ZA200506614B - 1-phenylalkanecarboxylic acid derivatives for the treatment of neurodegenerative diseases - Google Patents
1-phenylalkanecarboxylic acid derivatives for the treatment of neurodegenerative diseases Download PDFInfo
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- ZA200506614B ZA200506614B ZA200506614A ZA200506614A ZA200506614B ZA 200506614 B ZA200506614 B ZA 200506614B ZA 200506614 A ZA200506614 A ZA 200506614A ZA 200506614 A ZA200506614 A ZA 200506614A ZA 200506614 B ZA200506614 B ZA 200506614B
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- South Africa
- Prior art keywords
- compounds
- chf
- alkyl
- branched
- linear
- Prior art date
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- 208000015122 neurodegenerative disease Diseases 0.000 title claims description 7
- 230000004770 neurodegeneration Effects 0.000 title claims description 5
- 239000002253 acid Substances 0.000 title description 9
- 150000001875 compounds Chemical class 0.000 claims description 43
- 125000000217 alkyl group Chemical group 0.000 claims description 28
- 125000004432 carbon atom Chemical group C* 0.000 claims description 19
- 229910052799 carbon Inorganic materials 0.000 claims description 18
- 229910052731 fluorine Inorganic materials 0.000 claims description 18
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 16
- 239000011737 fluorine Substances 0.000 claims description 16
- 238000002360 preparation method Methods 0.000 claims description 15
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 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
- 208000024827 Alzheimer disease Diseases 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 6
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- 125000003289 ascorbyl group Chemical group [H]O[C@@]([H])(C([H])([H])O*)[C@@]1([H])OC(=O)C(O*)=C1O* 0.000 claims description 5
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- 125000000623 heterocyclic group Chemical group 0.000 claims description 5
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- IYYZUPMFVPLQIF-UHFFFAOYSA-N dibenzothiophene Chemical compound C1=CC=C2C3=CC=CC=C3SC2=C1 IYYZUPMFVPLQIF-UHFFFAOYSA-N 0.000 claims description 4
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Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
1-PHENYLALKANECARBOXYLIC ACID DERIVATIVES FOR THE
TREATMENT OF NEURODEGENERATIVE DISEASES
The present invention concerns 1-phenylalkanecarboxylic acids, pro- drugs and bioisosters on the carboxylic moiety thereof. The invention is also directed to a process for their preparation and the use thereof in the prevention or in the therapeutical treatment of neurodegenerative diseases, in particular
Alzheimer's disease.
INTRODUCTION
Alzheimer's disease is a neurodegenerative disorder characterized by atrophy of the cerebral cortex and by a massive loss of cortical neurons and cholinergic projections of the nucleus basalis towards the cortex. From a histopathologic point of view there is a diffuse presence of extracellular and perivascular neuritic plaques and intracellular neurofibrillary tangles in the cerebral parenchyma of Alzheimer patients.
Neuritic plaques are mainly composed of aggregates of a protein with 39-43 amino acid residues known as B-amyloid (BA), and, depending on the numbers of aminoacids, ABss, AB4g, APsz and ABss.
In addition to these histopathologic lesions, there is lack in some neurotransmitters, particularly acetylcholine, serotonin, noradrenalin, dopamine, glutamate and substance P. The pharmacological approaches aimed at ‘increasing acetylcholine cerebral levels, mainly through acetylcholine- esterase inhibitors, attained poor results from the clinical standpoint, or anyhow results which cannot significantly prevent the progress of the disease.
For this reason, in recent years interest has been focused on the mechanisms of formation of the main pathologic lesions in the brain of the patients, namely both neuritic plaques and neurofibrillary tangles, and more effective therapeutical approaches have been looked for.
CONFIRMATION COPY
PRIOR ART
Epidemiological studies evidenced that chronic administration of non steroid anti-inflammatory drugs (NSAIDs) significantly decreases the onset of
Alzheimer's disease in the population regularly taking these drugs. The mechanism underlying such NSAID preventive action has not been fully elucidated yet, but is apparently connected with their ability of inhibiting cyclooxygenase (COX) enzymes.
More recently, a novel pharmacological action of some non steroid anti- inflammatory drugs (NSAIDs) has been described: indomethacin, sulindac, ibuprofen and flurbiprofen can selectively reduce the production of the most neurotoxic isoform of B-amyloid peptide in cell cultures, namely the form containing 42 amino acids (Af), thus favouring the release of a less harmful isoform, APs (Weggen et al., Nature 2001; 414 (6860): 212-6). However, the inhibition of the production of AP, which can be ascribed to the interaction of these drugs with y-secretase (a macromolecular/multiprotein enzymatic complex with aspartyl-protease activity) has been observed in vitro at very high concentrations. Plasma and cerebral levels corresponding to the dosages used in the in vitro experimentation could significantly increase in treated patients the risk of side effects typical of COX inhibitors, such as gastrointestinal bleeding and perforating ulcers.
WO 01/78721 claims a method of preventing, delaying or reversing the progression of Alzheimer's disease by administering an Af4, lowering agent, under conditions in which levels of Afsq are increased and levels of Af, are left unchanged. Furthermore, methods and materials for identifying and developing AB, lowering agents and methods for identifying agents that increase the risk of developing, or hasten progression of, Alzheimer's disease, are disclosed. The examples concern indomethacin and flufenamic acid derivatives, but no examples concerning flurbiprofen derivatives are reported.
Jantzen et al, J Neurosci 2002; 22: 2246-2254, described a flurbiprofen derivative capable of releasing nitric oxide. The paper generically states that flurbiprofen derivatives are apparently more efficacious than other NSAIDs in clearing P-amyloid deposits, but no mention concerning any Aas; lowering selective activity is made.
In this therapeutical scenario, and in the light of the potential problems of conventional NSAIDs, novel derivatives having more selective and more potent inhibitory activity on the peptide ABs, while inhibiting to a lesser extent, or not inhibiting at all, cyclooxygenase would be a significant improvement in therapies aimed at preventing the onset of Alzheimer's disease and/or at delaying the cognitive decline that represent an early stage disease.
Substituted 1-phenyl-2,2-dialkyl carboxylic derivatives were described as anti-inflammatory, analgesic and antipyretic agents in GB 1,198,212, US 3,978,071, US 757,136, GB 1,352,723, JP49100089 and JP 50046669. 3-Halo-4-alkyl- or cycloalkyl- substituted 1-phenylcycloalkanecarboxylic derivatives were described in JP-4,7047,375 and FR-2,012,285, as substances with the same activity.
In the paper from Kuzuna S et al (Takeda Kenkyushoho 1975, 34, 467- 473) dealing with a structure-activity study of a series of phenylacetic derivatives, it is generically stated that the introduction of a cyclopropane group at the position of a carbon atom decreases the anti-inflammatory and analgesic activities.
In WO 99/41224 novel biaryl-acetic acid derivatives with anti- inflammatory activity as cyclooxygenase-2 inhibitors, useful for the treatment of a number of diseases, including Alzheimer's disease, are claimed.
The present invention concerns 1-phenylalkanecarboxylic acids, their pro-drugs, and bioisosters on the carboxylic moiety, the process for the preparation thereof, pharmaceutical compositions containing them and the use thereof in the prevention or therapeutical treatment of neurodegenerative diseases, in particular Alzheimer's disease.
The compounds of the invention inhibit the release of APs peptide thereby being able to modulate gamma-secretase activity without affecting other important metabolic processes.
The present invention is directed to compounds of general formula (I):
R ov
Ar ®
R, ® wherein:
R and R, are the same and are selected from the group of linear or branched
C,-C4 alkyl; otherwise they form a 3 to 6 carbon atoms ring with the carbon atom to which they are linked;
Gis: - a COOR" group wherein R" is H, linear or branched C,-C; alkyl, C3-Ce cycloalkyl or ascorbyl; - a CONH, or a CONHSO,R" group wherein R" is linear or branched
C;-C, alkyl or C;-C¢ cycloalkyl; - a tetrazolyl residue;
R, is H, CF; OCF; or a halogen selected from the group of F, Cl, Br, I, preferably fluorine.
Ar is a group of formula
\ 5s wherein R; represents one or more groups independently selected from: - halogen as previously defined; - CF3; - C3-Cy cycloalkyl optionally substituted with one or more C,-Cy alkyl and/or oxo groups; - CH=CH; = CN; - CH,OH; - methylendioxy or ethylendioxy; : - NO, - phenyl optionally substituted with one or more of the following groups: halogen; CF;; OCF;; OH; linear or branched C;-Cy alkyl; a saturated heterocycle with at least 4 carbon atoms and at least | heteroatom; C;-Cy cycloalkyl in turn optionally substituted with one or more of the following groups linear or branched C;-C, alkyl, CF; or OH; - ORy4 or NHCOR, wherein Ry is CFs, linear or branched C,-Cs alkenyl or alkynyl; benzyl; phenyl optionally substituted with one or more of the following groups: halogen, CFj, OCF3, OH, linear or branched C;-C, alkyl; a saturated eterocycle with at least 4 carbon atoms and at least 1 heteroatom; C;-Cg cycloalkyl in turn optionally substituted with one or more of the following groups: linear or branched C;-C4 alkyl, CF; or OH; - SRs, SO,R;5 or COR wherein Rs is linear or branched C;-Cs alkyl; ‘otherwise Ar is aheterocycle ring selected from the group of thiophene, benzothiophene, dibenzothiophene, thianthrene, pyrrole, pyrazole, furan, benzofuran, dibenzofuran, indole, isoindole, imidazole, benzoimidazole, oxazole, isoxazole, benzoxazole, thiazole, pyridine, pyrimidine, pyrazine, pyridazine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, pyrazole, pyran, benzopyran, pyrrolizine, phtalazine,
AMENDED SHEET 2006 -03- 12
1,5-naphthyridine, 1,3-dioxole, 1,3-benzodioxole, optionally substituted with one or more groups Rs as defined above; pharmaceutically acceptable salts and esters thereof.
A first group of preferred compounds is that in which: 5s TR and R, form a 3 carbon atoms ring with the carbon atom to which they are linked;
R; is fluorine;
G is COOR", wherein R" is H, linear or branched C;-C4 alkyl, C3-Cs cycloalkyl or ascorbyl;
Ar is phenyl as defined above.
A second group of preferred compounds is that in which:
R and R, form a 3 carbon atoms ring with the carbon atom to which they are linked;
R; is fluorine;
Gis CONH, or CONHSO,R" wherein R"' is linear or branched C,;-C, alkyl or
C;-Cg cycloalkyl;
Ar is phenyl as defined above.
A third group of preferred compounds is that in which: both R and R; are methyl;
Rj is fluorine;
G is COOR" wherein R" is as defined above;
Ar is phenyl as defined above.
A fourth group of preferred compounds is that in which: both R and R, are methyl;
Rj is fluorine;
G is CONH, or CONHSO,R", wherein R"' is as defined above;
Ar is phenyl as defined above.
A fifth group of preferred compounds is that in which:
R and R, form a 3 carbon atoms ring with the carbon atom to which they are linked;
R, is fluorine; )
G is COOR" wherein R" is as defined above;
Ar is a heterocycle as defined above.
A sixth group of preferred compounds is that in which: both R and R, are methyl;
R, is fluorine;
G is COOR" wherein R" is as defined above;
Ar is a heterocycle as defined above.
Particularly preferred are the following compounds: 2-methyl-2(2-fluoro-4'-trifluoromethylbiphen-4-yl)propionic acid (CHF 4810); 2-methyl-2(2-fluoro-4'cyclohexyl biphen-4-yl)propionic acid (CHF 4961); 1-(2-fluoro-4'-trifluoromethylbiphenyl-4-yl)cyclopropanecarboxylic acid (CHF 5022); 1-(4'-cyclohexyl-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acid (CHF 5023); 1-(4'-benzyloxy-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acid (CHF 5042); 1-(2-fluoro-4'-isopropyloxybiphenyl-4-yl)cyclopropanecarboxylic acid (CHF 5044); 1-(2-fluoro-3'-trifluoromethoxybiphenyl-4-yl)cyclopropanecarboxylic acid (CHF 5045); 1-(2-fluoro-4'-trifluoromethoxybiphenyl-4-yl)cyclopropanecarboxylic acid (CHF 5046); 1-(2-fluoro-3'-trifluoromethylbiphenyl-4-yl)cyclopropanecarboxylic acid (CHF 5058);
1-(4'-cyclopentyl-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acid (CHF
1-(4'-cycloheptyl-2-fluorobiphenyl-4-yl)eyclopropanecarboxylic acid (CHF 5060);
1-(2'-cyclohexyl-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acid (CHF 5061); 1-(2-fluoro-4'-hydroxybiphenyl-4-yl)cyclopropanecarboxylic acid (CHF 5070); 1-[2-fluoro-4'~(tetrahydropyran-4-yloxy)biphenyl-4-yl]-cyclopropane-
carboxylic acid (CHF 5071); 1-(2,3",4'-trifluorobiphenyl-4-yl)cyclopropanecarboxylic acid (CHF 5073); 1-(3',4'-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acid (CHF 5074); 1-(3',5'-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acid (CHF
5075); 1-(3'-chloro-2,4'-difluorobiphenyl-4-yl)cyclopropanecarboxylic acid (CHF 5076); 1-(4-benzo[b]thiophen-3-yl-3-fluorophenyl)cyclopropanecarboxylic acid (CHF 5077);
1-(2-fluoro-4'-prop-2-inyloxy-biphenyl-4-yl)-cyclopropanecarboxylic acid (CHF 5078); 1-(4'-cyclohexyloxy-2-fluoro-biphenyl-4-yl)-cyclopropanecarboxylic acid (CHF 5079);
1-[2-fluoro-4'-(tetrahydropyran-4-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid (CHF 5080); 1-[2-fluoro-4'-(4-oxo-cyclohexyl)-biphenyl-4-yl]-cyclopropanecarboxylic acid (CHF 5081); 2-(2"-fluoro-4-hydroxy-[1,1":4',1 "Jtert-phenyl-4"-yl)-cyclopropanecarboxylic acid (CHF 5083); 1- [4'-(4,4-dimethylcyclohexyl)-2-fluoro] 1,1'-biphenyl]-4-yl]-cyclopropane- carboxylic acid (CHF 5084); 1- [2-fluoro-4'-[[4-(trifluoromethyl)benzoyl] ammino][1,1'-biphenyl]-4-y1]- cyclopropanecarboxylic acid (CHF 5094); 1-[2-fluoro-4'-[[4-(trifluoromethyl)cyclohexyl] oxy][1,1'-biphenyl]-4-yl]- cyclopropanecarboxylic acid (CHF 5096); 1-[2-fluoro-4'-[(3,3,5,5-tetramethylcyclohexyl)oxy][1,1'-biphenyl}-4-yl}- cyclopropanecarboxylic acid (CHF 5102); 1-[4'-[(4,4-dimethylcyclohexyl)oxy]-2-fluoro[1,1'-biphenyl]-4-yl]- cyclopropanecarboxylic acid (CHF 5103); 1-(2,3',4"-trifluoro[1,1":4',1 "_tert-phenyl]-4-yl)-cyclopropanecarboxylic acid (CHF 5104); : 1-(2,2',4"-trifluoro{1,1':4',1 "_tert-phenyl]-4-yl)-cyclopropanecarboxylic acid (CHF 5105); 1-(2,3'-difluoro-4"-hydroxy[1,1":4',1" -tert-phenyl]-4-yl)-cyclopropane- carboxylic acid (CHF 5106); 1-(2,2'-difluoro-4"-hydroxy(1,1":4',1 "_tert-phenyl]-4-yl)-cyclopropane- carboxylic acid (CHF 5107); 2-(2-fluoro-3',5"-bis(chloro)biphen-4-yl)propionic acid amide (CHF 5125).
A more preferred group of compounds is that in which R and R; form a 3 carbon atoms ring with the carbon atom to which they are linked;
R, is fluorine;
G is COOH;
Ar is phenyl substituted with one or more groups in such a way as that the log
P (the partition coefficient between n-octanol and water) of the whole molecule is equal or higher than 4.5 as calculated in silico by using the software QikProp® release version 2.1 (Schrodinger Inc).
It has indeed been found that the higher the log P of the molecule, the greater is the inhibition potency of the release of APs, peptide and that particularly potent compounds are those whose log P is equal or higher than 4.5, preferably higher than 5.0.
Examples of these compounds are CHF 5022, CHF 5074, CHF 5096,
CHF 5105, CHF 5106 and CHF 5107.
The invention also relates to the pharmaceutically acceptable salts and esters prepared in order to increase the crossing of the hemato-encephalic barrier.
A further object of the present invention are the compounds of formula (I) as medicaments, in particular the use thergof in the preparation of pharmaceutical compositions for the treatment and/or the prevention of neurodegenerative diseases such as Alzheimer's disease.
Still a further object of the invention are solid or liquid pharmaceutical compositions, preferably for the oral use, comprising at least one compound of formula (I) in admixture with pharmaceutically acceptable excipients and/or carriers, for example those described in Remington's Pharmaceutical Sciences
Handbook, XVII Ed., Mack Pub., N.Y., U.S.A.
The compounds of general formula (I) wherein R" is H can be prepared according to methods of literature by palladium-catalyzed reaction between an aryl halide of formula (II)
COOH xX : * am in which R, R; and R; are as defined above and X is bromine or iodine, preferably iodine, with a boronic acid or ester ArB(OL), in which L is an alkyl chain, under the conditions reported in Scheme 1.
R oO Na,CO, °
DME, 80°C, 15-48h 1 OH AsB(OL), (LH, alkyl) N 1 OH
Pd an (TTP),
DME = 1,2-dimethoxyethane
TTP = triphenylphosphine
Scheme 1
The compounds of formula (II) are commercially available, or can be prepared according to the following synthetic routes.
Derivatives in which R and R; are straight or branched C,-C, alkyl (11a).
Said compounds can be prepared according to the synthetic route shown in Scheme 2 , starting from the arylacetic acids of formula (III) in which R and R, are as defined above and X is bromine or iodine.
The acid of formula (III) is esterified, alkylated, and optionally hydrolysed if the group G in the final product is COOH.
R RR, o R KR (o] MeOH/HLSO, i or NaH 0 - a ;
OH EEEE——
X Bee x OMe y-crper x OMe
R,=C,-C, alkyl
R, R, R, (um
RR,
KOH/EtOH 0] ———e 25C,2-5h OH (1a)
X
R,
Scheme 2
Derivatives in which R and R; form a 3-6 carbon ring with the carbon atom to which they are linked (IIb)
Said compounds are either commercially available, or can be prepared according to the synthetic route reported in Scheme 3 in which n is an integer of 1to 4.
X
R, R, R,
NBS NaCN toluene/wat
EtOH
CC b a r NaOH
NBS= N-Br succinimide
Re NaOH Ro ———
C methanol/wat ®
NV | \7% O oO
Scheme 3
Boronic acids or the corresponding boronates are either commercially available or can be prepared from the corresponding halide according to methods known in literature.
The compounds of formula (I) wherein G is COOR", where R" is linear or branched C;-Cq alkyl, C3-Cs cycloalkyl or ascorbyl, can be prepared by esterifying the compounds of formula (I) in which G is COOH.
The compounds of formula (I) in which G is CONH, or CONHSO,R" where R™ is linear or branched C;-C4 alkyl or C;-C¢ cycloalkyl can be prepared by reaction of the corresponding esters with NH; or the amine
NH,SO;R™.
The compounds of formula (I) in which G is tetrazolyl can be prepared from compounds of formula (I) according to known methods, for example transforming the carboxylic acid into amide, dehydrating the amide to nitrile and reacting the latter with tributyltin azide.
EXAMPLES OF CHEMICAL PREPARATION yl)propionic acid (CHF 4810)
Preparation of methyl [2-(2-fluoro-4'-trifluoromethylbiphen-4-yl) propionate
A solution of 2-(2-fluoro-4' -trifluoromethylbiphenyl-4-yl)propionic acid (0.2 g, 0.64 mmoles) in methanol (3 ml) is added with 98% sulfuric acid (0.3 g) and refluxed for 2.5 hours. The solvent is removed under vacuum, the residue is taken up with ethyl acetate (5 ml) and washed with a 5% NaHCO; solution (5 ml), then with water. The solution is dried over Na;SOq and concentrated under vacuum to afford an oil (0.2 g, 95%).
HPLC - UV purity (215 nm): 95%
Preparation of methyl [2-methyl-2-( 2-fluoro-4'-trifluoromethylbiphen-4- yl Ipropionate
A solution of methyl [2-(2-fluoro-4'-trifluoromethylbiphen-4- yl)]propionate (0.2 g, 0.61 mmoles) in anhydrous THF (3 ml) at 0°C and under nitrogen atmosphere, is added with 60% NaH (30 mg, 0.75 mmoles).
The mixture is stirred for 30 minutes and added with CH,l (70 wi, 0.91 mmoles). After 3h the mixture is concentrated under vacuum and taken up with ethyl acetate (5 ml). The resulting solution is washed with a 5% NaHCO; solution (5 ml), then with water, dried over Na,SO,, concentrated under vacuum to give an oil (0.18 g, 87%) which is used for the subsequent reaction without further purification.
Preparation of 2-methyl-2-( 2-fluoro-4'-trifluoromethylbiphen-4-yl)propionic acid
A solution of methyl [2-methy]-2-(2-fluoro-4'-trifluoromethylbiphen-4- yl)}propionate (0.18 g, 0.53 mmoles) in ethanol (5 ml) is added with KOH (60 mg, 1 mmol) and kept under stirring for 3h at room temperature. The mixture is diluted with H,0O (5 ml) and the solution is washed with ethyl ether (5 ml).
The organic phase is discarded. The aqueous phase is acidified to pH=2 with
HC], then extracted with ethyl acetate (10 ml). The organic phase is dried over
Na,S0, and concentrated under vacuum to give a white solid, which is purified by flash chromatography on SiO; (eluent hexane/ethyl acetate 8/2 v/v) to obtain the product as a white solid (16 mg, 10%).
HPLC - UV purity (215 nm): 97%.
IH NMR (DMSO-d6): 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 (5, 6H);
MS (EI): 326 m/z (M+.), 281, 253.
Following the same procedure and using the suitable reactive, compound, CHF 4961 was prepared.
Example 2 - Preparation of 1-(2-fluorobiphenyl-4-yDcyclopropanecarboxylic acid (CHF 5041)
Preparation of 4-bromo-3-fluorobenzyl bromide
A solution of 4-bromo-3-fluorotoluene (10 g, 0.053 moles) in carbon tetrachloride (100 ml) is added with N-bromosuccinimide, (NBS; 14 g, 0.08 moles). The mixture is refluxed, added with dibenzoyl peroxide (100 mg, 0.4 mmoles), refluxed for 1 hour, then cooled at room temperature and extracted with water. The aqueous phase is discarded, the organic phase is washed with brine, dried over sodium sulfate and concentrated under vacuum to give an oil (16 g) which is subjected to chromatography on a silica gel column (150 g), eluting with hexane, to afford the product.
Preparation of 4-bromo-3-fluorophenylacetonitrile
A solution of 4-bromo-3-fluorobenzyl bromide (12.2 g, 0.03 moles) in ethanol (100 ml) is added with NaCN (2 g, 0.04 moles) and refluxed for 2 hours. The mixture is concentrated under vacuum; the resulting residue is taken up with water, then extracted with ethyl acetate. The organic phase is washed with brine, dried over sodium sulfate and concentrated under vacuum to give a dark oil (10 g), which is subjected to chromatography on a silica gel column (150 g), eluting with hexane:ethyl ether 7 :3, to afford the product in the solid form.
Preparation of 4-bromo-3-fluorophenylcyclopropanenitrile
A solution of 4-bromo-3-fluorophenylacetonitrile (5 g, 23 mmoles) in toluene (20 ml) is added with 35 mmoles of 1,2-dibromoethane, a 50% NaOH aqueous solution (20 ml) and tetrabutylammonium bromide (1.6 g, 5 mmoles).
The mixture is kept under stirring at room temperature for 5-12 hours, then diluted with water and extracted with ethyl acetate. The organic phase is washed with IN HCI, then with brine, finally dried and concentrated under vacuum to give a brown solid, which is subjected to chromatography on a silica gel column (200 g), eluting with hexane-ethyl ether 1-1, to afford the product in the solid form.
Preparation of 4-bromo-3-fluorophenylcyclopropanecarboxylic acid
A suspension of 4-bromo-3-fluorophenylcyclopropanenitrile (21 mmoles) in methanol (10 ml) is added with a 35% NaOH aqueous solution (40 ml) and a 35% H,0, aqueous solution (3 ml), then is refluxed for 4 hours, cooled at room temperature and added with 2N HCI (250 ml). The precipitated solid is collected by filtration and redissolved in a 5% NaHCO; aqueous solution (300 ml). The insoluble fraction is filtered off and the clear filtrate is acidified to pH=2 with 2N HCI. The product precipitates as a white solid, which is recovered by filtration and dried under vacuum.
Preparation of 1-(2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acid 800 mg (3.1 mmoles) of 4-bromo-3-fluorophenylcyclopropanecarboxylic acid and 650 mg (3.4 mmoles) of phenylboronic acid are suspended in 8 ml of a 2M K,CO; aqueous solution. The mixture is added with tetrabutylammonium bromide (960 mg, 3 mmoles) and palladium(Il) acetate
(40 mg, 0.18 mmoles) and heated at 130°C in a closed reactor for 30 minutes.
After cooling at room temperature, the mixture is added with 2M HCI (25 ml) and extracted with ethyl acetate. The organic phase is washed with IN HC}, then with brine, finally dried and concentrated under vacuum to give an oil (1.7 g), which is crystallized from isopropyl ether-hexane to afford the product as a white solid (0.2 2).
HPLC (215 nm) 98%.
MS (EI; TSQ 700; parameters 180 C; 70 V; 200 uA): 256 (M+.); 210; 196.
H-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).
Following the same procedure as described in Example 1, starting from the suitable 4-bromophenylcycloalkanecarboxylic acids and using the appropriate reactives, compounds CHF 5022, CHF 5023 CHF 5042, 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 were prepared.
Example 3 - Pharmacological activity
Inhibition of ABy; release in the supernatant of H4-15x cells
H4-15x cells (human neuroglioma cells transfected with the human gene encoding for the precursor of B-amyloid protein APP695) were cultured in flasks (in incubator at 37°C, under aqueous vapour saturated atmosphere with 5% carbon dioxide), in the presence of hygromycin and blasticidin, which maintain the selective pressure for the cells continuously expressing the gene of interest.
When the cells reached about 90% confluency, they were collected and re-seeded in 24 wells plates (2 x 10° cells each), in 0.5 ml of complete culture medium. After approx. 24 hours, when the cells had adhered to the well surface and reached confluency, the medium of each well was replaced with 0.5 ml of fresh culture medium, supplemented with a compound (TI) to 100 micromolar final concentration. Each tested concentration was repeated in triplicate. The molecules used for the treatment were previously dissolved in dimethylsulfoxide (DMSO) or in a dimethylsulfoxide/water mixture, the final concentration of DMSO in the wells not exceeding 1%. Thus the prepared plates were incubated again overnight (14-16 hours); afterwards the cell supernatant was taken from each well and ABs, and AP proteins were quantitated. The assay was carried out with an instrumentation for microplates chemoluminescence analysis, which allows to separately quantify the two proteins and is based on the immobilization of an analyte-antibody complex on paramagnetic microbeads. One of the antibodies of this complex is marked with a ruthenium compound which, upon electrochemical excitement, gives a light signal, having intensity proportional to the amount of analyte present.
Inhibition of cyclooxygenase-1 (COX-1) in rat whole blood
Whole blood was taken from the rat abdominal aorta and immediately placed in heparinized tubes. Aliquots of heparinized blood (500 pl) were preincubated with 100 pM concentration of the tested compounds or with the only carrier (DMSO) for 1 h at 37°C. Eicosanoid production was induced by addition of calcium ionophore A23187 (final concentration 5x10 M) and was interrupted after 30 minute incubation by quickly placing the samples in dry ice. Thereafter, samples were centrifuged (12000 g x 3 minutes a 4°C) and the production of TxB, thromboxane B2 was calculated by radioimmunoassay.
The results expressed as percent inhibition of AB, release at 100 uM and percent COX-1 inhibitory activity at the same concentration are reported in Table 1. Flurbiprofen used as comparison at the same concentration showed approx. 25% inhibition of AB, release and 100% COX-1 inhibitory activity.
Table 1: Percent inhibition of ABs, release and percent COX-1 inhibitory activity of representative compounds of the invention at 100 uM concentration. % inhibition of AB42 % COX-1 inhibitory
Compound release activity carasio [sso [
ChFsoss | sas [00
Cirsoso | sis [03
CHF 5083 EC —
ChFsoe | 700 [08 |]
Chrsios | eos | 19
Claims (15)
1. Compounds of general formula (I): oh Ar “ R, m wherein: R and R, are the same and are linear or branched C;-Cy4 alkyl; or they form a 3 to 6 carbon atoms ring with the carbon atom to which they are linked; Gis: - a COOR" group wherein R" is H, linear or branched C;-C, alkyl, C3-Cs cycloalkyl, or ascorbyl; - a CONH, or a CONHSO,R™ group wherein R" is linear or branched C,-C; alkyl or C;-Cg cycloalkyl; - a tetrazolyl residue; R, is H, CF;, OCF; or a halogen selected from the group of F, Cl, Br, I, preferably fluorine. Ar is a group of formula \ > wherein Rj represents one or more groups independently selected from: - halogen as previously defined; - CFs; - C»-Cy cycloalkyl optionally substituted with one or more C;-C, alkyl and/or 0x0 groups;
- CH=CH;
- CN;
- CH,0H;
- methylendioxy or ethylendioxy;
- NO,
- phenyl optionally substituted with one or more of the following groups: halogen; CF;; OCF3; OH; linear or branched C;-C4 alkyl; a saturated eterocycle with at least 4 carbon atoms and at least 1 heteroatom; C;-Cs cycloalkyl in turn optionally substituted with one or more of the following groups linear or branched C;-C4 alkyl, CF; or OH;
- OR, or NHCOR, wherein Ry is CFs, linear or branched C,-C¢ alkenyl or alkynyl; benzyl; phenyl optionally substituted with one or more of the following groups: halogen, CF;, OCF, OH, linear or branched C;-Cq4 alkyl; a saturated eterocycle with at least 4 carbon atoms and at least 1 heteroatom; C3-Cg cycloalkyl in turn optionally substituted with one or more of the following groups: linear or branched C;-C;4 alkyl, CF; or OH;
- SRs, SO,Rs or COR; wherein Rs is linear or branched C;-Cs alkyl;
otherwise Ar is an eterocycle ring selected from the group of thiophene, benzothiophene, dibenzothiophene, thianthrene, pyrrole, pyrazole, furan, benzofuran, dibenzofuran, indole, isoindole, benzofurane, imidazole, benzoimidazole, oxazole, isoxazole, benzoxazole, thiazole, pyridine, pyrimidine, pyrazine, pyridazine, quinoline, isoquinoline, quinazoline,
quinoxaline, cinnoline, pyrazole, pyran, benzopyran, pyrrolizine, phtalazine, 1,5-naphthyridine, 1,3-dioxole, 1,3-benzodioxole, optionally substituted with one or more groups R; as defined above; pharmaceutically acceptable salts and other esters thereof.
2. Compounds as claimed in claim 1, wherein R and R, form a 3 carbon atom ring with the carbon atom to which they are linked; R; is fluorine; G is a COOR" group in which R" is H, linear or branched C;-C4 alkyl, C3-Cs cycloalkyl or ascorbyl; Ar is phenyl as defined in claim 1.
3. Compounds as claimed in claim 1, wherein R and R; form a 3 carbon atom cycle with the carbon atom to which they are linked; R, is fluorine; G is a CONH, or CONHSO,R"" in which R" is linear or branched C;-C4 alkyl or C3-Cg cycloalkyl; Ar is phenyl as defined in claim 1.
4, Compounds as claimed in claim 1, wherein both R and R; are CHj; R; is fluorine; G is COOR" in which R" is as defined in claim 1; Ar is phenyl as defined in claim 1.
5. Compounds as claimed in claim 1, wherein voth R and R; are CHjs; R; is fluorine; G is a CONH, or CONHSO,R" in which R"' is as defined above; Ar is phenyl substituted with an optionally substituted phenyl.
6. Compounds as claimed in claim 1, wherein R and R, form a 3 carbon atoms ring with the carbon atom to which they are linked; R; is fluorine; G is a COOR" group in which R" is as defined above; Ar is a heterocycle as defined in claim 1.
7. Compounds as claimed in claim 1, wherein both R and R, are CHj; G is a COOR" group in which R" is as defined above; Rj is fluorine; Ar is a heterocycle as defined in claim 1.
8. Compounds as claimed in claim 1 wherein R and R, form a 3 carbon atoms ring with the carbon atom to which they are linked; G is COOH; R; is fluorine; Ar is phenyl substituted with one or more groups in such a way as that the log P of the whole molecule is equal or higher than 4.5 as calculated in silico by using the software QikProp® release version 2.1 (Schrodinger Inc).
9. Compounds as claimed in claim 8 selected from the group of CHF 5022, CHF 5074, CHF 5096, CHF 5105 and CHF 5106 and CHF 5107.
10. Compounds as claimed in claims 1-9 as medicaments.
11. Pharmaceutical compositions containing a compound of formula (I) in admixture with pharmaceutically acceptable carriers and/or excipients.
12. Pharmaceutical compositions as claimed in claim 11, for the oral administration.
13. The use of the compounds of formula (I) as claimed in claims 1 to 9, for the preparation of a medicament for the treatment of diseases connected with an increased production of neurotoxic peptide Ago.
14. The use of the compounds of formula (I) as claimed in claims 1 to 9, for the preparation of a medicament for the preventive or therapeutical treatment of neurodegenerative diseases.
15. The use of the compounds of formula (I) as claimed in claim 14, for the treatment of Alzheimer's disease.
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