-carboxylic acid (CHF5071);
1-(2,3 ', 4 '-trifluoro-biphenyl-4-yl) cyclopropane-carboxylic acid (CHF 5073);
1-(3 ', 4 '-bis-chloro-2-fluorine biphenyl-4-yls) cyclopropane-carboxylic acid (CHF 5074);
1-(3 ', 5 '-bis-chloro-2-fluorine biphenyl-4-yls) cyclopropane-carboxylic acid (CHF 5075);
1-(3 '-chloro-2,4 '-DfBP-4-yl) cyclopropane-carboxylic acid (CHF 5076);
1-(4-benzo [b] thiene-3-yl--3-fluorophenyl) cyclopropane-carboxylic acid (CHF 5077);
1-(the fluoro-4 '-propyl-2-alkynyloxy group-biphenyl-4-yl of 2-)-cyclopropane-carboxylic acid (CHF 5078);
1-(the fluoro-biphenyl-4-of 4 '-cyclohexyloxy-2-yl)-cyclopropane-carboxylic acid (CHF 5079);
Fluoro-4 '-(tetrahydropyran-4-base)-biphenyl-4-yl of 1-[2-]-cyclopropane-carboxylic acid (CHF5080);
Fluoro-4 '-(4-oxo-cyclohexyl)-biphenyl-4-yl of 1-[2-]-cyclopropane-carboxylic acid (CHF5081);
2-(2 " fluoro-4-hydroxyl-[1,1 ': 4 ', 1 "] tertiary phenyl-4 "-yl)-cyclopropane-carboxylic acid (CHF 5083);
1-[4 '-(4,4-Dimethylcyclohexyl)-2-fluorine [1,1 '-xenyl]-4-yl]-cyclopropane-carboxylic acid (CHF 5084);
Fluoro-4 '-[[4-(trifluoromethyl) benzoyl] amino] [1,1 '-the xenyl]-4-yl of 1-[2-]-cyclopropane-carboxylic acid (CHF 5094);
Fluoro-4 '-[[4-(trifluoromethyl) cyclohexyl] oxygen base] [1,1 '-the xenyl]-4-yl of 1-[2-]-cyclopropane-carboxylic acid (CHF 5096);
Fluoro-4 '-[(3,3,5,5-tetramethyl-ring hexyl) oxygen base] [1,1 '-the xenyl]-4-yl of 1-[2-]-cyclopropane-carboxylic acid (CHF 5102);
1-[4 '-[(4,4-Dimethylcyclohexyl) oxygen base]-2-fluorine [1,1 '-xenyl]-4-yl]-cyclopropane-carboxylic acid (CHF 5103);
1-(2,3 ', 4 " trifluoro [1,1 ': 4 ', 1 " tertiary phenyl]-4-yl)-cyclopropane-carboxylic acid (CHF5104);
1-(2,2 ', 4 " trifluoro [1,1 ': 4 ', 1 " tertiary phenyl]-4-yl)-cyclopropane-carboxylic acid (CHF5105);
1-(2,3 '-bis-fluoro-4 " hydroxyl [1,1 ': 4 ', 1 " tertiary phenyl]-4-yl)-cyclopropane-carboxylic acid (CHF 5106);
1-(2,2 '-bis-fluoro-4 " hydroxyl [1,1 ': 4 ', 1 " tertiary phenyl]-4-yl)-cyclopropane-carboxylic acid (CHF 5107);
2-(2-fluoro-3 ', 5 '-bis-(chlorine) biphenyl-4-yl) propionic acid acid amides (CHF 5125).
Preferred one group of compound is, wherein:
R and R
1together with the carbon atom connecting with them, form the ring of 3 carbon atoms;
R
2for fluorine;
G is COOH;
Ar is the phenyl being replaced by one or more groups, makes like this logP (partition ratio between n-Octanol and water) of whole molecule be equal to or greater than 4.5, as passing through to use software
2.1 editions (Schrodinger Inc) calculates.
The log P that has been found that molecule is higher, to A β
42larger and the special compounds effective of inhibition effect that peptide discharges is this compounds, and its log P is equal to or greater than 4.5, is preferably greater than 5.0.
The example of these compounds is CHF 5022, CHF 5074, CHF 5096, CHF 5105, CHF 5106 and CHF 5107.
The invention still further relates to as increasing and stride across pharmaceutically acceptable salt and ester class prepared by hemato encephalic barrier.
Another object of the present invention is that the compound of general formula (I) is as the application of medicine, and particularly they are for the preparation for the treatment of and/or preventing neurodegenerative disease, such as the application in the pharmaceutical composition of alzheimer's disease.
Another object of the present invention is the solid or the composition of liquid medicine that are preferred for orally using, comprise the mixture of at least one general formula (I) compound and pharmaceutically acceptable vehicle and/or carrier, described vehicle and/or carrier are for example described in < < RemingtonShi pharmaceutical science handbook > > (Remington ' s Pharmaceutical Sciences Handbook) XVIIEd., Mack Pub., N.Y., in U.S.A..
Can, according to literature method, prepare through the following steps the compound of general general formula (I), wherein R " be H:
In scheme 1, under the condition of report, make aryl halide and boric acid or the ester ArB (OL) of general formula (II)
2between carry out the reaction of palladium-catalysis, the structural formula of its formula of (II) is as follows:
Wherein R, R
1and R
2as above-mentioned, define and X is bromine or iodine, preferably iodine;
At ArB (OL)
2in, L is alkyl chain.
DME=1,2-glycol dimethyl ether
TTP=triphenyl phosphine
Scheme 1
The compound of general formula (II) be purchased or can be according to following synthetic by way of preparation.
derivative, wherein R and R
1
for straight or branched C
1
-C
4
alkyl (IIa)
Can as raw material, prepare described compound according to synthesizing by way of the Arylacetic acids class using general formula (III) shown in scheme 2, in general formula (III), R and R
2as above-mentioned, define and X is bromine or iodine.
Make acid esters, the alkylation of general formula (III) and be optionally hydrolyzed, condition is that the group G on end product is COOH.
Scheme 2
derivative, wherein R and R
1
the carbon atom being connected with them forms the ring of 3-6 carbon
(IIb)
Described compound be purchased or can be according to report in scheme 3 synthetic by way of preparation, the integer that wherein n is 1-4.
Scheme 3
Boric acid or corresponding borate be purchased or can by corresponding halogenide, be prepared according to known in the literature method.
The compound of the general formula (I) that can be COOH by esterification G is prepared the compound of general formula (I), and wherein G is COOR ", wherein R " is straight or branched C
1-C
4alkyl, C
3-C
6cycloalkyl or ascorbigen.
Can be by making corresponding ester class and NH
3or amine NH
2sO
2" compound of general formula (I) is prepared in ' reaction to R, and wherein G is CONH
2or CONHSO
2r " ', wherein R " ' be straight or branched C
1-C
4alkyl or C
3-C
6cycloalkyl.
Can be according to currently known methods, for example carboxylic acid changed into acid amides, make dehydration of amide obtain nitrile and make the latter react with tributyl tin trinitride the compound of preparing general formula (I), wherein G is tetrazyl.
Embodiment
Chemical preparation embodiment
embodiment 1:2-methyl-2-(the fluoro-4 '-trifluoromethyl-biphenyl-4-yl of 2-) propionic acid (CHF
4810) preparation
the preparation of [2-(the fluoro-4 '-trifluoromethyl-biphenyl-4-yl of 2-)] methyl propionate
In 2-(the fluoro-4 '-trifluoromethyl-biphenyl-4-yl of the 2-) solution of propionic acid (0.2g, 0.64mmoles) in methyl alcohol (3ml), add 98% sulfuric acid (0.5g) and reflux 2.5 hours.Except desolventizing, resistates is dissolved in to ethyl acetate (5ml) and uses 5%NaHCO in a vacuum
3solution (5ml), then wash with water.Use Na
2sO
4dry this solution is also concentrated and obtain oily matter (0.2g, 95%) in a vacuum.
HPLC-UV purity (215nm): 99%
[the preparation of 2-methyl-2-(the fluoro-4 '-trifluoromethyl-biphenyl-4-yl of 2-) methyl propionate
To [2-(the fluoro-4 '-trifluoromethyl-biphenyl-4-yl of the 2-)] methyl propionate (0.2g at 0 ℃ and in nitrogen environment, 0.61mmoles) in the solution in anhydrous THF (3ml), add 60%NaH (30mg, 0.75mmoles).This mixture is stirred 30 minutes and adds CH
3i (70 μ l, 0.91mmoles).After 3 hours, concentrate in a vacuum this mixture and use ethyl acetate (5ml) to dissolve.Use 5%NaHCO
3solution (5ml), then wash gained solution with water, use Na
2sO
4dry this solution, and concentrated and obtain oily matter (0.18g, 87%) in vacuum, without being further purified the reaction of using it for subsequently.
the preparation of 2-methyl-2-(the fluoro-4 '-trifluoromethyl-biphenyl-4-yl of 2-) propionic acid
To [2-methyl-2-(the fluoro-4 '-trifluoromethyl-biphenyl-4-yl of 2-)] methyl propionate (0.18g, 0.53mmoles) in the solution in ethanol (5ml), add KOH (60mg, 1mmol) and at room temperature keep stirring 3 hours.Use H
2o (5ml) dilutes this mixture and also with ether (5ml), washs this solution.Discard organic phase.With HCl by aqueous phase as acidified to pH=2, then use ethyl acetate (10ml) extract.Use Na
2sO
4dry this organic phase also concentrates in a vacuum and obtains white solid, is passed through quick SiO
2chromatography purification (eluent hexane/ethyl acetate 8/2 v/v) and obtain product, is white solid (16mg, 10%).
HPLC-UV purity (215nm): 97%.
1H NMR(DMSO-d
6)：12.56(s br，1H)；7.84(d，2H)；7.78(d，2H)；7.57(dd，1H)；7.32(s，1H)；7.29(m，1H)；1.52(s，6H)；MS(EI)：326m/z(M+.)，281，253。
According to same steps and use suitable reagent to prepare Compound C HF 4961.
the preparation of embodiment 2:1-(2-fluorine biphenyl-4-yl) cyclopropane-carboxylic acid (CHF 5041)
the preparation of the bromo-3-fluoro benzyl bromide of 4-
In solution to 4-bromine-3-fluorine methylbenzene (10g, 0.053moles) in tetracol phenixin (100ml), add N-bromine succinimide (NBS; 14g, 0.08moles).This mixture that refluxes, adds dibenzoyl peroxide (100mg, 0.4mmoles) wherein, refluxes 1 hour, then at room temperature cooling and use water extraction.Aqueous phase discarded, by salt water washing organic phase, by dried over sodium sulfate concentrated and obtain oily matter (16g) in a vacuum, makes it carry out silica gel column chromatography (150g), with hexane wash-out, obtains product.
the preparation of 4-bromine-3-fluorophenyl acetonitrile
In solution to the bromo-3-fluoro benzyl bromide of 4-(12.2g, 0.03moles) in ethanol (100ml), add NaCN (2g, 0.04moles) and reflux 2 hours.Concentrated this mixture in a vacuum; With water dissolution gained resistates, then by ethyl acetate, extract.By salt water washing organic phase, by dried over sodium sulfate concentrated and obtain dark oily matter (10g) in a vacuum, make it carry out silica gel column chromatography (150g), with hexane: 7: 3 wash-outs of ether and obtain the product of solid form.
the preparation of 4-bromine-3-fluorophenyl cyclopropylniitrile
To 4-bromine-3-fluorophenyl acetonitrile (5g, 23mmoles) in the solution in toluene (20ml), add 1 of 35mmoles, 2-ethylene dibromide, the 50%NaOH aqueous solution (20ml) and Tetrabutylammonium bromide (1.6g, 5mmoles).This mixture is at room temperature kept stirring 5-12 hour, then dilute with water extracting by ethyl acetate.Then use salt water washing organic phase with 1N HCl, final dry and concentrated and obtain brown solid in a vacuum, make it carry out silica gel column chromatography (200g), with hexane-ether 1-1 wash-out, obtain the product of solid form.
the preparation of 4-bromine-3-fluorophenyl cyclopropane-carboxylic acid
In suspension to 4-bromine-3-fluorophenyl cyclopropylniitrile (21mmoles) in methyl alcohol (10ml), add the 35%NaOH aqueous solution (40ml) and 35%H
2o
2the aqueous solution (3ml), then refluxes 4 hours, at room temperature cooling and add 2N HCl (250ml).By filtering the solid of collecting precipitation and being dissolved in again 5%NaHCO
3the aqueous solution (300ml).Filter out insoluble fraction and also with 2N HCl, clear filtrate is acidified to pH=2.Product precipitation, is white solid, is passed through filtered and recycled dry in a vacuum.
the preparation of 1-(2-fluorine biphenyl-4-yl) cyclopropane-carboxylic acid
The phenyl-boron dihydroxide of the 4-bromine-3-fluorophenyl cyclopropane-carboxylic acid of 800mg (3.1mmoles) and 650mg (3.4mmoles) is suspended in to the 2M K of 8ml
2cO
3in the aqueous solution.To adding in Tetrabutylammonium bromide (960mg, 3mmoles) and acid chloride (II) (40mg, 0.18mmoles) the closed reactor at 130 ℃ in this mixture, heat 30 minutes.After at room temperature cooling, to adding 2MHCl (25ml) in this mixture and extracting by ethyl acetate.With 1NHCl, then use salt water washing organic phase, final dry and concentrated and obtain oily matter (1.7g) in a vacuum, make its crystallization and obtain product from isopropyl ether-hexane, be white solid (0.2g).
HPLC(215nm)98％。
MS (EI; TSQ700; Parameter 180 C; 70 V; 200 uA): 256 (M+.); 210; 196.
1H-NMR(DMSO)：12.41(s br，1H)；7.56-7.35(m，6H)；7.27(m，1H)；7.24(s，1H)；1.48(m，2H)；1.22(m，2H)。
According to step identical described in embodiment 1, take suitable 4-bromophenyl cycloalkanes carboxylic-acid as raw material and use suitable reagent to prepare Compound C HF 5022, CHF 5023, CHF5042, CHF 5045, CHF 5046, CHF 5058, CHF 5059, CHF 5060, CHF 5061, CHF 5070, CHF 5071, CHF 5073, CHF 5074, CHF 5075, CHF 5076, CHF 5077, CHF 5078, CHF 5079, CHF 5080, CHF 5081, CHF 5083, CHF 5084, CHF 5094, CHF 5096, CHF 5102, CHF 5103, CHF 5104, CHF5105, CHF 5106, CHF 5107 and CHF 5002.
embodiment 3-pharmacologically active
a β in H4-15x cell conditioned medium liquid
42
the inhibition discharging
Having in Totomycin and the blasticidin flask under existing (in the insulation can at 37 ℃, in the steam-laden atmosphere surrounding that contains 5% carbonic acid gas) cultivate H4-15x cell (using the human glioma cell of the people's gene transfection of coding amyloid beta APP695 precursor), this system maintains selection pressure to the cell of gene that continuous expression is paid close attention to.
When cell reaches approximately 90% fusion rate, collect them and be again seeded in 24 hole flat board (each 2x10
5individual cell) on the complete substratum of 0.5ml in.After approximately 24 hours, when cell and hole surface are adhered and obtain merging, with 0.5ml, supplemented to the fresh culture of the compound (I) of 100 micromole's final concentrations and replaced the substratum in each hole.To each test concentrations according to triplicate repetition.In advance by for the treatment of molecule be dissolved in methyl-sulphoxide (DMSO) or be dissolved in methyl-sulphoxide/water mixture, the final concentration of DMSO in hole is no more than 1%.Therefore, again by the dull and stereotyped incubated overnight (14-16 hour) of preparation; After this from each hole, get supernatant liquor and to A β
42with A β
40protein quantification.Use for the instrumentation of microtest plate chemiluminescence analysis and carry out this test, it allows the quantitative and immobilization on paramagnetic microballon based on analyte-antibody complex respectively of two kinds of protein.With one of antibody of this mixture of ruthenium compound mark, carrying out electrochemistry while exciting, this compound can produce the optical signal of the intensity that is directly proportional to the amount of the analyte existing.
the inhibition of COX-1 in rat whole blood (COX-1)
From rat aorta, get whole blood and put into immediately heparinization test tube.By the test compounds of 100 μ M concentration or only use carrier (DMSO) by (l) pre-incubation 1 hour at 37 ℃ of 500 μ of the aliquot of heparinization whole blood.By adding calcium ion carrier A 23187 (final concentration 5x10
-5m) induction eicosanoid produced and by sample being put into fast to dry ice, interrupted insulation after 30 minute.After this centrifugal sample (12000gx3 minute at 4 ℃) calculate TxB by radioimmunoassay
2the output of thromboxane B2.
To be expressed as A β under 100 μ M
42the result that release suppresses per-cent and COX-1 suppresses active per-cent under same concentrations is reported in table 1.With same concentrations, by the flurbiprofen comparing, show approximately 25% A β
42the COX-1 that discharges restraining effect and 100% suppresses active.
Table 1: the A β of the representational compound of the present invention under 100 μ M concentration
42discharge inhibition per-cent and COX-1 and suppress active per-cent
| Compound | Aβ 42Discharge and suppress % | COX-1 suppresses active % |
| CHF 4961 | 76.6 | 5.2 |
| CHF 4810 | 58.0 | - |
| CHF 5022 | 55.4 | 0.0 |
| CHF 5045 | 56.4 | 8.3 |
| CHF 5046 | 70.4 | 2.6 |
| CHF 5058 | 54.8 | 0.0 |
| CHF 5070 | 22.4 | 0.0 |
| CHF 5071 | 28.1 | 0.4 |
| CHF 5073 | 67.4 | 4.8 |
| CHF 5074 | 79.2 | 0.5 |
| CHF 5076 | 71.4 | 5.5 |
| CHF 5078 | 57.5 | 3.6 |
| CHF 5080 | 51.8 | 0.3 |
| CHF 5081 | 52.3 | 6.1 |
| CHF 5083 | 81.1 | - |
| CHF 5096 | 70.0 | 0.8 |
| CHF 5105 | 90.7 | 1.9 |
| CHF 5106 | 79.9 | 0.0 |
| CHF 5107 | 83.3 | 1.1 |
Claims (6)
1. be prepared as follows the method for the compound of general formula:
Wherein:
R and R
1together with the carbon atom connecting with them, form the ring of 3-6 carbon atom;
R
2f;
Ar is
with
R
3represent one or more halogens independently selected from F, Cl, Br, I;
Described method comprises: in scheme 1, under the condition of report, make boric acid or ester ArB (OL)
2with the aryl halide condensation of general formula (II),
Wherein as defined above, L is H or alkyl chain to Ar, and wherein said condensation step is the reaction of palladium catalysis, wherein R, R
1and R
2as above-mentioned, define and X is bromine or iodine;
2. the method for claim 1, wherein X is bromine.
3. the method for claim 1, wherein R and R
1together with the carbon atom connecting with them, form the ring of 3 carbon atoms.
4. method as claimed in claim 3, wherein R
3for Cl.
5. the method as described in claim 1-4 any one, the aryl halide of its formula of (II) is prepared by the method by comprising the steps:
Wherein X is bromine or iodine, R
2f, the integer that n is 1-4.
6. method as described in claim 5, wherein X is bromine.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITMI20030311 ITMI20030311A1 (en) | 2003-02-21 | 2003-02-21 | 2-FENYL-2-DIALKYL-ACETIC ACIDS FOR THE TREATMENT OF ALZHEIMER DISEASE. |
| ITMI2003A000311 | 2003-02-21 | ||
| ITMI2003A002068 | 2003-10-23 | ||
| ITMI20032068 ITMI20032068A1 (en) | 2003-10-23 | 2003-10-23 | DERIVATIVES OF 1-PHENYLCYCLOALCANCARBOSSYIC ACID FOR THE TREATMENT OF NEURODEGENERATIVE DISEASES. |
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| WO2011015287A2 (en) * | 2009-08-04 | 2011-02-10 | Chiesi Farmaceutici S.P.A. | Process for the preparation of derivatives of 1-(2-halobiphenyl-4-yl)-cyclopropanecarboxylic acid |
| CN106431900A (en) * | 2010-04-01 | 2017-02-22 | 奇斯药制品公司 | Novel polymorphs and salts |
| TR201809263T4 (en) * | 2013-06-24 | 2018-07-23 | Chiesi Farm Spa | IMPROVED PROCESS FOR THE PREPARATION OF 1- (2-FLORO [1,1'-BIPHENYL] -4-YL) -CYCLOPROPANKARBOXYLIC ACID DERIVATIVES |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5994379A (en) * | 1998-02-13 | 1999-11-30 | Merck Frosst Canada, Inc. | Bisaryl COX-2 inhibiting compounds, compositions and methods of use |
| CN1385244A (en) * | 2001-05-16 | 2002-12-18 | 拜尔公司 | Preparation and use of palladium catalyst for cross-coupling reaction |
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|---|---|---|---|---|
| JPS4994680A (en) * | 1973-01-22 | 1974-09-09 | ||
| JPS5046669A (en) * | 1973-03-28 | 1975-04-25 | ||
| GB1442707A (en) * | 1973-07-07 | 1976-07-14 | Yoshitomi Pharmaceutical | Substituted phenylalkanoic acids and their derivatives and pharma ceutical compositions thereof |
| JPS58177977A (en) * | 1982-04-09 | 1983-10-18 | Grelan Pharmaceut Co Ltd | 4-phenylpyrazole |
-
2003
- 2003-02-21 IT ITMI20030311 patent/ITMI20030311A1/en unknown
-
2004
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5994379A (en) * | 1998-02-13 | 1999-11-30 | Merck Frosst Canada, Inc. | Bisaryl COX-2 inhibiting compounds, compositions and methods of use |
| CN1385244A (en) * | 2001-05-16 | 2002-12-18 | 拜尔公司 | Preparation and use of palladium catalyst for cross-coupling reaction |
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| CN100398506C (en) | 2008-07-02 |
| ZA200506614B (en) | 2006-12-27 |
| CN101328117A (en) | 2008-12-24 |
| ITMI20030311A1 (en) | 2004-08-22 |
| CN1751018A (en) | 2006-03-22 |
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