HK1115579A1 - (biphenyl) carboxylic acids and derivatives thereof - Google Patents
(biphenyl) carboxylic acids and derivatives thereof Download PDFInfo
- Publication number
- HK1115579A1 HK1115579A1 HK08105984.9A HK08105984A HK1115579A1 HK 1115579 A1 HK1115579 A1 HK 1115579A1 HK 08105984 A HK08105984 A HK 08105984A HK 1115579 A1 HK1115579 A1 HK 1115579A1
- Authority
- HK
- Hong Kong
- Prior art keywords
- biphenyl
- benzyloxy
- acetic acid
- trifluoromethyl
- acid
- Prior art date
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
The invention relates to compounds having the general formula (I) and/or salts or esters thereof, wherein A, X, R1-R6The definitions of (a) are given below.
Furthermore, the invention relates to the use of said compounds for the treatment of alzheimer's disease and their use for the modulation of gamma-secretase activity.
Alzheimer's disease is the most common form of age-related neurodegenerative disease. The disease is primarily, but not exclusively, associated with aging and is clinically manifested not only by progressive loss of memory, cognition, reasoning and judgment, but also by emotional instability and progressive leading to profound mental decline and death.
The pathological hallmarks that define alzheimer's disease are the presence of neurofibrillary tangles and amyloid plaques in the brain, which are thought to play a major role in the pathogenesis of the disease.
These plaques are composed mainly of peptides formed by cleavage products of β Amyloid Precursor Protein (APP), a 695 amino acid protein, whose function has so far been the subject of various hypotheses only.
APP is processed in 2 steps, the first step (catalyzed by β -secretase) producing the secretory peptide and the membrane-bound C99 fragment.
C99 is a substrate for a second proteolytic activity mediated by gamma-secretase, resulting in the production of peptides ranging from 37-42 residues.
The amount of the longer isoform, a β 42, is selectively increased in patients carrying certain mutations of a specific protein (presenilin), which mutations have been associated with early onset familial alzheimer's disease.
Thus, a β 42 is believed by many to be the major cause of alzheimer's disease pathogenesis.
It is now clear that the γ -secretase activity cannot be attributed to one specific protein, but is in fact related to a diverse set of proteins comprising Aph1, the slow protein, the presenilin and Pen-2 (reviewed by De Strooper (2003) Neuron 38, 9).
Thus, while the molecular mechanism of the second cleavage is still unclear to date, the γ -secretase-complex has become one of the major targets for the search for compounds useful in the treatment of alzheimer's disease.
Other clues for exploring new treatments come from epidemiological studies, and it appears that examples of the ingestion of certain nonsteroidal anti-inflammatory drugs ("NSAIDs") are associated with a reduced risk of developing Alzheimer's disease (Akiyama et al (2000) neurobiol. aging 21, 383; McGeer et al (1996) Neurology 47, 425; Rogers et al (1993) Neurology 43, 1609; Anthony et al (2004) Neurology 54, 6; Stewart et al (1997) Neurology 48, 626; In't Veld et al (1999) neurobiol. aging 19, 607).
Indeed, this finding was recently supported by biochemical studies in which the effects of certain NSAIDs on gamma-secretase were demonstrated (Weggen et al (2001) Nature 414, 6860, 212; Morihara et al (2002) J. neurochem.4, 1009; Eriksen (2003) J. Clin. invest.112, 440).
The development of additional compounds that exhibit similar effects has been hampered to date due to the lack of understanding of the molecular mechanisms of the effects.
Thus, there is a strong need to modulate gamma-secretase activity thereby opening new compounds for the treatment of the alzheimer's disease pathway.
It is an object of the present invention to provide such compounds.
This object is achieved by a compound having the general formula (T) and/or a salt or ester thereof,
wherein
A is selected from phenyl and C3-7Cycloalkyl and heterocyclyl rings;
x is C optionally substituted by one or more groups selected from F, Cl, Br, I and optionally by one or more groups selected from F, Cl, Br, I1-C4Linear C substituted by alkyl substituents1-C4An alkylene group;
R1and R2Independently of one another, from H; alkyl selected from CH3、C2H5Iso C3H7N is C3H7Iso C4H9N is C4H9And secondary C4H9C is tertiary C4H9(ii) a Alkenyl radical selected from C2H3Iso C3H5N is C3H5N is C4H7Iso C4H7And secondary C4H7(ii) a Or R1And R2Is part of a saturated or unsaturated ring having 3 to 6C atoms and may contain one or more heteroatoms from N, S or O in the ringIf more than one heteroatom is present, the heteroatoms may be the same or different;
R3、R4、R5and R6Independently selected from H, F, Cl, Br, I, CN, OH, C (O) N (R)7R8)、S(O)2R7、SO2N(R7R8)、S(O)N(R7R8)、N(R7)S(O)2R8、N(R8)S(O)R8、S(O)2R7、N(R7)S(O)2N(R8R8a)、SR7、N(R7R8)、N(R7)C(O)R8、N(R7)C(O)N(R8R8a)、N(R7)C(O)OR8、OC(O)N(R7R8)、C(O)R7Substituted and unsubstituted C1-C4Alkyl and substituted and unsubstituted C1-C4-alkoxy, wherein C1-C4-alkyl and C1-C4The substituents of both groups-alkoxy being selected from F, Cl, Br, I, CF3；
R7、R8、R8aIndependently selected from H, C1-C4Alkyl, heterocyclyl and C3-7Cycloalkyl radicals, in which C1-C4Alkyl, heterocyclyl and C3-7Cycloalkyl is optionally substituted with one or more substituents independently selected from F, Cl, Br, I and CF3Is substituted with the substituent(s).
The term "substituted" as used herein includes both partial and total substitution. The substituents may be saturated or unsaturated.
Esters are esters of the formula (I) in which H in the carboxyl group is replaced by an organic residue R7aAnd (4) substitution. Suitable organic residues are familiar to the person skilled in the art. Preferred R7aComprising the following:
unsubstituted or at least mono-substituted alkyl (preferably C)1-C10Alkyl), alkenyl (preferably C)2-C10Alkenyl), alkynyl (preferably C)3-C10-alkynyl) and unsubstituted or at least mono-substituted, saturated or unsaturated, non-aromatic or aromatic rings having 3 to 6C-atoms, which may contain one or more heteroatoms from N, S or O in the ring, which heteroatoms, if more than one are present, may be the same or different. The substituents are selected from halogen, alkyl, alkenyl, alkynyl, N, S, O, carboxyl, sulfonyl, and the like, which may be further substituted.
Examples of the aromatic group which is usually used include aryl (e.g., phenyl) and heteroaryl, which may be substituted, preferably by the above-mentioned substituents.
The term "C1-C4Alkyl "refers to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl.
“C3-7Cycloalkyl radicals "or" C3-7Cycloalkyl ring "means a cycloalkyl chain having 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl. Each hydrogen of the cycloalkyl carbon may be substituted with a substituent.
"Heterocyclyl" or "heterocycle" means a cyclopentane, cyclohexane or cycloheptane ring containing up to a maximum number of double bonds (fully saturated, partially saturated or unsaturated aromatic or non-aromatic), wherein at least one carbon atom up to 4 carbon atoms are selected from the group consisting of sulfur (including-S (O) -, -S (O))2-), oxygen and nitrogen (including ═ n (o) -, where the ring is attached to the rest of the molecule through a carbon or nitrogen atom. Examples of heterocycles include, but are not limited to, furan, thiophene, pyrrole, pyrroline, imidazole, imidazoline, pyrazole, pyrazoline, oxazole, oxazoline, isoxazole, isoxazoline, thiazole, thiazoline, isothiazole, isothiazoline, thiadiazole, thiadiazoline, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, thiadiazolidine, sulfolane, pyran, dihydropyran, tetrahydropyran, imidazolidine, pyridine, pyridazine, pyrazine, pyrimidine, piperazine, piperidine, morpholine, tetrazole, triazole, triazolidine, tetrazolidine, azazapine, and the likeOr homopiperazine. "heterocyclic" also means azetidine.
In a preferred embodiment, the present invention relates to a compound having the general formula (I) and/or a salt or ester thereof, wherein a; x; r1And R2(ii) a And R3、R4、R5And R6Independently of one another, have the following meanings:
a is phenyl, cyclopropyl, cyclohexyl or 6-membered aromatic heterocycle;
x is C optionally substituted by one or more substituents from the group consisting of F, Cl, Br, I and optionally by one or more substituents F, Cl, Br, I1-C4Alkyl substituted CH2A group; and/or
R1And R2Is H; or R1Is H and R2Is CH3、C2H5、C3H7Or C4H9Or an isomer thereof; or R1And R2Is CH3Or R is1、R2Together with the carbon atom to which they are attached form a cyclopropyl ring; and/or
R3、R4、R5And R6Independently selected from H, OH; c partially or totally substituted by F, Cl, Br, I1-C4Alkyl or C1-C4An alkoxy group; c (O) NH2、S(O)2-C1-C4Alkyl, S (O)2-a heterocyclic group.
In this group of embodiments, A, X, R is even more preferred1And R2And R3、R4、R5And R6All radicals have the meanings defined above.
More preferably A, X, R1And R2And R3、R4、R5And R6Independently of one another, have the following meanings:
a is phenyl; and/or
X is CH2Or CHCH3(ii) a And/or
R1And R2Is H; or R1Is H and R2Is CH3、C2H5、C3H7Or C4H9Or an isomer thereof; or R1And R2Is CH3(ii) a Or R1、R2Together with the carbon atom to which they are attached form a cyclopropyl ring; and/or
R3、R4、R5And R6Independently selected from H, OH, CH3、OCH3、CF3、OCF3、C(O)NH2、S(O)2-C1-C4Alkyl, S (O)2-heterocyclyl, F and Cl;
and/or salts or esters thereof.
In this group of embodiments, A, X, R is even more preferred1And R2And R3、R4、R5And R6All radicals have the meanings defined above.
In an even more preferred embodiment, the present invention relates to a compound selected from the group consisting of:
I) [5- (4-fluoro-benzyloxy) -4' -trifluoromethyl-biphenyl-3-yl ] -acetic acid;
II) [5- (4-isopropyl-benzyloxy) -4' -trifluoromethyl-biphenyl-3-yl ] -acetic acid;
III) [ 4' -trifluoromethyl-5- (4-trifluoromethyl-benzyloxy) -biphenyl-3-yl ] -acetic acid;
IV) [5- (4-methanesulfonyl-benzyloxy) -4' -trifluoromethyl-biphenyl-3-yl ] -acetic acid;
v) (5-cyclohexylmethoxy-4' -trifluoromethyl-biphenyl-3-yl-acetic acid;
VI) {5- [4- (pyrrolidine-1-sulfonyl) -benzyloxy ] -4' -trifluoromethyl-biphenyl-3-yl } -acetic acid;
VII) (5-benzyloxy-biphenyl-3-yl) -acetic acid;
VIII)2- (5-benzyloxy-4' -trifluoromethyl-biphenyl-3-yl) -pentanoic acid;
IX) (5-benzyloxy-3 ', 5' -dichloro-biphenyl-3-yl) -acetic acid;
x) 5-benzyloxy-4' -trifluoromethyl-biphenyl-3-yl) -acetic acid;
XI) (5-benzyloxy-3 ', 5' -bis-trifluoromethyl-biphenyl-3-yl) -acetic acid;
XII) (5-benzyloxy-3 ', 4' -dichloro-biphenyl-3-yl) -acetic acid;
XIII) (5-benzyloxy-4' -trifluoromethoxy-biphenyl-3-yl) -acetic acid;
XIV) (5-benzyloxy-3' -methoxy-biphenyl-3-yl) -acetic acid;
XV) (5-benzyloxy-3' -carbamoyl-biphenyl-3-yl) -acetic acid;
XVI) (5-benzyloxy-3' -hydroxy-biphenyl-3-yl) -acetic acid;
XVII) (5-benzyloxy-4' -methanesulfonyl-biphenyl-3-yl) -acetic acid;
XXIII) (5-benzyloxy-4' -sulfamoyl-biphenyl-3-yl) -acetic acid;
XIX)2- (5-benzyloxy-4' -trifluoromethyl-biphenyl-3-yl) -propionic acid;
XX)2- (5-benzyloxy-4' -trifluoromethyl-biphenyl-3-yl) -2-methyl-propionic acid;
XXI)1- (5-benzyloxy-4' -trifluoromethyl-biphenyl-3-yl) -cyclopropanecarboxylic acid;
XXII) (5-benzyloxy-4' -fluoro-biphenyl-3-yl) -acetic acid;
XXIII) (5-benzyloxy-4' -chloro-biphenyl-3-yl) -acetic acid;
XXIV) (4' -acetylamino-5-benzyloxy-biphenyl-3-yl) -acetic acid;
XXV) (5-benzyloxy-4' -hydroxy-biphenyl-3-yl) -acetic acid;
XXVI) (5-benzyloxy-4' -isopropoxy-biphenyl-3-yl) -acetic acid;
XXVII) (5-benzyloxy-3 ', 5' -difluoro-biphenyl-3-yl) -acetic acid;
XXVIII) (5-benzyloxy-3' -isopropoxy-biphenyl-3-yl) -acetic acid;
XXIX) (5-benzyloxy-4' -methoxy-biphenyl-3-yl) -acetic acid;
XXX) (5-benzyloxy-2' -methoxy-isoleu-3-yl) -acetic acid;
XXXI) (5-benzyloxy-2' -methyl-biphenyl-3-yl) -acetic acid;
XXXII) (5-benzyloxy-3' -methyl-biphenyl-3-yl) -acetic acid;
XXXIII) (5-benzyloxy-3' -trifluoromethyl-biphenyl-3-yl) -acetic acid;
XXXIV) (5-benzyloxy-2' -fluoro-biphenyl-3-yl) -acetic acid;
XXXV) (5-benzyloxy-4' -methyl-biphenyl-3-yl) -acetic acid;
XXXVI) (5-benzyloxy-3' -fluoro-biphenyl-3-yl) -acetic acid;
XXXVII) (5-benzyloxy-3' -chloro-biphenyl-3-yl) -acetic acid;
XXXVIII) (5-benzyloxy-3' -trifluoromethoxy-biphenyl-3-yl) -acetic acid;
XXXIX)2- {5- [4- (pyrrolidine-1-sulfonyl) -benzyloxy ] -4' -trifluoromethyl-biphenyl-3-yl } -pentanoic acid;
XL)2- (5-cyclopropylmethoxy-4' -trifluoromethyl-biphenyl-3-yl) -pentanoic acid;
XLI) [5- (4-chloro-benzyloxy) -4' -trifluoromethyl-biphenyl-3-yl ] -acetic acid;
XLII) (5-cyclopropylmethoxy-4' -trifluoromethyl-biphenyl-3-yl) -acetic acid;
XLIII) [5- (5-methyl-iso-5Azol-3-ylmethoxy) -4' -trifluoromethyl-biphenyl-3-yl]-acetic acid;
XLIV) [5- (3, 5-dichloro-benzyloxy) -4' -trifluoromethyl-biphenyl-3-yl ] -acetic acid;
XLV) [5- (tetrahydro-pyran-4-yloxy) -4' -trifluoromethyl-biphenyl-3-yl ] -acetic acid;
XLVI) [5- (4-dimethylsulfamoyl-benzyloxy) -4' -trifluoromethyl-biphenyl-3-yl ] -acetic acid;
XLVII) [5- (1-phenyl-ethoxy) -4' -trifluoromethyl-biphenyl-3-yl ] -acetic acid;
XLVIII) {5- [4- (morpholine-4-carbonyl) -benzyloxy ] -4' -trifluoromethyl-biphenyl-3-yl } -acetic acid;
XLIX) [ 4' -trifluoromethyl-5- (3-trifluoromethyl-benzyloxy) -biphenyl-3-yl ] -acetic acid;
l) [ 4' -trifluoromethyl-5- (2-trifluoromethyl-benzyloxy) -biphenyl-3-yl ] -acetic acid;
LI) (5-phenethyloxy-4' -trifluoromethyl-biphenyl-3-yl) -acetic acid;
LII) [5- (tetrahydro-pyran-2-ylmethoxy) -4' -trifluoromethyl-biphenyl-3-yl ] -acetic acid;
LIII) [5- (4-dimethylcarbamoyl-benzyloxy) -4' -trifluoromethyl-biphenyl-3-yl ] -acetic acid;
LIV) [5- (4-methylcarbamoyl-benzyloxy) -4' -trifluoromethyl-biphenyl-3-yl ] -acetic acid;
LV) {5- [4- (pyrrolidine-1-carbonyl) -benzyloxy ] -4' -trifluoromethyl-biphenyl-3-yl } -acetic acid;
LVI) {5- [4- (morpholine-4-sulfonyl) -benzyloxy ] -4' -trifluoromethyl-biphenyl-3-yl } -acetic acid;
LVII) [5- (4-trifluoromethoxy-benzyloxy) -4' -trifluoromethyl-biphenyl-3-yl ] -acetic acid;
LVIII) [5- (2-chloro-benzyloxy) -4' -trifluoromethyl-biphenyl-3-yl ] -acetic acid;
LIX) [5- (3-chloro-benzyloxy) -4' -trifluoromethyl-biphenyl-3-yl ] -acetic acid;
LX) [5- (4-methyl-benzyloxy) -4' -trifluoromethyl-biphenyl-3-yl ] -acetic acid;
LXI)2- (5-benzyloxy-4' -trifluoromethyl-biphenyl-3-yl) -pent-4-enoic acid;
LXII) (R) -2- (5-cyclopropylmethoxy-4' -trifluoromethyl-biphenyl-3-yl) -pentanoic acid;
LXIII) (S) -2- (5-cyclopropylmethoxy-4' -trifluoromethyl-biphenyl-3-yl) -pentanoic acid;
LXIV) R) -2- (5-benzyloxy-4' -trifluoromethyl-biphenyl-3-yl) -pentanoic acid;
LXV) (S) -2- (5-benzyloxy-4' -trifluoromethyl-biphenyl-3-yl) -pentanoic acid.
Certain compounds of the present invention and/or salts or esters thereof will exist in different stereoisomeric forms. All of these forms are the subject of the present invention.
The following are exemplary salts of the compounds of the invention included herein. The list of different salts shown below is not complete and is not intended to be limiting.
The compounds of the invention which contain one or more acidic groups can be used according to the invention, for example as their alkali metal, alkaline earth metal or ammonium salts. More precise examples of such salts include sodium, potassium, calcium, magnesium or salts with ammonia or organic amines such as ethylamine, ethanolamine, triethanolamine or amino acids.
The compounds of the invention containing one or more basic groups, i.e. groups which can be protonated, can be used according to the invention in the form of their addition salts with inorganic or organic acids.
Examples of suitable acids include hydrochloric, hydrobromic, phosphoric, sulfuric, nitric, methanesulfonic, p-benzenesulfonic, napadisylic, oxalic, acetic, tartaric, lactic, salicylic, benzoic, formic, propionic, pivalic, diethylacetic, malonic, succinic, pimelic, fumaric, maleic, malic, sulfamic, phenylpropionic, gluconic, ascorbic, isonicotinic, citric, adipic and other acids known to those skilled in the art.
The term "pharmaceutically acceptable" means approved by a regulatory agency, such as EMEA (europe) and/or FDA (usa), and/or any other national regulatory agency, for use in animals, preferably humans.
The compounds of the invention containing several basic groups can form different salts at the same time.
If the compounds of the invention contain both acidic and basic groups in the molecule, the invention also includes internal salts in addition to the salt forms mentioned.
The corresponding salts of the compounds of the invention can be obtained by conventional methods known to those skilled in the art, for example by contacting them with inorganic or organic acids or bases in solvents or dispersants, or by anion exchange or cation exchange with other salts.
Furthermore, the present invention includes all salts of the compounds of the invention which, due to their low physiological compatibility, are not suitable for direct use in medicine, but which are useful, for example, as intermediates in chemical reactions or for the preparation of pharmaceutically acceptable salts, or which are suitable for use in the study of the gamma-secretase modulating activity of the compounds of the invention in any suitable manner, for example in vitro assays.
Moreover, the present invention includes all solvates of the compounds of the present invention.
Furthermore, the present invention includes derivatives/prodrugs (including salts thereof) of the compounds of the present invention which contain physiologically tolerable and cleavable groups and which are metabolised to the compounds of the present invention in animals (preferably mammals, most preferably humans).
The invention also includes metabolites of the compounds of the invention.
The term "metabolite" refers to all molecules derived from the compounds of the present invention in a cell or organism, preferably a mammal.
Preferably the term "metabolite" relates to a molecule that is different from any molecule that is present in any such cell or organism under physiological conditions.
The structures of metabolites of the compounds of the invention will be apparent to any one of skill in the art using a variety of suitable methods.
The compounds of the general formula (I) can be prepared according to methods published in the literature or by analogous methods.
Methods for synthesizing the compounds are described, for example, in Houben-Weyl, Methodender Organischen Chemie (Methods of Organic Chemistry), Thieme-Verlag, Stuttgart, and Organic Reactions, John Wiley & Sons, New York.
Depending on the individual case, during the synthesis of the compounds of the general formula (I), it may be necessary or advantageous, in order to avoid side reactions, to temporarily block the functional groups by introducing protecting groups and deprotect them at a later stage of the synthesis, or to introduce functional groups in the form of precursor groups and convert them at a later stage into the desired functional groups. Suitable synthetic strategies, protecting groups and precursor groups are known to those skilled in the art.
If desired, the compounds of formula (I) may be purified by conventional purification methods, for example by recrystallization or chromatography. The starting materials for the preparation of the compounds of formula (I) are commercially available or can be prepared according to or analogously to literature procedures.
These may serve as the basis for preparing the compounds of the invention by several methods well known to those skilled in the art.
In particular, the compounds of the present invention are useful in the treatment of alzheimer's disease.
Further details regarding the use are disclosed below.
The compounds are useful for modulating gamma-secretase activity.
The term "modulating gamma-secretase activity" as used herein refers to the effect on the processing of APP by the gamma-secretase complex. Preferably it refers to an effect wherein the overall rate of processing of APP remains substantially the same as if the compound was not used, but wherein the relative amount of processed product is altered, more preferably such that the amount of Α β 42 peptide produced is reduced.
It has previously been demonstrated that the gamma-secretase complex is also involved in Notch protein processing. Notch is a signaling protein that plays a key role in developmental processes (as reviewed, for example, in Schweisguth F (2004) curr. biol.14, R129).
For the use of the compounds in therapy for the modulation of γ -secretase activity, Notch processing activity that does not interfere with γ -secretase activity appears to be particularly advantageous in order to avoid putative unwanted side effects.
Therefore, a compound having no influence on the Notch processing activity of the γ -secretase complex is preferable.
Within the meaning of the present invention, "influence on Notch processing activity" includes both cases where Notch processing activity is inhibited or activated by a certain factor.
In Shimizu et al (2000) mol.cell.biol, 20: 6913 compounds are defined as having no effect on Notch processing activity if said factor is less than 20, preferably less than 10, more preferably less than 5, most preferably less than 2 at a concentration of 30 μ M.
Such gamma-secretase modulation can be effected, for example, in a mammal. Exemplary mammals are mice, rats, guinea pigs, monkeys, dogs, cats. Modulation may also be effected in humans.
In a particular embodiment of the invention, said modulation is carried out in vitro or in cell culture.
As known to those skilled in the art, several in vitro and cell culture assays are available.
Examples of such assays are described in WO-03/008635.
The concentration of the various gamma-secretase cleavage products (A.beta. -peptide) can be determined by various methods known to those skilled in the art. Examples of such methods include peptide determination by mass spectrometry or detection by antibodies.
For example, suitable antibodies are available from Genetics Company, inc.
Other information is disclosed in, for example, n.ida et al (1996) j.biol.chem.271, 22908 and m.jensen et al (2000) mol.med.6, 291. Antibody-based kits are also available from Irnogenetics, Belgium.
Cells that can be used in these assays include cells that physiologically express the gamma-secretase complex, and cells that transiently express or stably express some or all of the interactors (interpctors) of the gamma-secretase complex.
Numerous available cell lines suitable for these assays are known to the skilled artisan.
Cells and cell lines of neuronal origin or of glial origin are particularly suitable. Furthermore, brain cells and tissues and their homogenate and membrane preparations can be used.
For example, these assays can be performed to study the effects of the compounds of the invention under different experimental conditions and configurations.
In addition, these assays can be performed as part of the study of the function of the gamma-secretase complex.
For example, one or more interactors of the gamma-secretase complex (in its wild-type form or carrying certain mutations and/or modifications) of an animal (preferably a mammal, more preferably a human) may be expressed in certain cell lines and the effects of the compounds of the invention may be studied.
The mutant form of the interactor used may be that of some animals (preferably mammals, more preferably humans) which have already been described, or that of said animals which have not previously been described.
Modifications of the gamma-secretase complex interactor include both any physiological modification of the interactor and any modification that has been described in biological systems as a modification of proteins.
Examples of such modifications include, but are not limited to, glycosylation, phosphorylation, prenylation, myristoylation, and farnesylation.
In addition, the compounds of the present invention may be used in the preparation of medicaments for modulating gamma-secretase activity.
The invention further relates to the use of said compounds for the preparation of a medicament for modulating gamma-secretase activity.
The gamma-secretase activity can be modulated in different ways, i.e. to produce different profiles of the various a β -peptides.
Preferably, the use of the compounds for modulating gamma-secretase activity resulting in a reduction in the relative amount of a β 42 protein produced.
The respective administration doses, administration routes, preparations, and the like are further disclosed below.
The invention further relates to the use of the compounds of the invention for the treatment of diseases associated with elevated levels of a β 42 production.
The term "treatment", as used herein, is intended to refer to all processes in which disease progression may be slowed, interrupted, retarded, or arrested, but not necessarily all symptoms are shown to be eliminated.
The term "elevated a β 42 production level" as used herein refers to a state in which the rate of a β 42-peptide production is increased due to an overall increase in APP processing, or preferably it refers to a state in which a β 42 peptide production is increased due to an improved profile of APP processing products compared to wild type/non-pathological states.
As outlined above, this elevated level of Α β 42 production is a hallmark of patients developing or suffering from alzheimer's disease.
Furthermore, the present invention relates to compositions comprising the compounds of the invention in admixture with an inert carrier.
In a preferred embodiment, the present invention relates to compositions comprising a compound of the present invention in admixture with an inert carrier, wherein the inert carrier is a pharmaceutical carrier.
The term "carrier" refers to a diluent, adjuvant, excipient, or vehicle with which the compound is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, including, but not limited to, peanut oil, soybean oil, mineral oil, sesame oil and the like. When the pharmaceutical composition is administered orally, water is the preferred carrier. When the pharmaceutical composition is administered intravenously, saline and aqueous dextrose are preferred carriers. Saline solutions and aqueous dextrose and glycerol solutions are preferred as liquid carriers for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol and the like. The composition may contain minor amounts of wetting or emulsifying agents or pH buffering agents as desired. These compositions may take the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained release formulations and the like. The compositions may be formulated as suppositories with conventional binders and carriers such as triglycerides. Oral formulations may include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, and the like. Examples of suitable Pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by e.w. martin. These compositions should contain a therapeutically effective amount of the compound (preferably in purified form) together with an appropriate amount of carrier so as to provide a suitable form for administration to a patient. The formulation should be suitable for the mode of administration.
In addition, the present invention relates to a process for the preparation of a compound of the invention comprising the steps of: the phenylacetic acid derivatives, optionally protected, of said derivatives are coupled with suitable aromatic compounds, optionally further functionalising and deprotecting the biphenyl compounds thus obtained.
In one embodiment, a dihydroxybenzeneacetic acid derivative is alkylated with an inorganic base (e.g., an alkali metal carbonate, typically potassium carbonate) and a benzyl halide (typically benzyl bromide) in a suitable solvent (e.g., acetonitrile). The resulting alcohol is converted to the triflate using, for example, trifluoromethanesulfonic anhydride, an organic base (e.g., pyridine) in a suitable solvent (e.g., dichloromethane). The triflate can then be coupled with a boronic acid under various conditions known to those skilled in the art for such Suzuki couplings, typically with a solvent (e.g., 1, 2-dimethoxyethane), an alkali metal halide (e.g., cesium fluoride), and a palladium compound (e.g., tetrakis (triphenylphosphine) palladium (0)).
Optionally, the process for preparing the compounds of the invention further comprises the steps of: reacting a biphenyl compound with a suitable halide or dihalide to produce a compound of the invention, wherein R is1、R2At least one of which is not H.
Esters can be converted to acids with a base (e.g., an alkali metal hydroxide, typically lithium hydroxide) in the presence of water and other suitable solvents (e.g., tetrahydrofuran and methanol).
In another embodiment of the preparation of the compounds of the present invention, dibromofluorobenzene may be treated with benzyl alcohol in the presence of an alkali metal hydride, usually sodium hydride, in a suitable aprotic solvent, such as tetrahydrofuran. The product may be treated with a suitable malonic acid derivative, such as tert-butyl ethyl malonate, in the presence of an alkali metal hydride, typically sodium hydride, and a metal halide, typically a copper halide, preferably copper bromide. Further treatment in an acidic solvent (e.g., acetic acid) at elevated temperatures provides benzyloxy-bromobenzoate. Under various conditions known to those skilled in the art for such Suzuki couplings, which can be coupled with a boronic acid, solvents such as 1, 2-dimethoxyethane and water, alkali metal carbonates such as potassium carbonate and palladium compounds such as tetrakis (triphenylphosphine) palladium (0) are commonly used.
The ester can be converted to the acid with a base (e.g., an alkali metal hydroxide, typically lithium hydroxide) in the presence of water and other suitable solvents (e.g., tetrahydrofuran and methanol).
If desired, the biphenylcarboxylic acid can be alkylated by treatment with a suitable base (e.g., metal hexamethyldisilylamide, typically LiHMDS) and a suitable halide in a suitable aprotic solvent (e.g., tetrahydrofuran) at a suitable temperature (typically-15 ℃).
In another embodiment, such groups may be introduced by treating the ester with a suitable base (e.g., an alkali metal hydride, typically sodium hydride) and with a suitable halide in a suitable solvent (e.g., DMF) at a suitable temperature (e.g., -4 ℃).
The ester can be converted to the acid with a base (e.g., an alkali metal hydroxide, typically lithium hydroxide) in the presence of water and other suitable solvents (e.g., tetrahydrofuran and methanol).
Furthermore, the present invention relates to a method for the preparation of a medicament comprising the steps of:
a) preparation of the Compounds of the invention
b) A medicament formulated with the compound.
The compounds of the invention and their pharmaceutically acceptable salts, optionally in combination with other pharmaceutically active compounds suitable for the treatment or prevention of alzheimer's disease (e.g. aricept (eisai), donepezil (pfizer), Cognex (Warner-Lambert), tacrine (Warner-Lambert), axura (merz), memantine (merz) or any other drug known to the person skilled in the art suitable for the treatment or prevention of alzheimer's disease, can be administered as such, in admixture with each other or in the form of a pharmaceutical formulation, to an animal, preferably to a mammal, especially a human, as a medicament thereof.
Various delivery systems are known which can be used to administer the compounds of the present invention for the treatment of alzheimer's disease/modulation of gamma-secretase activity, for example, encapsulation in liposomes, microparticles and microcapsules.
If not delivered directly to the central nervous system (preferably the brain), it may be advantageous to select and/or modify the method of administration so that the pharmaceutical compound crosses the blood-brain barrier.
Methods of introducing the drug include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes.
The compounds may be administered by any convenient route, for example, by infusion, by bolus injection, by absorption through epithelial or mucocutaneous linings, and may be administered with other biologically active agents.
Can be administered systemically or locally. In addition, it may be desirable to introduce the pharmaceutical compositions of the present invention into the central nervous system by any suitable route, including intraventricular and intrathecal injection; ventricular injections may be advanced through, for example, an intraventricular catheter connected to a reservoir (reservoir), such as an Ommaya reservoir. Pulmonary administration may also be employed, for example, by use of an inhaler or nebulizer and formulation with an aerosolized agent.
In another embodiment, the compounds may be delivered in vesicles, particularly liposomes (Langer (1990) Science 249, 1527; Treat et al (1989) lipometers in the therapy of infection diseases and Cancer, Lopez-Berestein and Fidler, eds., Liss, New York, 353; Lopez-Berestein, id., 317).
In yet another embodiment, the compound may be delivered by a controlled release system. In one embodiment, a pump (Sefton (1987) CRC Crit. Ref. biomed. Eng.14, 201; Buchwald et al (1980) Surgery 88, 507; Saudek et al (1989) N. Engl. J. Med.321, 574) may be used. In another embodiment, polymeric materials may be used (Medical Applications of Controlled Release, Langer and Wise, eds., CRC Press, Boca Raton, Florida (1974); Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball eds., Wiley, New York (1984); Ranger and Peppas (1983) Macromol. Sci.Rev. Macromol. Chem.23, 61; Levy et al (1985) Science 228, 190; During et al (1989) Ann. neuron.25, 351; Howard et al (1989) J. Neurosurg.71, 858). In yet another embodiment, a Controlled Release system may be placed near the therapeutic target, i.e., at the brain, whereby only a portion of the systemic dose is required (e.g., Goodson, 1984, by Medical Applications of Controlled Release, supra, Vol.2, 115). Other controlled release systems are discussed by Langer in reviews (1990, Science 249, 1527).
In order to select the appropriate route of administration, the skilled person should also consider that routes of administration have been selected for other known anti-alzheimer's disease agents.
For example, Aricept/Donepzil and Cognex/tacrine (all acetylcholinesterase inhibitors) can be administered orally, and Axura/Memantine (NMDA receptor antagonist) is marketed as both a tablet/liquid and as an intravenous solution.
Furthermore, the skilled person will consider useful data regarding the route of administration of NSAID family members in clinical trials and other studies investigating their effect on alzheimer's disease.
To select an appropriate dosage, one skilled in the art should select a dosage that has proven to be non-toxic in preclinical and/or clinical studies and that may correspond to or deviate from the values given in advance.
The exact dosage employed in the formulation will also depend on the route of administration and the severity of the disease or condition, and should be decided according to the judgment of the practitioner and the specifics of each patient. However, suitable dosage ranges for intravenous administration are generally about 20-500 micrograms of active compound per kilogram of body weight. Suitable dosage ranges for intranasal administration are generally from about 0.01mg/kg body weight to 1mg/kg body weight. Effective doses can be extrapolated from dose-response curves from in vitro or animal model test systems.
An exemplary animal model is a transgenic mouse line "Tg 2576" containing the APP695 form with the double mutation KM670/671 NL. See, for example, the following: U.S. Pat. Nos. 5877399 and Hsiao et al (1996) Science 274, 99 and Kawarabayahsi T (2001) J.Neurosci.21, 372; frautschy et al (1998) am.J.Pathol.152, 307; irizary et al (1997) j.neuropathohol.exp.neurol.56, 965; lehman et al (2003) neurobiol. aging24, 645.
Practical valuable data from several studies is available to those skilled in the art, which can guide the skilled person in selecting the appropriate dose for the selected treatment regimen.
Numerous studies have been published which illustrate the effect of various molecules on gamma-secretase activity. Exemplary studies are Lim et al (2001) neurobiol. aging 22, 983; lim et al (2000) J Neurosci.20, 5709; weggen et al (2001) Nature 414, 212; eriksen et al (2003) J Clin invest.112, 440; yah et al (2003) J Neurosci.23, 7504.
General rule
All reactions were carried out under inert gas. NMR spectra were obtained using Bruker dpx 400. LCMS was performed on Agilent 1100 using ZORBAX for method A and method BSB-C18, 4.6X 150mm, 5 micron column; for method C, ZORBAX is usedSB-C18, 4.6X 75mm, 3.5 micron column. The column flow rate was 1ml/min, the solvents used were water and acetonitrile (0.1% TFA), and the injection volume was 10 ul. The wavelengths were 254 and 210 nm. The method is described as follows:
| method of producing a composite material | Flow rate of flow | Solvent(s) |
| A | 1ml/min | 0-1.5min5-95％MeCN 1.5-6min95％MeCN 6-6.5min95％-5％MeCN |
| B | 1ml/min | 0-11min5-95％MeCN 11-13min95％MeCN 13-14min95％-5％MeCN |
| C | 1ml/min | 0-1.5 min30-95％MeCN 1.5-4.5min95％ 4.5-5min95％-5％MeCN |
Abbreviations
| Ac | Acetyl group |
| d | Double peak |
| DCM | Methylene dichloride |
| DME | 1, 2-dimethoxyethane |
| DMF | N, N-dimethylformamide |
| DMSO | Dimethyl sulfoxide |
| e.e. | Enantiomeric excess |
| eq | Equivalent weight |
| Et | Ethyl radical |
| EtOAc | Ethyl acetate |
| g | Keke (Chinese character of 'Keke') |
| h | Hour(s) |
| HPLC | High pressure liquid chromatography |
| K2CO3 | Potassium carbonate |
| 1 | Lifting of wine |
| LCMS | Liquid chromatography-mass spectrometry |
| LDA | Lithium diisopropylamide |
| M | Molarity of the solution |
| m | Multiple peaks |
| Me | Methyl radical |
| min | Minute (min) |
| mol | Mole of |
| NMR | Nuclear magnetic resonance |
| q | Quartet peak |
| RT | Retention time |
| s | Single peak |
| sat | Saturation of |
| t | Triplet peak |
| TFA | Trifluoroacetic acid |
| THF | Tetrahydrofuran (THF) |
Examples
Example 1: preparation of [5- (4-fluoro-benzyloxy) -4' -trifluoromethyl-biphenyl-3-yl]-acetic acid (I)
(3, 5-dihydroxy-phenyl) -acetic acid methyl ester (0.500g, 2.75mmol) in MeCN (5ml) with K2CO3(0.095g, 6.88mmol) and 4-fluorobenzyl bromide (0.520g, 2.75 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was directly purified by flash column chromatography (EtOAc: isohexane) to give [3- (4-fluoro-benzyloxy) -5-hydroxy-phenyl]-methyl acetate (0.15 g).
[3- (4-fluoro-benzyloxy) -in DCM (5ml)) -5-hydroxy-phenyl]Methyl acetate (0.14g) was treated with pyridine (116. mu.l, 1.44mmol) and trifluoromethanesulfonic anhydride (0.16g, 0.58mmol) was added dropwise. The mixture was stirred at room temperature for 3 h. The mixture was diluted with additional DCM, washed with HCl solution (1M aq), dried (MgSO)4) And concentrated in vacuo to give [3- (4-fluoro-benzyloxy) -5-trifluoromethanesulfonyloxy-phenyl]Methyl acetate as a brown-orange oil (0.16 g).
Reacting [3- (4-fluoro-benzyloxy) -5-trifluoromethanesulfonyloxy-phenyl]Methyl acetate (0.15g) was combined with CsF (0.13g, 0.83mmol), 4-trifluorotolueneboronic acid (0.086g, 0.45mmol) and tetrakis (triphenylphosphine) palladium (0) (0.013g, 0.011mmol) in DME (4 ml). The mixture was heated to 90 ℃ for 10min in a CEM microwave. The mixture was diluted with EtOAc, water and NaHCO3The solution (sat aq) was washed and dried (MgSO4) And concentrated under vacuum. The residue was purified by flash column chromatography (EtOAc: isohexane) to give 5- (4-fluoro-benzyloxy) -4' -trifluoromethyl-biphenyl-3-yl]Methyl acetate (0.035g) as a white solid.
5- (4-fluoro-benzyloxy) -4' -trifluoromethyl-biphenyl-3-yl in THF (2ml)]Methyl acetate (0.035g) was treated with LiOH solution (210ul, 1M aq) and a few drops of MeOH. The mixture was stirred at rt for 2h, then diluted with water, acidified with HCl solution (2M aq) and extracted with EtOAc (x 3). The combined extracts were dried (MgSO)4) And concentrated under vacuum. Purification of the crude product by preparative HPLC to give 5- (4-fluoro-benzyloxy) -4' -trifluoromethyl-biphenyl-3-yl]Acetic acid as a white solid (0.012g, 0.03 mmol).1H NMR(CDCl3) δ 7.65(q, 4H), 7.41(q, 2H)7.07(m, 4H), 6.94(s, 1H), 5.06(s, 2H), 3.68(s, 2H); LCMS method (A), 5.2 min.
Example 2: screening for Compounds of the invention for modulating Gamma-secretase Activity
Screening was performed with SKN neuroblastoma cells carrying the APP- "Swedish (Swedish) mutant" (mutated at positions 595 and 596, the numbering of which is based on APP695) grown in DMEM/NUT-mix F12(HAM) supplied by Gibco (cat No.31330-38) containing 5% serum/Fe and supplemented with 1% non-essential amino acids, 100U/ml penicillin/streptomycin.
The cells were grown to near confluence.
For the descriptions in Citron et al (1997) Nature Medicine 3: 67 was subjected to screening.
IC50 values for γ -secretase activity for selected compounds of the invention.
The activity range is as follows: a is less than 1 uM; b is 1-10 uM; c is 10-100 uM; d is 100-300uM.
| Number of Compounds | Range of activity |
| I) | B |
| II) | B |
| III) | A |
| IV) | C |
| V) | A |
| VI) | B |
| VII) | B |
| VIII) | A |
| IX) | B |
| X) | B |
| XI | B |
| XII | B |
| XIII | B |
| XIV | C |
| XV | C |
| XVI | C |
| XVII | C |
| XVIII | C |
| XIX | B |
| XX | B |
| XXI | B |
| XXII | C |
| XXIII | B |
| XXIV | D |
| XXV | D |
| XXVI | C |
| XXVII | C |
| XXVIII | C |
| XXIX | C |
| XXX | C |
| XXXI | C |
| XXXII) | C |
| XXXIII) | C |
| XXXIV) | C |
| XXXV | C |
| XXXVI | C |
| XXXVII | D |
| XXXVIII | B |
| XXXIX | B |
| XL | B |
| XLI | B |
| XLII | B |
| XLIII | C |
| XLIV | B |
| XLV) | C |
| XLVI | B |
| XLVII | B |
| XLVIII | C |
| XLIX | B |
| L | B |
| LI | B |
| LII | D |
| LIII | D |
| LIV | D |
| LV | C |
| LVI | C |
| LVII | B |
| LVIII | B |
| LIX | B |
| LX | B |
Example 3: determination of the cyclooxygenase activity of the Compounds of the invention1 and cyclooxygenase-2 (Cox-1, Cox-2)
Inhibition of Cox-1 and Cox-2 was determined using a colorimetric Cox inhibitor screening assay provided by Cayman Chemical Company, Ann Arbor, MI, USA. (Cat. No.760111) according to manufacturer's instructions.
The following compounds showed < 50% inhibition at 100 μ M:
[5- (4-fluoro-benzyloxy) -4' -trifluoromethyl-biphenyl-3-yl ] -acetic acid;
[ 4' -trifluoromethyl-5- (4-trifluoromethyl-benzyloxy) -biphenyl-3-yl ] -acetic acid;
(5-cyclohexylmethoxy-4' -trifluoromethyl-biphenyl-3-yl) -acetic acid;
{5- [4- (pyrrolidine-1-sulfonyl) -benzyloxy ] -4' -trifluoromethyl-biphenyl-3-yl } -acetic acid;
2- (5-benzyloxy-4' -trifluoromethyl-biphenyl-3-yl) -pentanoic acid;
(5-benzyloxy-3 ', 5' -dichloro-biphenyl-3-yl) -acetic acid;
5-benzyloxy-4' -trifluoromethyl-biphenyl-3-yl) -acetic acid;
(5-benzyloxy-4' -trifluoromethoxy-biphenyl-3-yl) -acetic acid;
2- (5-benzyloxy-4' -trifluoromethyl-biphenyl-3-yl) -propionic acid;
2- (5-benzyloxy-4' -trifluoromethyl-biphenyl-3-yl) -2-methyl-propionic acid;
1- (5-benzyloxy-4' -trifluoromethyl-biphenyl-3-yl) -cyclopropanecarboxylic acid;
2- {5- [4- (pyrrolidine-1-sulfonyl) -benzyloxy ] -4' -trifluoromethyl-biphenyl-3-yl } -pentanoic acid;
2- (5-cyclopropylmethoxy-4' -trifluoromethyl-biphenyl-3-yl) -pentanoic acid;
(5-cyclopropylmethoxy-4' -trifluoromethyl-biphenyl-3-yl) -acetic acid;
[5- (3, 5-dichloro-benzyloxy) -4' -trifluoromethyl-biphenyl-3-yl ] -acetic acid;
[5- (4-dimethylsulfamoyl-benzyloxy) -4' -trifluoromethyl-biphenyl-3-yl ] -acetic acid;
[5- (1-phenyl-ethoxy) -4' -trifluoromethyl-biphenyl-3-yl ] -acetic acid.
Example 4: preparation of [5- (4-isopropyl-benzyloxy) -4' -trifluoromethyl-biphenyl-3-yl]-acetic acid (II)
The procedure is as in example 1, substituting 4-fluorobenzyl bromide with 4-isopropylbenzyl bromide.
1H NMR(CDCl3)δ 7.66(m，4H)，7.38(d，2H)，7.27(d，2H)，7.13(s，1H)， 7.11(s，1H)，6.97(s，1H)，5.07(s，2H)，3.70(s，2H)，2.93 (m，1H)，1.26(d，6H)；
LCMS method (a), RT ═ 5.0 min.
Example 5: preparation of [ 4' -trifluoromethyl-5- (4-trifluoromethyl-benzyloxy) -biphenyl-3-yl]-acetic acid (III)
The procedure is as in example 1, substituting 4-fluorobenzyl bromide with 4-trifluoromethyl benzyl bromide.
1H NMR(CDCl3)δ 7.60-7.70(m，6H)，7.56(d，2H)，7.12(s，1H)，7.11(s，1H)，6.95(s，1H)，5.17(s，2H)，3.70(s，2H)；
LCMS method (a), RT ═ 4.5 min.
Example 6: preparation of [5- (4-methanesulfonyl-benzyloxy) -4' -trifluoromethyl-biphenyl-3-yl]-acetic acid (IV)
The procedure is as in example 1, substituting 1-bromomethyl-4-methanesulfonyl-benzene for 4-fluorobenzyl bromide.
1H NMR(CDCl3)δ 7.93(d，2H)，7.55-7.65 (m，6H)，7.11(s，1H)，7.04(s，1H)，6.93(s，1H)，5.17(s，2H)，3.60(s，2H)，3.03(s，3H)；
LCMS methods (A), (M-H)-) 462.9，RT＝3.9min。
Example 7: preparation of (5-cyclohexylmethyloxy-4' -trifluoromethyl-biphenyl-3-yl) -acetic acid (V)
The procedure is as in example 1, substituting bromomethyl-cyclohexane for 4-fluorobenzyl bromide.
1H NMR(CDCl3)δ 7.67(s，4H)，7.07(s，1H)，7.03(s，1H)，6.86(s，1H)，3.78(d，2H)，3.69(s，2H)，1.80-167(m，6h)，1.38-1.15(m，3H)，1.14-1.00(m，2H)；
LCMS method (a), RT ═ 5.5 min.
Example 8: preparation of {5- [4- (pyrrolidine-1-sulfonyl) -benzyloxy-group]-4' -trifluoromethyl-biphenyl-3-yl } -acetic acid (VI)
The procedure is as in example 1, 4-fluorobenzyl bromide is replaced by 4- (pyrrolidine-1-sulfonyl) -benzyl bromide.
1H NMR(CDCl3)δ 7-85(d，2H)，7.58-7.72(m，6H)，7.14(s，1H)，7.11(s，1H)，6.96(s，1H)，5.19(s，2H)，3.71(s，2H)，3.20-3.30(m，4H)，1.70-1.80(m，4H)；
LCMS method (a), RT ═ 4.2 min.
Example 9: preparation of (5-benzyloxy-biphenyl-3-yl) -acetic acid (VII)
Preparation of 1-benzyloxy-3, 5-dibromobenzene
Benzyl alcohol (9.7ml, 94mmol) was added dropwise to NaH in THF (150ml) at room temperature(4.0 g of a 60% suspension in mineral oil, 100mmol) and the mixture stirred at room temperature for 1h before addition of 1, 3-dibromo-5-fluorobenzene (15.9g, 62.5 mmol). The reaction was stirred at rt for 12 h. Water was carefully added and THF was evaporated under reduced pressure. The residue was extracted with isohexane (x3), the combined organic extracts were washed with NaOH solution (1M aq), water, brine, and dried (MgSO)4) Filtering, and concentrating under reduced pressure. The residue was purified by flash column chromatography (EtOAc: petroleum ether) to give 1-benzyloxy-3, 5-dibromobenzene (14.7g, 65mmol) as a colorless liquid in 69% yield.
1H NMR(CDCl3)δ 7.45-7.33(M，5H)，7.30-7.28(m，1H)，7.10-7.08(m，2H)，5.02(s，2H).
Preparation of (3-benzyloxy-5-bromo-phenyl) -acetic acid ethyl ester
Tert-butyl malonate ethyl ester (10.2ml, 53.8mmol) was added dropwise to the solution in II at room temperatureTo a suspension of an alkane (200ml) in NaH (2.2g of a 60% suspension in mineral oil, 53.8mmol) was added the mixture was stirred at this temperature for 1h before adding CuBr (7.7g, 53.8mmol) and 1-benzyloxy-3, 5-dibromobenzene (9.2g, 26.9 mmol). The reaction mixture was heated to reflux for 5 h. HCl solution (1M aq, 100ml) was added carefully and the mixture was extracted with isohexane (x 3). The combined organic extracts were washed with HCl solution (1M aq), water, brine, dried (MgSO)4) Filtering, and concentrating under reduced pressure. The residue was purified by flash column chromatography (EtOAc: petroleum ether) to afford, in order of elution, recovered 1-benzyloxy-3, 5-dibromobenzene (3.2g, 9.4mmol) (35% yield) and 2- (3-benzyloxy-5-bromo-phenyl) -malonic acid tert-butyl ester ethyl ester (7.2g, containing 1.4 equivalents of malonic acid tert-butyl ester ethyl ester, 10mmol) as a colorless liquid in 37% yield.
Tert-butyl 2- (3-benzyloxy-5-bromophenyl) malonate ethyl ester (7.2g, containing 1.4 equivalents of tert-butyl malonate ethyl ester, 10mmol) was dissolved in glacial AcOH (50ml), and heated backStream 12 h. AcOH was removed under reduced pressure. The residue was poured over Na2CO3Solution (sat aq), the mixture was extracted with EtOAc (x 3). The combined organic extracts were washed with water, brine and dried (MgSO)4) Filtration and concentration under reduced pressure gave ethyl (3-benzyloxy-5-bromo-phenyl-) acetate (6.8g, 9.7mmol) as a yellow liquid in 97% yield.
1H NMR(CDCl3)δ 7.44-7.30(m，5H)，7.07-7.03(m，2H)，6.87-6.84(M，1H)，5.03(s，2H)，4.15(q，2H)，3.54(S，2H)，1.26(t，3H).
Preparation of (5-benzyloxy-biphenyl-3-yl) -acetic acid ethyl ester
(3-benzyloxy-5-bromophenyl) -acetic acid ethyl ester (0.250g, 0.72mmol), phenylboronic acid (0.10g, 0.86mmol) and tetrakis (triphenylphosphine) palladium (0) (0.04g, 0.04mmol) were suspended in K2CO3Solution (0.72ml, 1.44mmol, 2M aq) and DME (2ml) in a mixture. The reaction mixture was irradiated in a CEM microwave at 120 ℃ for 30 min. The reaction mixture was diluted with water and Et2O (x3) extraction. The combined organic extracts were washed with water and dried (MgSO)4) Filtering, and concentrating under reduced pressure. The residue was purified by flash column chromatography (EtOAc: petroleum ether) to give (5-benzyloxy-biphenyl-3-yl-acetic acid ethyl ester (0.12g, 0.35mmol) as a colorless gum in 48% yield.
1H NMR(CDCl3)δ7.59-7.54(m，2H)，7.48-7.30(m，8H) 7.13-7.11(m，2H)，6.94-6.91(m，1H)，5.12(s，2H)，4.16(q，2H)，3.64(s，2H)，1.27(t，3H).
Preparation of (5-benzyloxy-biphenyl-3-yl) -acetic acid
NaOH solution (1ml, 1M aq) was added to a solution of (5-benzyloxy-biphenyl-3-yl) -acetic acid ethyl ester (0.12g, 0.35mmol) in EtOH (2ml) and the mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with HCl solution (2M aq) and extracted with EtOAc (x 3). Washing the combined organic extracts with water, brine and drying: (MgSO4) Filtration and concentration under reduced pressure gave (5-benzyloxybiphenyl-3-yl) acetic acid (0.12g, 0.31mmol) as a colorless solid in 90% yield.
1H NMR(CDCl3)δ 7.57-7.56(m，2H)，7.48-7.30(m，8H)，7.15-7.10(m，2H)，6.94-6.90(m，1H)，5.11(s，2H)， 3.69(s，2H)；
LCMS method (a), RT ═ 4.2 min.
Example 10: preparation of 2- (5-benzyloxy-4' -trifluoromethyl-biphenyl-3-yl) -pentanoic acid (VIII)
(5-benzyloxy-4' -trifluoromethyl-biphenyl-3-yl) -acetic acid (0.09g, 0.23mmol) in THF (1.2ml) was added dropwise to a solution of LHMDS in hexane (0.49ml, 0.49mmol, 1.0M) at-15 deg.C. After 30min iodopropane (0.08ml, 0.82mmol) in THF (0.3ml) was added and the mixture was stirred for a further 30min at-15 ℃. The mixture was then quenched by pouring a mixture of ice and HCl solution (2M aq) into the mixture. Then extracted with EtOAc (× 2) and extracted with NaHSO3The solution (10% aq) was washed and dried (UgSO)4) The organics were then concentrated in vacuo to afford a yellow oil. The oil was purified by flash column chromatography (EtOAc: petroleum ether) to give 2- (5-benzyloxy-4' -trifluoromethyl-biphenyl-3-yl) -pentanoic acid (0.016g, 0.04mmol) in 18% yield.
1H NMR(CDCl3)δ 7.69-7.63(m，4H)，7.47-7.42(m，2H)，7.40(t，2H)，7.35-7.31(m，1H)，7.13-7.09(m，2H)，7.01-6.99(m，1H)，5.11(s，2H)，3.63-3.59 (m，1H)，2.11-2.03 (m，1H)，1.84-1.75(m，1H)，1.36-1.26(m，2H)0.92(t，3H)；
LCMS method (a), (M-H-)385, RT ═ 4.9 min.
Example 11: preparation of (5-benzyloxy-3 ', 5' -dichloro-biphenyl-3-yl) -acetic acid (IX)
The procedure is as in example 9, 3, 5-dichlorophenylboronic acid being used instead of phenylboronic acid.
1H NMR(CDCl3)δ7.30-7.55(m，8H)，7.05(s，2H)，6.92(s，1H)，5.11(s，2H)，3.69(s，2H)；
LCMS method (a), RT ═ 5.0 min.
Example 12: preparation of 5-benzyloxy-4' -trifluoromethyl-diyl-3-yl) -acetic acid (X)
The procedure is as in example 9, 4-trifluoromethyl-phenylboronic acid being used instead of phenylboronic acid.
1H NMR(CDCl3)δ7.66(m，4H)，7.30-7.48(m，5H)，7.11(s，2H)，6.97(s，1H)，5.11(s，2H)，3.71(s，2H)；
LCMS method (a), RT ═ 4.3 min.
Example 13: preparation of (5-benzyloxy-3 ', 5' -bis-trifluoromethyl-biphenyl-3-yl) -acetic acid (XI)
The procedure is as in example 9, 3, 5-bistrifluoromethylphenylboronic acid being used instead of phenylboronic acid.
1H NMR(CDCl3)δ 7.96(br s，2H)，7.85(br s，1H)，7.48-7.32(m.5H)，7.13-7.09(m，2H)，7.02-7.00 (m，1H)，5.13(s，2H)，3.72(s，2H)；
LCMS method (a), RT ═ 4.6 min.
Example 14: preparation of (5-benzyloxy-3 ', 4' -dichloro-biphenyl-3-yl) -acetic acid (XII)
The procedure is as in example 9, 3, 4-dichlorophenylboronic acid being used instead of phenylboronic acid.
1H NMR(CDCl3)δ 7.63(d，1H)，7.50-7.30(m，7H)，7.0g-7.03 (m，2H)，6.96-6.93 (m，1H)，5.10(s，2H)，3.68(s，2H)；
LCMS method (a), RT ═ 4.6 min.
Example 15: preparation of (5-benzyloxy-4' -trifluoromethoxy-biphenyl-3-yl) -acetic acid (XIII)
The procedure is as in example 9, 4-trifluoromethoxybenzeneboronic acid being used instead of phenylboronic acid.
1H NMR(CDCl3)δ7.58-7.53(m，2H)7.47-7.31(m，5H)，7.29-7.23(m，2H)，7.09-7.05(m，2H)，6.95-6.92(m，1H)，5.11(s，2H)，3.67(s，2H)；
LCMS method (a), RT ═ 4.4min.
Example 16: preparation of (5-benzyloxy-3' -methoxy-biphenyl-3-yl) -acetic acid (XIV)
The procedure is as in example 9, substituting 3-methoxybenzeneboronic acid for phenylboronic acid.
1H NMR(CDCl3)δ 7.47-7.32(m，6H)，7.12-7.07(m，4H)，6.93-6.89(m，2H)，5.11(s，2H)，3.85(s，3H)，3.69(s，2H)；
LCMS method (a), RT ═ 4.2 min.
Example 17: preparation of (5-benzyloxy-3' -carbamoyl-biphenyl-3-yl) -acetic acid (XV)
The procedure is as in example 9, substituting benzamide-3-boronic acid for phenylboronic acid.
1H NMR(CDCl3)δ 12.3 O-12.45(br，1H)，8.13(s，2H)，7.87-7.79(m，2H)，7.56-7.22(m，8H)，6.97(s，1H)，5.18(s，2H))，3.63(s，2H)；
LCMS method (a), RT ═ 3.6 min.
Example 18: preparation of (5-benzyloxy-3' -hydroxy-biphenyl-3-yl) -acetic acid (XVI)
The procedure is as in example 9, 3-hydroxyphenylboronic acid being used instead of phenylboronic acid.
1H NMR(CDCl3)δ 7.45-7.28(m，6H)，7.13-7.08(m，3H) 7.01(s，1H)，6.91(s，1H)，6.97(s，1H)，6.82-6.08(m，1H)5.09(s，2H)，3.67(s，2H)；
LCMS method (a), RT ═ 3.8 min.
Example 19: preparation of (5-benzyloxy-4' -methanesulfonyl-biphenyl-3-yl) -acetic acid (XVII)
The procedure is as in example 9, 4-methanesulfonylphenylboronic acid being used instead of phenylboronic acid.
1H NMR(CDCl3)δ 7.98(d，2H)，7.74-7.72(d，2H)，7.46-7.35(m，5H)，7.13-7.12(m，2H)，7.00(s，1H)5.12(s，2H)，3.71(s，2H)3.09(s，3H)；
LCMS method (a), RT ═ 3.8 min.
Example 20: preparation of (5-benzyloxy-4' -sulfamoyl-biphenyl-3 yl) -acetic acid (XVIII)
The procedure is as in example 9, substituting benzenesulphonamide-4-boronic acid pinacol ester for benzeneboronic acid.
1H NMR(CDCl3)δ7.89-7.83(m，4H)，7.49-7.21(m，9H)，7.00(s，1H)，5.17(s，2H)，3.62(s，2H)；
LCMS method (a), RT ═ 3.6 min.
Example 21: preparation of 2- (5-benzyloxy-4' -trifluoromethyl-biphenyl-3-yl) -propionic acid (XIX)
The procedure is as in example 10, methyl iodide being used instead of propyl iodide.
1HNMR(CDCl3)δ 7.70-7.62(m，4H)，7.48-7.30(m，5H)，7.15-7.09(m，2H)，7.02-7.00(m，1H)，5.12(s，2H)，3.80(q，1H)，1.56(d，3H)；LCMS method(B)，RT＝12.3min.
LCMS method (B), RT ═ 12.3 min.
Example 22: preparation of 2- (5-benzyloxy-4 '-trifluoromethyl-biphenyl-3-yl) -2-methyl-propionic acid (XX) preparation of methyl-2- (5-benzyloxy-4' -trifluoromethyl-biphenyl-3-yl) -2-methyl-propionic acid ester
Methyl (5-benzyloxy-4' -trifluoromethyl-biphenyl-3-yl) -acetate (0.15g, 0.37mmol) in DMF (1.5ml) was added dropwise to a suspension of NaH (0.072g, 60% suspension in mineral oil, 1.79mmol) in DMF (1ml) at-4 deg.C and the mixture was stirred for 1h before addition of iodomethane (0.12ml, 1.86 mmol). The reaction was stirred between-4 ℃ and 0 ℃ for 2.5h, diluted with DMF and warmed to room temperature overnight. NH is carefully added4Cl solution (sat aq), the mixture was extracted with EtOAc. The combined organic extracts were washed with brine and dried (MgSO)4) Filtering, and concentrating under reduced pressure. The residue was purified by flash column chromatography (EtOAc: petroleum ether) to give 2- (5-benzyloxy-4' -trifluoromethyl-biphenyl-3-yl) -2-methyl-propionic acid methyl ester (0.12g, 0.28) as a colorless oil in 76% yield.
LCMS method (3), RT ═ 5.6 min.
Preparation of 2- (5-benzyloxy-4' -trifluoromethyl-biphenyl-3-yl-2-methyl-propionic acid
A solution of 2- (5-benzyloxy-4' -trifluoromethyl-biphenyl-3-yl) -2-methyl-propionic acid methyl ester (0.12g, 0.28mmol) in THF (4ml) was treated with a solution of KOH (0.17g, 3.00mmol) in methanol and water (3ml, 6: 1) at room temperature. After 2 days the mixture was acidified with citric acid and extracted with EtOAc. With NaHCO3The combined organic extracts were washed with brine, dried (MgSO)4) Filtering, and concentrating under reduced pressure. The residue was purified by flash column chromatography (EtOAc: petroleum ether) to give 2- (5-benzyloxy-4' -trifluoromethyl-biphenyl-3-yl) -2-methyl-propionic acid (0.045g, 0.11mmol) as a white solid in 39% yield.
1H NMR(CDCl3)δ 7.67((m，4H)，7.47(m，2H) 7.41(m，2H)，7.36(m，1H)，1.13(m，1H)，7.07(m，1H)，7.00(m，1H)，5.12(s，2H)，3.66(s，3H)，1.61(s，6H)；
LCMS method (a), RT ═ 4.8 min.
Example 23: preparation of 1- (-5-benzyloxy-4' -fluoromethyl-biphenyl-3-yl) -cyclopropanecarboxylic acid (XXI)
The procedure is as in example 22, substituting 1, 2-dibromoethane for iodomethane to give 1- (5-benzyloxy-4' -trifluoromethyl-biphenyl-3-yl) -cyclopropanecarboxylic acid as a white solid.
1H NMR(d4-MeOD)7.79-7.71(m，4H)，7.50-7.46(m，2H)7.42-736(m，2H)，7.35-7.29(m，1H)7.25-7.23(m，1H)，7.17-7.14(m，1H)，7.08-7.05(m，1H)，5.17(s，2H)，1.59(s，6H)；
LCMS method (a), RT ═ 4.7 min.
In a similar manner to example 9, the following compounds were synthesized, substituting the appropriate boronic acid for phenylboronic acid:
| example number | Name (R) | LC method | Retention time (min) |
| 24 | (5-benzyloxy-4' -fluoro-biphenyl-3-yl) -acetic acid (XXII) | A | 4.2 |
| 25 | (5-benzyloxy-4' -chloro-biphenyl-3-yl) -acetic acid (XXIII) | A | 4.4 |
| 26 | (4' -acetylamino-5-benzyloxy-biphenyl | B | 9.1 |
| -3-yl) -acetic acid (XXIV) | |||
| 27 | (5-benzyloxy-4' -hydroxy-biphenyl-3-yl) -acetic acid (XXV) | B | 9.4 |
| 28 | (5-benzyloxy-4' -isopropoxy-biphenyl-3-yl) -acetic acid (XXVI) | B | 11.9 |
| 29 | (5-benzyloxy-3 ', 5' -difluoro-biphenyl-3-yl) -acetic acid (XXVII) | C | 3.2 |
| 30 | (5-benzyloxy-3' -isopropoxy-biphenyl-3-yl) -acetic acid (XXVIII) | A | 4.4 |
| 31 | (5-benzyloxy-4' -methoxy-biphenyl-3-yl-acetic acid (XXIX) | B | 10.9 |
| 32 | (5-benzyloxy-2' -methoxy-biphenyl-3-yl-acetic acid (XXX) | B | 11.0 |
| 33 | (5-benzyloxy-2' -methyl-biphenyl-3-yl) -acetic acid (XXXI) | B | 11.5 |
| 34 | (5-benzyl)Oxy-3' -methyl-biphenyl-3-yl) -acetic acid (XXXII) | B | 11.6 |
| 35 | (5-benzyloxy-3' -trifluoromethyl-biphenyl-3-yl) -acetic acid (XXXIII) | B | 11.8 |
| 36 | (5-benzyloxy-2' -fluoro-biphenyl-3-yl) -acetic acid (XXXIV) | A | 4.2 |
| 37 | (5-benzyloxy-4' -methyl-biphenyl-3-yl) -acetic acid (XXXV) | C | 3.2 |
| 38 | (5-benzyloxy-3' -fluoro-biphenyl-3-yl) -acetic acid (XXXVI) | C | 3.1 |
| 39 | (5-benzyloxy-3' -chloro-biphenyl-3-yl) -acetic acid (XXXVII) | C | 3.3 |
| 40 | (5-benzyloxy-3' -trifluoromethoxy-biphenyl-3-yl) -acetic acid (XXXVIII) | C | 3.3 |
Example 41: preparation of 2- {5- [4- (pyrazin-1-sulfonyl) -benzyloxy-benzene]-4' -trifluoromethyl-biphenyl-3-yl } -pentanoic acid (XXXIX)
The procedure is as in example 10, using 5- [4- (pyrrolidine-1-sulfonyl) -benzyloxy ] -4 ' -trifluoromethyl-biphenyl-3-yl-acetic acid (which is itself prepared according to the procedure of example 9, using 4- (pyrrolidine-1-sulfonyl) -benzyl alcohol instead of benzyl alcohol) instead of (5-benzyloxy-4 ' -trifluoromethyl-biphenyl-3-yl) -acetic acid to give 2- {5- [4- (pyrrolidine-1-sulfonyl) -benzyloxy ] -4 ' -trifluoromethyl-biphenyl-3-yl } -pentanoic acid, LC method B, retention time 12.6 min.
Example 42: preparation of 2- (5-Cyclopropylmethoxy-4' -trifluoromethyl-biphenyl-3-yl) -pentanoic acid (XL)
The procedure is as in example 10, substituting 5-cyclopropylmethoxy-4 ' -trifluoromethyl-biphenyl-3-yl-acetic acid (which was itself prepared according to the procedure of example 9, substituting cyclopropylmethanol for benzyl alcohol) for (5-benzyloxy-4 ' -trifluoromethyl-biphenyl-3-yl) -acetic acid to give 2- (5-cyclopropylmethoxy-4 ' -trifluoromethyl-biphenyl-3-yl) -pentanoic acid. LC method B, retention time 12.8 min.
Example 43: preparation of [5-, (4-chloro-benzyloxy) -4' -trifluoromethyl-biphenyl-3-yl]-acetic acid (XLI)
To a solution of (5-benzyloxy-4' -trifluoromethyl-biphenyl-3-yl) -acetic acid (2.5g, 5.5mmol) in EtOH (50mL) was added 10% Pd/C (5% wt) in H2The resulting black suspension was stirred for 5 hours. The resulting mixture was filtered through celite and evaporated to dryness. The residue was purified by flash column chromatography (EtOAc: petroleum ether) to give 2.3g (93%) (5-hydroxy-4' -trifluoromethyl-biphenyl-3-yl) -acetic acid ethyl ester as a white solid.
(5-hydroxy-4' -trifluoromethyl-biphenyl-3-yl) -acetic acid ethyl ester (70mg, 0.22mmol), K in MeCN (2mL) was added2CO3(60mg, 2.0 equiv.), the suspension of 4-chlorobenzyl bromide (50mg, 1.1 equiv.) is heated at 80 ℃ for 2 hours. The resulting suspension was filtered and evaporated to dryness. The residue is purified by flash column chromatography (EtOAc: petroleum ether) to yield 85mg (83%) [5- (4-chloro-benzoyloxy) -4' -trifluoromethyl-biphenyl-3-yl]-ethyl acetate as a clear oil.
Hydrolysis of [5- (4-chloro-benzoyloxy) -4 '-trifluoromethyl-biphenyl-3-yl ] -acetic acid ethyl ester (3) (85mg, 0.19mmol) as described in example 9 gave 71mg (90%) [5- (4-chloro-benzyloxy) -4' -trifluoromethyl-biphenyl-3-yl ] -acetic acid as a white solid. LC method C, retention time 3.4 min.
In a similar manner, using a suitable halide as alkylating agent, the following compounds were prepared:
| example number | Name (R) | LC method | Retention time (min) |
| 44 | (5-Cyclopropylmethoxy-4' -trifluoromethyl-biphenyl-3-yl) -acetic acid (XLII) | A | 4.3 |
| 45 | [5- (5-methyl-iso-methyl)Azol-3-ylmethoxy) -4' -trifluoromethyl-biphenyl-3-yl]-acetic acid (XLIII) | A | 4.0 |
| 46 | [5- (3, 5-dichloro-benzyloxy) -4' -trifluoromethyl-biphenyl-3-yl]-acetic acid (XLIV) | A | 5.0 |
| 47 | [5- (tetrahydro-pyran-4-ylmethoxy) -4' -trifluoromethyl-biphenyl-3-yl group]-acetic acid (XLV) | A | 4.2 |
| 48 | [5- (4-dimethylsulfamoyl-benzyloxy) -4' -trifluoromethy l-biphenyl-3-yl]-acetic acid (XLVI) | A | 4.1 |
| 49 | [5- (1-phenyl-ethoxy) -4' -trifluoromethyl-biphenyl-3-yl]-acetic acid (XLVII) | A | 4.5 |
| 50 | {5- [4- (morpholine-4-carbonyl) -benzyloxy ] -benzyl]-4' -trifluoromethyl-biphenyl-3-yl } -acetic acid (XLVIII) | C | 2.9 |
| 51 | [ 4' -trifluoromethyl-5- (3-trifluoromethyl-benzyloxy) -biphenyl-3-yl]-acetic acid (XLIX) | C | 3.4 |
| 52 | [ 4' -trifluoromethyl-5- (2-trifluoromethyl-benzyloxy) -biphenyl-3-yl]-acetic acid (L) | C | 3.4 |
| 53 | (5-Phenylethoxy-4' -trifluoromethyl-biphenyl-3-yl) -acetic acid (LI) | C | 3.3 |
| 54 | [5- (tetrahydro-pyran-2-ylmethoxy) -4' -trifluoromethyl-biphenyl-3-yl group]-acetic acid (LII) | C | 3.1 |
| 55 | [5- (4-dimethylcarbamoyl-benzyloxy) -4' -trifluoromethyl-biphenyl-3-yl]-acetic acid (LIII) | C | 2.9 |
| 56 | [5- (4-Methylcarbamoyl-benzyloxy) -4' -trifluoromethyl-biphenyl-3-yl]-acetic acid (LIV) | C | 2.8 |
| 57 | {5- [4- (pyrrolidine-1-carbonyl) -benzyloxy-group]-4' -trifluoromethyl-biphenyl-3-yl } -acetic acid (LV) | C | 3.0 |
| 58 | {5- [4- (morpholine-4-sulfonyl) -benzyloxy-benzene]-4' -trifluoromethyl-biphenyl-3-yl } -acetic acid (LVI) | C | 3.1 |
| 59 | [5- (4-trifluoromethoxy-benzyloxy) -4' -trifluoromethyl-biphenyl-3-yl]-acetic acid (LVII) | C | 3.2 |
| 60 | [5- (2-chloro-benzyloxy) -4' -trifluoromethyl-biphenyl-3-yl]-acetic acid (LVIII) | C | 3.4 |
| 61 | [5- (3-chloro-benzyloxy) -4' -trifluoromethyl-biphenyl-3-yl]-acetic acid (LIX) | C | 3.4 |
| 62 | [5- (4-methyl-benzyloxy) -4' -trifluoromethyl-biphenyl-3-yl]-acetic acid (LX) | C | 3.4 |
Example 63: preparation of 2- (5-benzyloxy-4' -trifluoromethyl-biphenyl-3-yl) -pent-4-enoic acid (LXI)
Prepared according to example 10, substituting allyl iodide for iodopropane to give 2- (5-benzyloxy-4' -trifluoromethyl-biphenyl-3-yl) -pent-4-enoic acid, LC method C, retention time 3.5 min.
Example 64: preparation of (R) -2- (5-cyclopropylmethoxy)Yl-4 '-trifluoromethyl-biphenyl-3-yl) -pentanoic acid (LXII) and (S) -2- (5-cyclopropylmethoxy-4' -trifluoromethyl-biphenyl-3-yl) -pentanoic acid (LXIII)
The 2- (5-cyclopropylmethoxy-4' -trifluoromethyl-biphenyl-3-yl) -pentanoic acid enantiomer was isolated on a 5cm Chiralpak AD column with 70/30 heptane/isopropanol containing 0.1% acetic acid as eluent at a flow rate of 80 ml/min. The first peak from the column is indicated as R*The second peak is S*。
Example 65: preparation of (R) -2- (5-benzyloxy-4 '-trifluoromethyl-biphenyl-3-yl) -pentanoic acid (LXIV) and (S) -2- (5-benzyloxy-4' -trifluoromethyl-biphenyl-3-yl) -pentanoic acid (LXV)
The 2- (5-benzyloxy-4' -trifluoromethyl-biphenyl-3-yl) -pentanoic acid enantiomer was isolated on a 8cm Chiralpak AD column with methanol and 0.1% TFA as eluent at a flow rate of 80 ml/min. The first peak from the column at 16min is indicated as R*And the second peak at 26min is S*。
Example 66: screening for Compounds of the invention for modulating Gamma-secretase Activity
Screening was performed with SKN neuroblastoma cells carrying the wild type APP695, grown in DMEM/NUT-mix F12(HAM) supplied by Gibco (cat No.31330-38) containing 5% serum/Fe and supplemented with 1% non-essential amino acids.
The cells were grown to near confluence.
For the descriptions in Citron et al (1997) Nature Medicine 3: 67 was subjected to screening.
IC50 values for γ -secretase activity for selected compounds of the invention.
The following compounds show IC50 < 10 uM:
(R) -2- (5-cyclopropylmethoxy-4' -trifluoromethyl-biphenyl-3-yl) -pentanoic acid;
(S) -2- (5-cyclopropylmethoxy-4' -trifluoromethyl-biphenyl-3-yl) -pentanoic acid;
(R) -2- (5-benzyloxy-4' -trifluoromethyl-biphenyl-3-yl) -pentanoic acid;
(S) -2- (5-benzyloxy-4' -trifluoromethyl-biphenyl-3-yl) -pentanoic acid.
Example 67: demonstration of CNS penetration
In vivo studies: the drug compound in 10% propylene glycol, 7.5% ethanol and 82.5% polyethylene glycol was orally administered at 100mg/kg to a total of 24 mice (C57). At the indicated times (2, 4 and 8 hrs) a group of 8 mice were sacrificed and plasma and brain tissue samples were collected according to NIH guidelines.
Biological analysis: plasma samples were prepared as follows. 200 microliters of acetonitrile containing an internal standard was added to 100 μ L of plasma to precipitate the protein. After vortexing, the samples were centrifuged at 10000g for 10min and the supernatant was transferred to an HPLC sample bottle for LC-MS-MS analysis. Calibration standards were prepared by directly adding the appropriate volume of drug stock to blank plasma (from untreated animals) and processed in the same manner as collected plasma samples.
Brain tissue is first homogenized in 2 volumes of PBS buffer (e.g., 100mg tissue is homogenized in 200. mu.L PBS). 200 microliters of acetonitrile containing an internal standard was added to 100 μ L of homogenate to precipitate the protein. Each homogenate was processed in triplicate. After vortexing, the samples were centrifuged at 10000g for 10min and the supernatant was transferred to an HPLC sample bottle for LC-MS-MS analysis. Calibration standards were prepared by directly adding appropriate volumes of drug stock to empty brain homogenate (from untreated animals) and processed in the same manner as collected plasma samples.
In operation, LC-MS-MS analysis was performed in ESI cation mode. A general LC gradient from 95% aqueous to 95% acetonitrile was used on a Sciex4000 triple quadrupole mass spectrometer connected to an Agilent 1100 HPLC system. Mass spectrometry was performed for 11 minutes.
The percentage of brain to plasma concentrations in the above conditions are given in (R)*) -2- (5-benzyloxy-4' -trifluoromethyl-biphenyl-3-yl) -pentanoic acid is 28.6 for (S)*) -2- (5-benzyloxy-4' -trifluoromethyl-biphenyl-3-yl-pentanoic acid is 32.0.
Example 68: demonstration of in vivo efficacy
The Α β 42-lowering agents of the present invention are useful in the treatment of AD in mammals (e.g. humans) or in animal models (e.g. mice, rats or guinea pigs) that demonstrate efficacy. The mammal may not be diagnosed with AD, or may not have a genetic predisposition to AD, but may be transgenic such that it overproduces and eventually deposits a β in a similar manner to that observed in humans.
The a β 42 lowering agent can be administered in any standard form using any standard method. For example, but not limited to, the a β 42 lowering agent may be in the form of a liquid, tablet or capsule for oral or injectable administration. The Α β 42 lowering agent can be administered at any dose sufficient to significantly reduce Α β 42 levels in plasma, CSF or brain.
To determine whether short-term administration of an a β 42-lowering agent reduces a β 42 levels in vivo, 2-3 month old Tg2576 mice expressing APP695 containing the "swedish" mutant, or a transgenic mouse model developed by Fred Van Leuven, doctor k.u.leuven, Belgium and colleagues that neuronal-specifically expresses a human amyloid precursor protein clinical mutant [ V717I ] (Moechars et al, 1999 j. biol. chem.274, 6483) can be used. The exclusive right for this model has been transferred to reMYND NV. The single transgenic mice showed spontaneous progressive accumulation of β -amyloid (a β) in the brain, eventually producing amyloid plaques in the lower foot, hippocampus and cortex. Animals of this age had high levels of a β in the brain, but no detectable a β deposition. The examination of mice treated with a β 42 lowering agent will be compared to untreated mice or to vehicle treated mice, and brain levels of soluble a β 42 and total a β will be quantified using standard techniques. The treatment period may vary from hours to days and once the time course of the effect can be established, the treatment period will be adjusted based on the results of the a β 42 reduction.
Typical protocols for measuring a β 42 reduction in vivo are indicated, but are only one of many protocol variants that can be used to optimize detectable levels of a β. For example, aliquots of the compound can be dissolved in DMSO (a volume equal to 1/10 of the final volume of the formulation), sonicated for 20 seconds, vortexed, and further diluted (1: 10) with a 10% (w/v) solution of hydroxypropyl beta cyclodextrin (HBC, Aldrich, RefN.degree.33, 260-7) in PBS.
The Α β 42 lowering agent may be administered orally as one dose 3-4 hours prior to sacrifice and analysis or alternatively may be administered over a period of days with the animals being sacrificed 3-4 hours after administration of the last dose.
Blood was collected at sacrifice. Blood collection was performed by cardiac puncture during anesthesia with a mixture of Ketalar (ketamine), Rompun (2% xylazine), and atropine (2: 1), collected in EDTA-treated collection tubes. The blood was centrifuged at 4000g for 5 minutes at 4 ℃ and the plasma was recovered for analysis.
Mice were anesthetized with a mixture of Ketalar (ketamine), Rompun (2% xylazine), and atropine (2: 1) and cardiorinsed with physiological serum at 4 ℃.
The brain was separated from the cranium and hindbrain, and the forebrain was isolated by incision at the coronal/frontal plane. The cerebellum is removed. The forebrain is evenly divided into left and right hemispheres by using a midline sagittal plane cut (midline sagittal cut).
One hemisphere was immediately immersed in liquid nitrogen and stored at-70 ℃ until homogenized for biochemical analysis.
Brain pot (Potter), glass tube (without detergent, 2 cm)3) And a mechanical homogenizer (650 rpm). A volume of 6, 5X 1/2 brain weight of freshly prepared 20mM Tris/HCl buffer (pH 8.5) containing protease inhibitors (1 tablet per 50ml Tris/HCl buffer, complete. TM., Roche, Mannheim, Germany) was usedUsed as a homogenization buffer.
Samples were transferred from-70 ℃ to a sample holder with liquid nitrogen and each sample was pre-warmed by incubation on the bench for a few seconds prior to homogenization. The homogenate was collected in Beckman centrifuge tubes TLX and collected on ice prior to centrifugation. Between 2 samples, the pots and glass tubes were carefully rinsed with detergent-free distilled water (AD) and blotted dry with absorbent paper.
The samples were centrifuged at 48000rpm (135,000Xg) for 1 hour and 20 minutes at 4 ℃ in a pre-cooled ultracentrifuge (Beckman, Mannheim, Germany). The supernatant (soluble fraction containing secreted APP and amyloid peptides) was separated from the pellet (membrane fraction containing membrane-bound APP fragments and plaque-associated amyloid peptides (for aged mice)).
A reverse phase column (C18-Sep-Pack Vac 3cc cartridges, Waters, Massachusetts, Mass.) was packed in a vacuum system, washed with 80% acetonitrile in 0, 1% trifluoroacetic acid (A-TFA) followed by 2 washes with 0, 1% TFA. Samples were then loaded and the column was eluted sequentially with 5% and 25% A-TFA. The amyloid peptide was eluted with 75% A-TFA and the eluate was collected in a 2ml tube on ice. The eluate was lyophilized overnight in a vacuum centrifugal evaporator concentrator (Savant, Farmingdale, NY) and dissolved in 240 μ 1 sample dilution provided by the (resolve) ELISA kit.
To quantify The amount of human a β -42 in The soluble portion of The brain homogenate, a commercially available enzyme-linked immunosorbent assay (ELISA) kit (h Amyloid a β 42 ELISA high sensitive, The Genetics Company, Zurich, Switzerland) was used. ELISA was performed according to the manufacturer's instructions. Briefly, standards (dilutions of synthetic A.beta.1-42) and samples were prepared in 96-well polypropylene plates (Greiner bio-one, Frickenhausen, Germany) without protein binding capacity. Standards and samples were prepared at final concentrations of 1000, 500, 250, 125, 62.5, 31.3 and 15.6pg/ml using sample dilutions provided with an ELISA kit, in a final volume of 60. mu.l. Samples, standards and blanks (50 μ l) were added to an anti-a β coated polystyrene plate (capture antibody selectively recognizes the C-terminus of the antigen) to which was also added a selective anti-a β -antibody conjugate (biotin-labeled antibody) and incubated overnight at 4 ℃ to form antibody-amyloid-antibody complexes. The next day, streptavidin-peroxidase conjugate was added, and after 30 minutes the TMB/peroxide mixture was added, causing the substrate to convert to a colored product. The reaction was stopped by adding sulfuric acid (1M) and the color intensity was measured photometrically with an ELISA reader with a 450nm filter. Quantitation of the A β content of the samples was obtained by comparing the absorbance with a standard curve prepared with synthetic A β 1-42.
In this model, at least a 20% reduction in Α β 42 is beneficial compared to untreated animals.
Claims (10)
1. A compound having the general formula (I) and/or a pharmaceutically acceptable salt thereof,
wherein
A is selected from phenyl and C3-7Cycloalkyl, isoxazole and tetrahydropyran rings;
x is optionally substituted by one or more groups selected from F, Cl, Br, I and optionally substituted by one or more groups F, ClBr, I substituted C1-C4Linear C substituted by alkyl substituents1-C4An alkylene group;
R1、R2independently of one another, from H; alkyl selected from CH3、C2H5iso-C3H7n-C3H7iso-C4H9n-C4H9sec-C4H9T is-C4H9(ii) a Alkenyl radical selected from C2H3iso-C3H5n-C3H5n-C4H7iso-C4H7sec-C4H7(ii) a Or R1And R2Is a moiety of a saturated or unsaturated ring having 3-6C-atoms;
R3、R4、R5and R6Independently selected from H, F, Cl, Br, I, CN, OH, C (O) N (R)7R8)、S(O)2R7、SO2N(R7R8)、S(O)N(R7R8)、N(R7)S(O)2R8、N(R8)S(O)R8、S(O)2R7、N(R7)S(O)2N(R8R8a)、SR7、N(R7R8)、N(R7)C(O)R8、N(R7)C(O)N(R8R8a)、N(R7)C(O)OR8、OC(O)N(R7R8)、C(O)R7Substituted and unsubstituted C1-C4Alkyl and substituted and unsubstituted C1-C4-alkoxy, wherein C1-C4-alkyl and C1-C4The substituents of both groups-alkoxy being selected from F, Cl, Br, I, CF3；
R7、R8、R8aIndependently selected from H, C1-C4Alkyl, pyrrolidine, morpholine and C3-7Cycloalkyl radicals, in which C1-C4Alkyl, pyrrolidine, morpholine and C3-7Cycloalkyl is optionally substituted with one or more substituents independently selected from F, Cl, Br, I andCF3is substituted with the substituent(s).
2. The compound of claim 1 and/or a pharmaceutically acceptable salt thereof, wherein a; x; r1And R2(ii) a And R3、R4、R5And R6Independently of one another, have the following meanings:
a is phenyl, cyclopropyl, cyclohexyl;
x is C optionally substituted by one or more substituents from the group consisting of F, Cl, Br, I and optionally by one or more substituents F, Cl, Br, I1-C4Alkyl substituted CH2A group; and/or
R1And R2Is H; or R1Is H and R2Is CH3、C2H5、C3H7Or C4H9Or an isomer thereof; or R1And R2Is CH3Or R is1、R2Together with the carbon atom to which they are attached form a cyclopropyl ring; and/or
R3、R4、R5And R6Independently selected from H, OH, C partially or totally substituted by F, Cl, Br, I1-C4Alkyl or C1-C4An alkoxy group; c (O) NH2、S(O)2-C1-C4Alkyl, S (O)2Pyrrolidine, S (O)2-morpholine.
3. The compound and/or pharmaceutically acceptable salt of claim 1, wherein a; x; r1And R2(ii) a And R3、R4、R5And R6Independently of one another, have the following meanings:
a is phenyl; or
X is CH2Or CHCH3(ii) a Or
R1And R2Is H; or R1Is H and R2Is CH3、C2H5、C3H7Or C4H9Or an isomer thereof; or R1And R2Is CH3Or R is1、R2Together with the carbon atom to which they are attached form a cyclopropyl ring; or
R3、R4、R5And R6Independently selected from H, OH, CH3、OCH3、CF3、OCF3、C(O)NH2、S(O)2-C1-C4Alkyl, S (O)2Pyrrolidine, S (O)2Morpholine, F and Cl.
4. A compound of claim 1 selected from the group consisting of:
I) [5- (4-fluoro-benzyloxy) -4' -trifluoromethyl-biphenyl-3-yl ] -acetic acid;
II) [5- (4-isopropyl-benzyloxy) -4' -trifluoromethyl-biphenyl-3-yl ] -acetic acid;
III) [ 4' -trifluoromethyl-5- (4-trifluoromethyl-benzyloxy) -biphenyl-3-yl ] -acetic acid;
IV) [5- (4-methanesulfonyl-benzyloxy) -4' -trifluoromethyl-biphenyl-3-yl ] -acetic acid;
v) (5-cyclohexylmethoxy-4' -trifluoromethyl-biphenyl-3-yl) -acetic acid;
VI) {5- [4- (pyrrolidine-1-sulfonyl) -benzyloxy ] -4' -trifluoromethyl-biphenyl-3-yl } -acetic acid;
VII) (5-benzyloxy-biphenyl-3-yl) -acetic acid;
VIII)2- (5-benzyloxy-4' -trifluoromethyl-biphenyl-3-yl) -pentanoic acid;
IX) (5-benzyloxy-3 ', 5' -dichloro-biphenyl-3-yl) -acetic acid;
x) 5-benzyloxy-4' -trifluoromethyl-biphenyl-3-yl) -acetic acid;
XI) (5-benzyloxy-3 ', 5' -bis-trifluoromethyl-biphenyl-3-yl) -acetic acid;
XII) (5-benzyloxy-3 ', 4' -dichloro-biphenyl-3-yl) -acetic acid;
XIII) (5-benzyloxy-4' -trifluoromethoxy-biphenyl-3-yl) -acetic acid;
XIV) (5-benzyloxy-3' -methoxy-biphenyl-3-yl) -acetic acid;
XV) (5-benzyloxy-3' -carbamoyl-biphenyl-3-yl) -acetic acid;
XVI) (5-benzyloxy-3' -hydroxy-biphenyl-3-yl) -acetic acid;
XVII) (5-benzyloxy-4' -methanesulfonyl-biphenyl-3-yl) -acetic acid;
XXIII) (5-benzyloxy-4' -sulfamoyl-biphenyl-3-yl) -acetic acid
XIX)2- (5-benzyloxy-4' -trifluoromethyl-biphenyl-3-yl) -propionic acid;
XX)2- (5-benzyloxy-4' -trifluoromethyl-biphenyl-3-yl) -2-methyl-propionic acid;
XXI)1- (5-benzyloxy-4' -trifluoromethyl-biphenyl-3-yl) -cyclopropanecarboxylic acid
XXII) (5-benzyloxy-4' -fluoro-biphenyl-3-yl) -acetic acid;
XXIII) (5-benzyloxy-4' -chloro-biphenyl-3-yl) -acetic acid;
XXIV) (4' -acetylamino-5-benzyloxy-biphenyl-3-yl) -acetic acid;
XXV) (5-benzyloxy-4' -hydroxy-biphenyl-3-yl) -acetic acid;
XXVI) (5-benzyloxy-4' -isopropoxy-biphenyl-3-yl) -acetic acid;
XXVII) (5-benzyloxy-3 ', 5' -difluoro-biphenyl-3-yl) -acetic acid;
XXVIII) (5-benzyloxy-3' -isopropoxy-biphenyl-3-yl) -acetic acid;
XXIX) (5-benzyloxy-4' -methoxy-biphenyl-3-yl) -acetic acid;
XXX) (5-benzyloxy-2' -methoxy-biphenyl-3-yl) -acetic acid;
XXXI) (5-benzyloxy-2' -methyl-biphenyl-3-yl) -acetic acid;
XXXII) (5-benzyloxy-3' -methyl-biphenyl-3-yl) -acetic acid;
XXXIII) (5-benzyloxy-3' -trifluoromethyl-biphenyl-3-yl) -acetic acid;
XXXIV) (5-benzyloxy-2' -fluoro-biphenyl-3-yl) -acetic acid;
XXXV) (5-benzyloxy-4' -methyl-biphenyl-3-yl) -acetic acid;
XXXVI) (5-benzyloxy-3' -fluoro-biphenyl-3-yl) -acetic acid;
XXXVII) (5-benzyloxy-3' -chloro-biphenyl-3-yl) -acetic acid;
XXXVIII) (5-benzyloxy-3' -trifluoromethoxy-biphenyl-3-yl) -acetic acid;
XXXIX)2- {5- [4- (pyrrolidine-1-sulfonyl) -benzyloxy ] -4' -trifluoromethyl-biphenyl-3-yl } -pentanoic acid;
XL)2- (5-cyclopropylmethoxy-4' -trifluoromethyl-biphenyl-3-yl) -pentanoic acid;
XLI) [5- (4-chloro-benzyloxy) -4' -trifluoromethyl-biphenyl-3-yl ] -acetic acid;
XLII) (5-cyclopropylmethoxy-4' -trifluoromethyl-biphenyl-3-yl) -acetic acid;
XLIII) [5- (5-methyl-iso-5Azol-3-ylmethoxy) -4' -trifluoromethyl-biphenyl-3-yl]-acetic acid;
XLIV) [5- (3, 5-dichloro-benzyloxy) -4' -trifluoromethyl-biphenyl-3-yl ] -acetic acid;
XLV) [5- (tetrahydro-pyran-4-ylmethoxy) -4' -trifluoromethyl-biphenyl-3-yl ] -acetic acid;
XLVI) [5- (4-dimethylsulfamoyl-benzyloxy) -4' -trifluoromethyl-biphenyl-3-yl ] -acetic acid;
XLVII) [5- (1-phenyl-ethoxy) -4' -trifluoromethyl-biphenyl-3-yl ] -acetic acid;
XLVIII) {5- [4- (morpholine-4-carbonyl) -benzyloxy ] -4' -trifluoromethyl-biphenyl-3-yl } -acetic acid;
XLIX) [ 4' -trifluoromethyl-5- (3-trifluoromethyl-benzyloxy) -biphenyl-3-yl ] -acetic acid;
l) [ 4' -trifluoromethyl-5- (2-trifluoromethyl-benzyloxy) -biphenyl-3-yl ] -acetic acid;
LI) (5-phenethyloxy-4' -trifluoromethyl-biphenyl-3-yl) -acetic acid;
LII) [5- (tetrahydro-pyran-2-ylmethoxy) -4' -trifluoromethyl-biphenyl-3-yl ] -acetic acid;
LIII) [5- (4-dimethylcarbamoyl-benzyloxy) -4' -trifluoromethyl-biphenyl-3-yl ] -acetic acid;
LIV) [5- (4-methylcarbamoyl-benzyloxy) -4' -trifluoromethyl-biphenyl-3-yl ] -acetic acid;
LV) {5- [4- (pyrrolidine-1-carbonyl) -benzyloxy ] -4' -trifluoromethyl-biphenyl-3-yl } -acetic acid;
LVI) {5- [4- (morpholine-4-sulfonyl) -benzyloxy ] -4' -trifluoromethyl-biphenyl-3-yl } -acetic acid;
LVII) [5- (4-trifluoromethoxy-benzyloxy) -4' -trifluoromethyl-biphenyl-3-yl ] -acetic acid;
LVIII) [5- (2-chloro-benzyloxy) -4' -trifluoromethyl-biphenyl-3-yl ] -acetic acid;
LIX) [5- (3-chloro-benzyloxy) -4' -trifluoromethyl-biphenyl-3-yl ] -acetic acid;
LX) [5- (4-methyl-benzyloxy) -4' -trifluoromethyl-biphenyl-3-yl ] -acetic acid;
LXI)2- (5-benzyloxy-4' -trifluoromethyl-biphenyl-3-yl) -pent-4-enoic acid;
LXII) (R) -2- (5-cyclopropylmethoxy-4' -trifluoromethyl-biphenyl-3-yl) -pentanoic acid;
LXIII) (S) -2- (5-cyclopropylmethoxy-4' -trifluoromethyl-biphenyl-3-yl) -pentanoic acid;
LXIV) (R) -2- (5-benzyloxy-4' -trifluoromethyl-biphenyl-3-yl) -pentanoic acid;
LXV) (S) -2- (5-benzyloxy-4' -trifluoromethyl-biphenyl-3-yl) -pentanoic acid.
5. Use of a compound according to any one of claims 1 to 4 for the manufacture of a medicament for modulating gamma-secretase.
6. Use of a compound according to any one of claims 1 to 4 for the manufacture of a medicament for the treatment of a disease associated with elevated levels of a β 42 production.
7. Use of a compound according to any one of claims 1 to 4 for the manufacture of a medicament for the treatment of alzheimer's disease.
8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4 in admixture with an inert carrier.
9. The compound of any one of claims 1-4 in the form of a pharmaceutically acceptable ester, wherein in the carboxy groupBy an organic residue R of7aIs substituted, and wherein R7aSelected from unsubstituted or at least mono-substituted C1-C10An alkyl group; c2-C10-an alkenyl group; c3-C10-an alkynyl group; and an unsubstituted or at least mono-substituted, saturated or unsaturated, non-aromatic ring or aromatic ring having 3 to 6C-atoms, which may contain one or more heteroatoms from N, S or O in the ring, which heteroatoms, if more than one are present, may be the same or different, said substituents being selected from halogen, alkyl, alkenyl, alkynyl, N, S, O, carboxyl, sulfonyl.
10. A process for the preparation of a medicament for modulating gamma-secretase, comprising the steps of:
a) preparing a compound of claim 1; and
b) formulating a medicament containing said compound.
Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP04025003.7 | 2004-10-21 | ||
| EP04025003 | 2004-10-21 | ||
| EP04026125.7 | 2004-11-04 | ||
| EP04026125A EP1650183A1 (en) | 2004-10-21 | 2004-11-04 | (Benzyloxy-biphenyl) acetic acids and derivatives thereof and their use in therapy |
| US64210005P | 2005-01-10 | 2005-01-10 | |
| US60/642,100 | 2005-01-10 | ||
| PCT/EP2005/011349 WO2006045554A1 (en) | 2004-10-21 | 2005-10-21 | (biphenyl) carboxylic acids and derivatives thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HK1115579A1 true HK1115579A1 (en) | 2008-12-05 |
| HK1115579B HK1115579B (en) | 2012-12-28 |
Family
ID=
Also Published As
| Publication number | Publication date |
|---|---|
| CY1112068T1 (en) | 2015-11-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR101326358B1 (en) | (biphenyl) carboxylic acids and derivatives thereof | |
| TWI435720B (en) | Triaryl compounds and derivatives thereof | |
| CA2650006C (en) | Substituted biphenyl carboxylic acids and derivatives thereof | |
| HK1115579A1 (en) | (biphenyl) carboxylic acids and derivatives thereof | |
| HK1115579B (en) | (biphenyl) carboxylic acids and derivatives thereof | |
| US20090105344A1 (en) | Biphenyl carboxylic acids and derivatives thereof | |
| HK1134923B (en) | Terphenyl derivatives for treatment of alzheimer's disease |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PC | Patent ceased (i.e. patent has lapsed due to the failure to pay the renewal fee) |
Effective date: 20161021 |