CN101328117A - 1-phenylalkanecarboxylic acid derivatives for the treatment of neurodegenerative diseases - Google Patents
1-phenylalkanecarboxylic acid derivatives for the treatment of neurodegenerative diseases Download PDFInfo
- Publication number
- CN101328117A CN101328117A CNA2008101007040A CN200810100704A CN101328117A CN 101328117 A CN101328117 A CN 101328117A CN A2008101007040 A CNA2008101007040 A CN A2008101007040A CN 200810100704 A CN200810100704 A CN 200810100704A CN 101328117 A CN101328117 A CN 101328117A
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- Prior art keywords
- chf
- halogen
- alkyl
- cycloalkyl
- branched
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- 230000004770 neurodegeneration Effects 0.000 title abstract description 7
- 208000015122 neurodegenerative disease Diseases 0.000 title abstract description 7
- 239000002253 acid Substances 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 31
- 238000000034 method Methods 0.000 claims abstract description 16
- 229910052731 fluorine Inorganic materials 0.000 claims description 22
- 239000011737 fluorine Substances 0.000 claims description 20
- 229910052799 carbon Inorganic materials 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- 150000001721 carbon Chemical group 0.000 claims description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims description 9
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 7
- 125000000623 heterocyclic group Chemical group 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- -1 cycloalkyl nitrile Chemical class 0.000 claims description 6
- 229910052740 iodine Inorganic materials 0.000 claims description 5
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Substances CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 150000001502 aryl halides Chemical class 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 claims description 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 claims description 2
- 125000000304 alkynyl group Chemical group 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 claims description 2
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- 230000005494 condensation Effects 0.000 claims 3
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- 125000005843 halogen group Chemical group 0.000 claims 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims 1
- 125000005907 alkyl ester group Chemical group 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 17
- 208000024827 Alzheimer disease Diseases 0.000 abstract description 10
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
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- 239000012141 concentrate Substances 0.000 description 9
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- 229940024606 amino acid Drugs 0.000 description 3
- 150000001413 amino acids Chemical group 0.000 description 3
- OMSJCIOTCFHSIT-KNUOEEMSSA-N ascorbigen Chemical compound C1=CC=C2C(CC3(O)C(=O)O[C@H]4[C@]3(O)OC[C@@H]4O)=CNC2=C1 OMSJCIOTCFHSIT-KNUOEEMSSA-N 0.000 description 3
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
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- 125000002999 4-(trifluoromethyl)benzoyl group Chemical group FC(C1=CC=C(C(=O)*)C=C1)(F)F 0.000 description 1
- 102000012440 Acetylcholinesterase Human genes 0.000 description 1
- 108010022752 Acetylcholinesterase Proteins 0.000 description 1
- 102000004580 Aspartic Acid Proteases Human genes 0.000 description 1
- 108010017640 Aspartic Acid Proteases Proteins 0.000 description 1
- 206010003694 Atrophy Diseases 0.000 description 1
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- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- 229940124638 COX inhibitor Drugs 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 229940093444 Cyclooxygenase 2 inhibitor Drugs 0.000 description 1
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- 208000012671 Gastrointestinal haemorrhages Diseases 0.000 description 1
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- 206010018338 Glioma Diseases 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- 206010029350 Neurotoxicity Diseases 0.000 description 1
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- 101800003906 Substance P Proteins 0.000 description 1
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- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 1
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- 230000008034 disappearance Effects 0.000 description 1
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- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
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- YQYJSBFKSSDGFO-FWAVGLHBSA-N hygromycin A Chemical compound O[C@H]1[C@H](O)[C@H](C(=O)C)O[C@@H]1Oc1ccc(\C=C(/C)C(=O)N[C@@H]2[C@@H]([C@H]3OCO[C@H]3[C@@H](O)[C@@H]2O)O)cc1O YQYJSBFKSSDGFO-FWAVGLHBSA-N 0.000 description 1
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Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention relates to 1-Phenylalkanecarboxylic acid derivatives, 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 on 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 the projection of basal nuclei cholinergic are 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 the brain essence in the patients with Alzheimer disease dispersivity.
Neuritic plaque mainly is made up of the protein aggregate that is called amyloid beta (β A) that has 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 that 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 purpose is mainly to increase the vagusstoff cerebral levels by acetylcholinesterase depressant are relatively poor or can not obtain significantly to prevent the effect of this disease development from the effect of clinical point acquisition.Owing to this reason, the attention in has in recent years concentrated in patient's brain on the mechanism that 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) has significantly reduced alzheimer's disease in the crowd who regularly takes these medicines outbreak.The mechanism of this class NSAID prophylactic effect is illustrated as yet fully, but obviously relevant with the ability of its inhibition cyclo-oxygenase (COX).
Recently described the new pharmacotoxicological effect of some non-steroidal anti-inflammatory drug (NSAIDs): indomethacin, sulindac, Ibuprofen BP/EP and flurbiprofen can optionally reduce most of neurotoxicity isotype generation of beta-amyloid peptide in the cell culture, promptly contain 42 amino acid whose form (A β
42), help a small amount of deleterious isotype A β thus
38Discharge that (Weggen etc., " nature " (Nature) 2001; 414 (6860): 212-6).Yet, under external high concentration, observed A β
42Generation is suppressed, and this can be owing to the interaction of these medicines and gamma-secretase (having the active macromole of aspartyl protease/polyprotein enzyme complex).Be equivalent to the blood plasma of used dosage in the experiment in vitro and brain concentration can significantly increase the harm of the patient that treats typical case COX inhibitor side effect, such as gastrointestinal hemorrhage and perforated ulcer.
Claimed prevention among the WO01/78721, delay or reverse the method for alzheimer's disease development, by at A β
38Level increases and A β
42Reduce A β under the condition that level remains unchanged
42Promoting agent carry out.In addition, disclose and be used for identifying and research and development reduce A β
42The method and the material and being used to of promoting agent identify the method for the promoting agent that increases alzheimer's disease development or fast-developing harm.Report the embodiment that relates to indomethacin and Flufenamic Acid derivative, but do not had 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 among the 22:2246-2254.This document described prevailingly flurbiprofen derivative obviously than NSAIDs remove aspect the amyloid beta settling more effective, but to any reduction A β
42The selection activity all do not relate to.
The problem that may exist in this treatment plan and according to conventional NSAID s is to peptide A β
42Having more selectivity and having more effectively suppresses active and lower or do not have inhibiting novel derivative can become purpose fully to be to prevent the Alzheimer onste and/or to delay to represent obvious improvement in the therapy that the cognitive ability of early stage disease stage descends to the inhibition degree of cyclo-oxygenase.
At GB 1,198,212, among US 3,978,071, US 757,136, GB 1,352,723, JP49100089 and the JP 50046669 with the 1-phenyl-2 that replaces, the 2-dialkyl carboxylic acid derivatives is described as antiphlogiston, anodyne and febrifuge.
JP-4, in 7047,375 and FR-2,012,285 with 3-halo-4-alkyl-or the 1-benzyl ring alkyl-carboxylic acid derivatives of cycloalkyl-replacement be described as having identical active material.
(Takeda Kenkyushoho 1975 in from the file of Kuzuna S of the structure-activity research that relates to a series of phenylacetic acid derivatives etc., 34,467-473) described prevailingly on the alpha-carbon atom position and to introduce the cyclopropane base and reduced anti-inflammatory and analgesic activity.
In WO 99/41224, the claimed numerous disease that is used for the treatment of, the new two aryl-acetic acids derivatives with anti-inflammatory activity that comprise alzheimer's disease are as cyclooxygenase-2 inhibitor
Summary of the invention
The present invention relates to 1-octadecyloxy phenyl carboxylic-acid, the prodrug on its carboxylic moiety and bioisoster, its preparation method, contain their pharmaceutical composition and the application in the neurodegenerative disease, particularly alzheimer's disease thereof in prevention or treatment.
Compound of the present invention suppresses A β
42Peptide discharges, and it is active and do not influence other important metabolic processes to regulate gamma-secretase thus.
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 they form the ring of 3-6 carbon atom with the carbon atom that they connected;
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
2Be H, CF
3, OCF
3Or be selected from the halogen of the group of F, Cl, Br, I, preferred fluorine;
Ar is following general formula:
R wherein
3Represent one or more groups that are independently selected from following groups:
The halogen of-above-mentioned definition;
-CF
3；
-optional 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；
-optional the phenyl that is replaced by one or more following groups: halogen; CF
3OCF
3OH; 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 the following groups
3-C
8Cycloalkyl: straight or branched C
1-C
4Alkyl, CF
3Or OH; OR
4Or NHCOR
4, R wherein
4Be CF
3, straight or branched C
2-C
6Alkenyl or alkynyl; Benzyl; Optional by the phenyl of the one or more replacements in the 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 the following groups
3-C
8Cycloalkyl: straight or branched C
1-C
4Alkyl, CF
3Or OH;
-SR
5, SO
2R
5Or COR
5, R wherein
5Be straight or branched C
1-C
6Alkyl;
Or Ar is the heterocycle that is selected from following group: thiophene, thionaphthene, dibenzothiophene, thianthrene, the 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, the 3-naphthyridine, 1, the 5-naphthyridine, 1, the 3-dioxole, 1,3-benzo dioxole, they are optional by one or more R as defined above
3Group replaces.
First group of preferred compound be, wherein:
R and R
1Form the ring of 3 carbon atoms with the carbon atom that they connected;
R
2Be 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
1Form the ring of 3 carbon atoms with the carbon atom that they connected;
R
2Be fluorine;
G is CONH
2Or CONHSO
2R " ', wherein R " ' is 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
2Be fluorine;
G is COOR ", wherein R " as above-mentioned definition;
Ar is as above-mentioned defined phenyl.
The 4th group of preferred compound be, wherein:
R and R
1Be methyl;
R
2Be fluorine;
G is CONH
2Or CONHSO
2R " ', wherein R " ' is as above-mentioned definition;
Ar is as above-mentioned defined phenyl.
The 5th group of preferred compound be, wherein:
R and R
1Form the ring of 3 carbon atoms with the carbon atom that they connected;
R
2Be fluorine;
G is COOR ", wherein R " as above-mentioned definition;
Ar is as above-mentioned defined heterocycle.
The 6th group of preferred compound be, wherein:
R and R
1Be methyl;
R
2Be fluorine;
G is COOR ", wherein R " as above-mentioned definition;
Ar is as above-mentioned defined heterocycle.
Be preferably as follows compound especially:
2-methyl-2 (2-fluoro-4 '-trifluoromethyl-biphenyl-4-yl) propionic acid (CHF 4810);
2-methyl-2 (2-fluoro-4 ' cyclohexyl biphenyl-4-yl) propionic acid (CHF 4961);
1-(2-fluoro-4 '-trifluoromethyl-biphenyl-4-yl) 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-(2-fluoro-4 '-isopropoxy biphenyl-4-yl) cyclopropane-carboxylic acid (CHF 5044);
1-(2-fluoro-3 '-trifluoromethoxy biphenyl-4-yl) cyclopropane-carboxylic acid (CHF 5045);
1-(2-fluoro-4 '-trifluoromethoxy biphenyl-4-yl) cyclopropane-carboxylic acid (CHF 5046);
1-(2-fluoro-3 '-trifluoromethyl-biphenyl-4-yl) 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 (CHF 5060);
1-(2 '-cyclohexyl-2-fluorine biphenyl-4-yl) cyclopropane-carboxylic acid (CHF 5061);
1-(2-fluoro-4 '-xenol-4-yl) cyclopropane-carboxylic acid (CHF 5070);
1-[2-fluoro-4 '-(tetrahydropyran-4-base oxygen base) biphenyl-4-yl]-cyclopropane-carboxylic acid (CHF5071);
1-(2,3 ', 4 '-trifluoro-biphenyl-4-yl) cyclopropane-carboxylic acid (CHF 5073);
1-(3 ', 4 '-two chloro-2-fluorine biphenyl-4-yls) cyclopropane-carboxylic acid (CHF 5074);
1-(3 ', 5 '-two 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-(2-fluoro-4 '-the third-2-alkynyloxy group-biphenyl-4-yl)-cyclopropane-carboxylic acid (CHF 5078);
1-(4 '-cyclohexyloxy-2-fluoro-biphenyl-4-yl)-cyclopropane-carboxylic acid (CHF 5079);
1-[2-fluoro-4 '-(tetrahydropyran-4-base)-biphenyl-4-yl]-cyclopropane-carboxylic acid (CHF5080);
1-[2-fluoro-4 '-(4-oxo-cyclohexyl)-biphenyl-4-yl]-cyclopropane-carboxylic acid (CHF5081);
2-(2 " fluoro-4-hydroxyl-[1,1 ': 4 ', 1 "] uncle phenyl-4 "-yl)-cyclopropane-carboxylic acid (CHF 5083);
1-[4 '-(4, the 4-Dimethylcyclohexyl)-2-fluorine [1,1 '-xenyl]-the 4-yl]-cyclopropane-carboxylic acid (CHF 5084);
1-[2-fluoro-4 '-[[4-(trifluoromethyl) benzoyl] amino] [1,1 '-xenyl]-the 4-yl]-cyclopropane-carboxylic acid (CHF 5094);
1-[2-fluoro-4 '-[[4-(trifluoromethyl) cyclohexyl] oxygen base] [1,1 '-xenyl]-the 4-yl]-cyclopropane-carboxylic acid (CHF 5096);
1-[2-fluoro-4 '-[(3,3,5,5-tetramethyl-ring hexyl) oxygen base] [1,1 '-xenyl]-the 4-yl]-cyclopropane-carboxylic acid (CHF 5102);
1-[4 '-[(4, the 4-Dimethylcyclohexyl) oxygen base]-2-fluorine [1,1 '-xenyl]-the 4-yl]-cyclopropane-carboxylic acid (CHF 5103);
1-(2,3 ', 4 " trifluoro [1,1 ': 4 ', 1 " uncle's phenyl]-the 4-yl)-cyclopropane-carboxylic acid (CHF5104);
1-(2,2 ', 4 " trifluoro [1,1 ': 4 ', 1 " uncle's phenyl]-the 4-yl)-cyclopropane-carboxylic acid (CHF5105);
1-(2,3 '-two fluoro-4 " hydroxyl [1,1 ': 4 ', 1 " uncle's phenyl]-the 4-yl)-cyclopropane-carboxylic acid (CHF 5106);
1-(2,2 '-two fluoro-4 " hydroxyl [1,1 ': 4 ', 1 " uncle's phenyl]-the 4-yl)-cyclopropane-carboxylic acid (CHF 5107);
2-(2-fluoro-3 ', 5 '-two (chlorine) biphenyl-4-yl) propionic acid acid amides (CHF 5125).
Preferred one group of compound is, wherein:
R and R
1Form the ring of 3 carbon atoms with the carbon atom that they connected;
R
2Be fluorine;
G is COOH;
The phenyl of Ar for being replaced by one or more groups makes the logP (partition ratio between n-Octanol and the water) of whole molecule be equal to or greater than 4.5 like this, as passing through to use software
2.1 version (Schrodinger Inc) is calculated.
The log P that has been found that molecule is high more, then to A β
42The big more and special compounds effective of the 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.
These examples for compounds are CHF 5022, CHF 5074, CHF 5096, CHF 5105, CHF 5106 and CHF 5107.
The invention still further relates to increase and stride across pharmaceutically acceptable salt and the ester class that hemato encephalic barrier prepares.
Another object of the present invention is the application of the compound of general formula (I) as medicine, and particularly they are used for the treatment of and/or prevent neurodegenerative disease in preparation, 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, the mixture that comprises at least a general formula (I) compound and pharmaceutically acceptable vehicle and/or carrier, described vehicle and/or carrier for example are described in " RemingtonShi pharmaceutical science handbook (Remington ' s Pharmaceutical Sciences Handbook) XVIIEd., Mack Pub., N.Y., among the U.S.A..
Can prepare the compound of general general formula (I) through the following steps, wherein R according to literature method " be H:
In scheme 1, make aryl halide and the boric acid or the ester ArB (OL) of general formula (II) under the condition of report
2Between carry out palladium-catalytic reaction, the structural formula of its formula of (II) is as follows:
Wherein R, R
1And R
2As above-mentioned definition and X is bromine or iodine, preferred iodine;
At ArB (OL)
2In, L is an alkyl chain.
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
Be straight or branched C
1
-C
4
Alkyl (IIa)
Can according to shown in the scheme 2 synthetic by way of with the Arylacetic acids class of general formula (III) as the described compound of feedstock production, in general formula (III), R and R
2As above-mentioned definition and X is bromine or iodine.
Make acid estersization, alkylation and optional being hydrolyzed of general formula (III), condition is that the group G on the end product is COOH.
Scheme 2
Derivative, wherein R and R
1
The carbon atom that is connected with them forms the ring of 3-6 carbon
(IIb)
Described compound be purchased or can be according to report in the scheme 3 synthetic by way of preparation, wherein n is the integer of 1-4.
Scheme 3
Boric acid or corresponding borate be purchased or can prepare by corresponding halogenide according to known method in the document.
Can be the compound of compound general formula (I) of the general formula (I) of COOH by esterification G, wherein G be 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 ' prepared in reaction general formula (I), wherein G is CONH to R
2Or CONHSO
2R " ', wherein R " ' is straight or branched C
1-C
4Alkyl or C
3-C
6Cycloalkyl.
Can for example carboxylic acid be changed into acid amides, make dehydration of amide obtain nitrile and make the latter and the compound of tributyl tin trinitride prepared in reaction general formula (I) according to currently known methods, wherein G is a tetrazyl.
Embodiment
Chemical preparation embodiment
Embodiment 1:2-methyl-2-(2-fluoro-4 '-trifluoromethyl-biphenyl-4-yl) propionic acid (CHF
4810) preparation
The preparation of [2-(2-fluoro-4 '-trifluoromethyl-biphenyl-4-yl)] methyl propionate
(0.2g 0.64mmoles) adds 98% sulfuric acid (0.5g) and refluxing 2.5 hours in the solution in methyl alcohol (3ml) to 2-(2-fluoro-4 '-trifluoromethyl-biphenyl-4-yl) propionic acid.Remove in a vacuum and desolvate, resistates is dissolved in ethyl acetate (5ml) and uses 5%NaHCO
3Solution (5ml), wash with water then.Use Na
2SO
4Dry this solution also concentrates in a vacuum and obtains oily matter (0.2g, 95%).
HPLC-UV purity (215nm): 99%
[the preparation of 2-methyl-2-(2-fluoro-4 '-trifluoromethyl-biphenyl-4-yl) methyl propionate
To 0 ℃ down and in the nitrogen environment [2-(2-fluoro-4 '-trifluoromethyl-biphenyl-4-yl)] methyl propionate (0.2g, 0.61mmoles) add in the solution in anhydrous THF (3ml) 60%NaH (30mg, 0.75mmoles).This mixture was stirred 30 minutes and add CH
3I (70 μ l, 0.91mmoles).After 3 hours, concentrate this mixture in a vacuum and use ethyl acetate (5ml) dissolving.Use 5%NaHCO
3Solution (5ml), wash gained solution with water then, use Na
2SO
4Dry this solution, and concentrate in the vacuum and obtain oily matter (0.18g, 87%), use it for subsequent reaction without being further purified.
The preparation of 2-methyl-2-(2-fluoro-4 '-trifluoromethyl-biphenyl-4-yl) propionic acid
To [2-methyl-2-(2-fluoro-4 '-trifluoromethyl-biphenyl-4-yl)] (0.18g, (60mg 1mmol) and at room temperature keeps stirring 3 hours methyl propionate 0.53mmoles) to add KOH in the solution in ethanol (5ml).Use H
2O (5ml) dilutes this mixture and washs this solution with ether (5ml).Discard organic phase.With HCl with aqueous phase as acidified to pH=2, use ethyl acetate (10ml) to extract then.Use Na
2SO
4Dry this organic phase also concentrates and obtains white solid in a vacuum, and it is passed through quick SiO
2Chromatography purification (eluent hexane/ethyl acetate 8/2v/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 as 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 4-bromo-3-fluoro benzyl bromide
(10g 0.053moles) adds N-bromine succinimide (NBS in the solution in tetracol phenixin (100ml) to 4-bromo-3-toluene fluoride; 14g, 0.08moles).This mixture that refluxes, (100mg 0.4mmoles), refluxed 1 hour, at room temperature cooled off then and used water extraction to wherein adding dibenzoyl peroxide.Aqueous phase discarded with salt water washing organic phase, with dried over sodium sulfate and concentrate in a vacuum and obtain oily matter (16g), makes it carry out silica gel column chromatography (150g), obtains product with the hexane wash-out.
The preparation of 4-bromo-3-fluorophenyl acetonitrile
To 4-bromo-3-fluoro benzyl bromide (12.2g, 0.03moles) add in the solution in ethanol (100ml) NaCN (2g, 0.04moles) and refluxed 2 hours.Concentrate this mixture in a vacuum; With water dissolution gained resistates, use ethyl acetate extraction then.With salt water washing organic phase, with dried over sodium sulfate and concentrate in a vacuum and obtain dark oily matter (10g), make it carry out silica gel column chromatography (150g), use hexane: 7: 3 wash-outs of ether and obtain the product of solid form.
The preparation of 4-bromo-3-fluorophenyl cyclopropylniitrile
To 4-bromo-3-fluorophenyl acetonitrile (5g, 23mmoles) add in the solution in toluene (20ml) 35mmoles glycol dibromide, the 50%NaOH aqueous solution (20ml) and Tetrabutylammonium bromide (1.6g, 5mmoles).This mixture was at room temperature kept stirring 5-12 hour, then dilute with water and use ethyl acetate extraction.Use salt water washing organic phase then with 1N HCl, final drying also concentrates in a vacuum and obtains brown solid, makes it carry out silica gel column chromatography (200g), obtains the product of solid form with hexane-ether 1-1 wash-out.
The preparation of 4-bromo-3-fluorophenyl cyclopropane-carboxylic acid
In the suspension of 4-bromo-3-fluorophenyl cyclopropylniitrile (21mmoles) in methyl alcohol (10ml), add the 35%NaOH aqueous solution (40ml) and 35%H
2O
2The aqueous solution (3ml) refluxed 4 hours then, at room temperature cooled off and added 2N HCl (250ml).Also be dissolved in 5%NaHCO again by the solid that filters collecting precipitation
3The aqueous solution (300ml).Filter out insoluble fraction and clear filtrate is acidified to pH=2 with 2N HCl.The product precipitation is white solid, and it is also dry in a vacuum by filtered and recycled.
The preparation of 1-(2-fluorine biphenyl-4-yl) cyclopropane-carboxylic acid
The phenyl-boron dihydroxide of the 4-bromo-3-fluorophenyl cyclopropane-carboxylic acid of 800mg (3.1mmoles) and 650mg (3.4mmoles) is suspended in the 2M K of 8ml
2CO
3In the aqueous solution.In this mixture, add Tetrabutylammonium bromide (960mg, 3mmoles) and acid chloride (II) (40mg, heating is 30 minutes 0.18mmoles) and in the closed reactor under 130 ℃.At room temperature after the cooling, in this mixture, add 2MHCl (25ml) and use ethyl acetate extraction.Use 1NHCl, use salt water washing organic phase then, final dry and concentrate in a vacuum and obtain oily matter (1.7g), make its crystallization and obtain product from isopropyl ether-hexane, be white solid (0.2g).
HPLC(215nm)98％。
MS (EI; TSQ700; Parameter 180C; 70V; 200uA): 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 identical step described in the embodiment 1, be raw material and use suitable reagent to prepare Compound C HF 5022 with suitable 4-bromophenyl cycloalkanes carboxylic-acid, 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, CHF 5105, CHF 5106, CHF 5107 and CHF 5002.
Embodiment 3-pharmacologically active
A β in the H4-15x cell conditioned medium liquid
42
The inhibition that discharges
In the flask in the presence of Totomycin and blasticidin are arranged (in the insulation can under 37 ℃, in the steam-laden atmosphere surrounding that contains 5% carbonic acid gas) cultivate H4-15x cell (with the human glioma cell of the people's gene transfection of coding amyloid beta APP695 precursor), this system is kept selection pressure to the cell of gene that continuous expression is paid close attention to.
When cell reaches about 90% fusion rate, collect them and be seeded in 24 hole flat boards again that (each is 2 * 10 years old
5Individual cell) in the complete substratum of the 0.5ml on.After about 24 hours,, replenished to the fresh culture of the compound (I) of 100 micromole's final concentrations with 0.5ml and to have replaced substratum in each hole when the adhesion of cell and hole surface and when obtaining merging.To each test concentrations according to triplicate repetition.The molecule that will be used to handle is dissolved in methyl-sulphoxide (DMSO) or is dissolved in methyl-sulphoxide/water mixture in advance, and the final concentration of DMSO in the hole is no more than 1%.Therefore, the dull and stereotyped incubated overnight that will prepare once more (14-16 hour); After this from each hole, get supernatant liquor and to A β
42With A β
40Protein quantification.The instrumentation that use is used for the microtest plate chemiluminescence analysis carry out this test, and its allows two kinds of protein respectively quantitatively and based on the immobilization of analyte-antibody complex on the paramagnetic microballon.With one of antibody of this mixture of ruthenium compound mark, carrying out electrochemistry when exciting, this compound can produce the optical signal of the intensity that is directly proportional with the amount of the analyte that exists.
The inhibition of cyclo-oxygenase in the rat whole blood-1 (COX-1)
Get whole blood and put into the heparinization test tube immediately from rat aorta.With the test compounds of 100 μ M concentration or only use carrier (DMSO) with the aliquot (500 μ l) of heparinization whole blood 37 ℃ of following pre-incubations 1 hour.By adding calcium ion carrier A 23187 (final concentration 5 * 10
-5M) induce eicosanoid to produce and after 30 minutes, interrupts being incubated by sample being put into fast dry ice.After this centrifugal sample (4 ℃ of following 12000g * 3 minute) also calculates 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 the table 1.Show about 25% A β with same concentrations as correlated flurbiprofen
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 (7)
1. prepare the compound of general formula (I), the method for its pharmaceutically acceptable salt:
Wherein:
R and R
1Form the ring of 3-6 carbon atom with the carbon atom that they connected;
R
3Represent one or more groups that are independently selected from following groups:
Be selected from the halogen of F, Cl, Br, I;
-CF
3；
-optional by one or more C
1-C
4The C that alkyl and/or oxo base replace
3-C
8Cycloalkyl;
-optional the phenyl that is replaced by one or more following groups: halogen as defined above; CF
3OCF
3OH; 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 the following groups
3-C
8Cycloalkyl: straight or branched C
1-C
4Alkyl, CF
3Or OH;
OR
4Or NHCOR
4, R wherein
4Be CF
3, straight or branched C
2-C
6Alkenyl or alkynyl; Benzyl; Optional by the phenyl of the one or more replacements in the 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 the following groups
3-C
8Cycloalkyl: straight or branched C
1-C
4Alkyl, CF
3Or OH;
Described method comprises the aryl halide condensation that makes suitable phenyl-boron dihydroxide or its alkyl ester and general formula (II),
Wherein R and R
1As above-mentioned definition and X is halogen atom.
2. the method for claim 1, wherein R and R
1Form the ring of 3 carbon atoms with the carbon atom that they connected.
3. method as claimed in claim 2, wherein R
3Be CL.
4. as each described method of claim 1-3, the halogen atom X of the compound of its formula of (II) is selected from Br or I.
5. as each described method of claim 1-4, wherein condensation step is palladium-catalytic reaction.
6. as each described method of claim 1-5, the aryl halide of its formula of (II) is to prepare by the method that comprises the steps:
(a) 4-halogen-3-toluene fluoride is changed into 4-halogen-3-fluoro benzyl bromide;
(b) bromine with step (a) changes into corresponding 4-halogen-3-fluorophenyl acetonitrile;
(c), obtain corresponding 4-halogen-3-fluorophenyl cycloalkyl nitrile with the acetonitrile of step (b) and suitable dibromo alkyl derivative condensation; With
(d) the cycloalkyl nitrile with step (c) changes into 4-halogen-3-fluorine cycloalkyl carboxylic acid.
7. the method described in claim 6, the dibromo alkyl derivative of wherein said step (c) is a glycol dibromide.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITMI2003A000311 | 2003-02-21 | ||
| ITMI20030311 ITMI20030311A1 (en) | 2003-02-21 | 2003-02-21 | 2-FENYL-2-DIALKYL-ACETIC ACIDS FOR THE TREATMENT OF ALZHEIMER DISEASE. |
| ITMI20032068 ITMI20032068A1 (en) | 2003-10-23 | 2003-10-23 | DERIVATIVES OF 1-PHENYLCYCLOALCANCARBOSSYIC ACID FOR THE TREATMENT OF NEURODEGENERATIVE DISEASES. |
| ITMI2003A002068 | 2003-10-23 |
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| CNB2004800047290A Division CN100398506C (en) | 2003-02-21 | 2004-02-19 | 1-phenylalkanecarboxylic acid derivatives for the treatment of neurodegenerative diseases |
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ID=36605990
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| CN200810100704.0A Expired - Fee Related CN101328117B (en) | 2003-02-21 | 2004-02-19 | 1-phenylalkanecarboxylic acid derivatives for the treatment of neurodegenerative diseases |
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| CN (2) | CN100398506C (en) |
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| CN106431900A (en) * | 2010-04-01 | 2017-02-22 | 奇斯药制品公司 | Novel polymorphs and salts |
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| EP2133322A1 (en) * | 2008-06-11 | 2009-12-16 | CHIESI FARMACEUTICI S.p.A. | Process of preparing derivatives of 1-(2-halobiphenyl-4-yl)-cyclopropanecarboxylic acid |
| ES2437163T3 (en) * | 2009-08-04 | 2014-01-09 | Chiesi Farmaceutici S.P.A. | Processes for the preparation of derivatives of 1- (2-halobiphenyl-4-yl) -cyclopropanecarboxylic acid |
| EP3013786B1 (en) * | 2013-06-24 | 2018-04-04 | Chiesi Farmaceutici S.p.A. | Improved process for the preparation of derivatives of 1-(2-fluoro[1,1'-biphenyl]-4-yl)-cyclopropanecarboxylic acid |
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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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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
- 2004-02-19 CN CNB2004800047290A patent/CN100398506C/en not_active Expired - Fee Related
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Patent 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 |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106431900A (en) * | 2010-04-01 | 2017-02-22 | 奇斯药制品公司 | Novel polymorphs and salts |
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| CN1751018A (en) | 2006-03-22 |
| ZA200506614B (en) | 2006-12-27 |
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