WO2004073705A1 - 1-phenyl-2- monoalkyl carboxylic acid derivatives for the treatment of neurodegenerative diseases - Google Patents
1-phenyl-2- monoalkyl carboxylic acid derivatives for the treatment of neurodegenerative diseases Download PDFInfo
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- WO2004073705A1 WO2004073705A1 PCT/EP2004/001595 EP2004001595W WO2004073705A1 WO 2004073705 A1 WO2004073705 A1 WO 2004073705A1 EP 2004001595 W EP2004001595 W EP 2004001595W WO 2004073705 A1 WO2004073705 A1 WO 2004073705A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/52—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing halogen
- C07C57/58—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing halogen containing six-membered aromatic rings
Definitions
- the present invention concerns novel l-phenyl-2-monoalkylcarboxylic acids, pro-drugs and bioisosters on the carboxylic moiety thereof.
- the invention is also directed to the process for their preparation and the use thereof in the preventive or 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 ⁇ -amyloid ( ⁇ A), and, depending on the numbers of aminoacids, A ⁇ 39 , A ⁇ 40 , A ⁇ 42 and A ⁇ 43 .
- ⁇ A ⁇ -amyloid
- NSAIDs non steroid anti-inflammatory drugs
- indomethacin, sulindac, ibuprofen and flurbiprofen can selectively reduce the production of the most neurotoxic isoform of ⁇ -amyloid peptide in cell cultures, namely the form containing 42 amino acids (A ⁇ 42 ), thus favouring the release of a less harmful isoform, A ⁇ 38 (Weggen et al., Nature 2001; 414 (6860): 212-6).
- WO 01/78721 claims a method of preventing, delaying or reversing the progression of Alzheimer's disease by administering an A ⁇ 42 lowering agent, under conditions in which levels of A ⁇ 38 are increased and levels of A ⁇ 42 are left unchanged. Furthermore, methods and materials for identifying and developing A ⁇ 42 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.
- novel derivatives having more selective and more potent inhibitory activity on the peptide A ⁇ 42 release 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.
- WO 99/41224 claims novel biaryl-acetic acid derivatives with anti- inflammatory activity as cyclooxygenase-2 (COX-2) inhibitors, useful for the treatment of a number of diseases, including Alzheimer's disease.
- COX-2 cyclooxygenase-2
- an inhibitory effect on the COX-2 is associated to side effects such as gastrointestinal bleeding and perforating ulcers.
- GB 1,396,726, GB 1,382,996, GB 1,359,987 disclose 2-biphen-4-yl propionic acid derivatives substituted in 2' and 4' as anti-inflammatory agents.
- the present invention concerns l-phenyl-2-monoalkyl carboxylic acids derivatives having a more selective inhibitory activity on the release of A ⁇ 42 peptide, thereby being able to modulate gamma-secretase activity without affecting other important metabolic processes.
- the invention is also directed to a process for their preparation, to pro- drugs and bioisosters on the carboxylic moiety thereof, to pharmaceutical compositions containing them and the use thereof in the prevention or therapeutical treatment of neurodegenerative diseases, in particular . Alzheimer's disease.
- DETAILED DESCRIPTION OF THE INVENTION is also directed to a process for their preparation, to pro- drugs and bioisosters on the carboxylic moiety thereof, to pharmaceutical compositions containing them and the use thereof in the prevention or therapeutical treatment of neurodegenerative diseases, in particular . Alzheimer's disease.
- the present invention is directed to compounds of general formula ( ⁇ ):
- R is linear or branched C 1 -C 4 alkyl
- G is:
- R is H, linear or branched C 1 -C 4 alkyl, C3-C 6 cycloalkyl or ascorbyl;
- Ri is CF 3) OCF 3 or a halogen selected from the group of F, CI, Br, I, preferably fluorine.
- Ar is a group of formula wherein R 2, R 3 and R 4 are independently selected from the group of:
- a group of preferred compounds is that in which: R is CH 3 ; Ri is fluorine; G is COOH; Ar is phenyl as defined above.
- Particularly preferred are the following compounds: 2-(2-fluoro-4'-trifluoromethylbi ⁇ hen-4-yl) ⁇ ro ⁇ ionic acid (CHF 4732); 2-(2-fluoro-3'-trifluoromethylbi ⁇ hen-4-yl) ⁇ ropionic acid (CHF 4729); 2-(2-fluoro-3',5'-bis(trifluoromethyl)biphen-4-yl) ⁇ ro ⁇ ionic acid (CHF 4801); 2-(4'-cyclohexyl-2-fluorobiphen-4-yl)propionic acid (CHF 4865).
- the invention also relates to the enantiomers, 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 thereof 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..
- R and Ri are as defined above and X is bromine or iodine, preferably iodine, with a boronic acid or ester ArB(OL) 2 in which L is an alkyl chain, under the conditions reported in Scheme 1.
- the compounds of formula (II) are commercially available, or can be prepared according to the following synthetic route.
- the process comprises the alkylation of a phenylacetic acid (III) with an alkyl halide RX', wherein R is as defined above and X' is halogen selected from CI, Br and I, according to what reported in Scheme 2:
- 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 1 -C 4 alkyl, C 3 -C 6 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 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.
- H4-15x cells human neuroglioma cells transfected with the human gene encoding for the precursor of ⁇ -amyloid protein APP695
- H4-15x cells 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.
- the cells When the cells reached about 90% confluency, they were collected and re-seeded in 24 wells plates (2 x 10 5 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 (I) 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%.
- DMSO dimethylsulfoxide
- the prepared plates were incubated again overnight (14-16 hours); afterwards the cell supernatant was taken from each well and A ⁇ 42 and A ⁇ 40 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.
- COX-1 cyclooxygenase- 1
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- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- General Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Psychiatry (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Hospice & Palliative Care (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IT000312A ITMI20030312A1 (it) | 2003-02-21 | 2003-02-21 | Derivati di acidi 2-fenil-2-alchil-acetici per il trattamento della malattia di alzheimer. |
ITMI2003A000312 | 2003-02-21 |
Publications (1)
Publication Number | Publication Date |
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WO2004073705A1 true WO2004073705A1 (en) | 2004-09-02 |
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PCT/EP2004/001595 WO2004073705A1 (en) | 2003-02-21 | 2004-02-19 | 1-phenyl-2- monoalkyl carboxylic acid derivatives for the treatment of neurodegenerative diseases |
Country Status (2)
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IT (1) | ITMI20030312A1 (it) |
WO (1) | WO2004073705A1 (it) |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005110963A1 (en) * | 2004-05-19 | 2005-11-24 | Cellzome Ag | (biphenyl-3-yl)-carboxylic acids and derivatives thereof and their use in therapy |
EP1604970A1 (en) * | 2004-05-19 | 2005-12-14 | Cellzome Ag | 2-(Biphenyl-3-yl)-carboxylic acids of gamma-secretase-modulating activity |
EP1650183A1 (en) * | 2004-10-21 | 2006-04-26 | Cellzome Ag | (Benzyloxy-biphenyl) acetic acids and derivatives thereof and their use in therapy |
WO2009036428A2 (en) * | 2007-09-14 | 2009-03-19 | Envivo Pharmaceuticals, Inc. | 1,3,4-trisubstituted benzenes |
WO2011131661A1 (en) | 2010-04-21 | 2011-10-27 | Chiesi Farmaceutici S.P.A. | 1-(2-fluorobiphenyl-4-yl)-alkyl carboxylic acid derivatives for the therapy of transthyretin amyloidosis |
US8188101B2 (en) | 2008-11-06 | 2012-05-29 | Astrazeneca Ab | Dihydropyridopyrimidines for the treatment of AB-related pathologies |
WO2014195323A1 (en) | 2013-06-04 | 2014-12-11 | Acturum Life Science AB | Pyrimidine compounds and their use as gamma secretase modulators |
WO2014195322A1 (en) | 2013-06-04 | 2014-12-11 | Acturum Life Science AB | Triazole compounds and their use as gamma secretase modulators |
US9611254B2 (en) | 2013-06-04 | 2017-04-04 | Acturum Life Science AB | Triazole compounds and their use as gamma secretase modulators |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999041224A1 (en) * | 1998-02-13 | 1999-08-19 | Merck Frosst Canada & Co. | Biaryl-acetic acid derivatives and their use as cox-2 inhibitors |
DE19907895A1 (de) * | 1999-02-24 | 2000-11-16 | Paz Arzneimittelentwicklung | Verwendung von R-Arylpropionsäuren zur Herstellung von Arzneimitteln zur Behandlung von Erkrankungen bei Mensch und Tier, welche durch die Hemmung der Aktivierung von NF-kB therapeutisch beeinflußt werden können |
WO2001078721A1 (en) * | 2000-04-13 | 2001-10-25 | Mayo Foundation For Medical Education And Research | Aβ42 LOWERING AGENTS |
-
2003
- 2003-02-21 IT IT000312A patent/ITMI20030312A1/it unknown
-
2004
- 2004-02-19 WO PCT/EP2004/001595 patent/WO2004073705A1/en active Search and Examination
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999041224A1 (en) * | 1998-02-13 | 1999-08-19 | Merck Frosst Canada & Co. | Biaryl-acetic acid derivatives and their use as cox-2 inhibitors |
DE19907895A1 (de) * | 1999-02-24 | 2000-11-16 | Paz Arzneimittelentwicklung | Verwendung von R-Arylpropionsäuren zur Herstellung von Arzneimitteln zur Behandlung von Erkrankungen bei Mensch und Tier, welche durch die Hemmung der Aktivierung von NF-kB therapeutisch beeinflußt werden können |
WO2001078721A1 (en) * | 2000-04-13 | 2001-10-25 | Mayo Foundation For Medical Education And Research | Aβ42 LOWERING AGENTS |
Cited By (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005110963A1 (en) * | 2004-05-19 | 2005-11-24 | Cellzome Ag | (biphenyl-3-yl)-carboxylic acids and derivatives thereof and their use in therapy |
EP1604970A1 (en) * | 2004-05-19 | 2005-12-14 | Cellzome Ag | 2-(Biphenyl-3-yl)-carboxylic acids of gamma-secretase-modulating activity |
US7825160B2 (en) | 2004-10-21 | 2010-11-02 | Cellzome Limited | (Biphenyl) carboxylic acids and derivatives thereof |
KR101326358B1 (ko) | 2004-10-21 | 2013-11-11 | 셀좀 리미티드 | (비페닐) 카르복실산 및 이의 유도체 |
JP2008517028A (ja) * | 2004-10-21 | 2008-05-22 | セルゾーム アーゲー | (ビフェニル)カルボン酸およびその誘導体 |
EA012417B1 (ru) * | 2004-10-21 | 2009-10-30 | Целльзом Лимитид | (бифенил)карбоновые кислоты и их производные |
EP1650183A1 (en) * | 2004-10-21 | 2006-04-26 | Cellzome Ag | (Benzyloxy-biphenyl) acetic acids and derivatives thereof and their use in therapy |
WO2006045554A1 (en) * | 2004-10-21 | 2006-05-04 | Cellzome Ag | (biphenyl) carboxylic acids and derivatives thereof |
WO2009036428A2 (en) * | 2007-09-14 | 2009-03-19 | Envivo Pharmaceuticals, Inc. | 1,3,4-trisubstituted benzenes |
WO2009036428A3 (en) * | 2007-09-14 | 2009-05-22 | Envivo Pharmaceuticals Inc | 1,3,4-trisubstituted benzenes |
US8188101B2 (en) | 2008-11-06 | 2012-05-29 | Astrazeneca Ab | Dihydropyridopyrimidines for the treatment of AB-related pathologies |
WO2011131661A1 (en) | 2010-04-21 | 2011-10-27 | Chiesi Farmaceutici S.P.A. | 1-(2-fluorobiphenyl-4-yl)-alkyl carboxylic acid derivatives for the therapy of transthyretin amyloidosis |
WO2014195323A1 (en) | 2013-06-04 | 2014-12-11 | Acturum Life Science AB | Pyrimidine compounds and their use as gamma secretase modulators |
WO2014195322A1 (en) | 2013-06-04 | 2014-12-11 | Acturum Life Science AB | Triazole compounds and their use as gamma secretase modulators |
US9439904B2 (en) | 2013-06-04 | 2016-09-13 | Acturum Life Science AB | Pyrimidine compounds and their use as gamma secretase modulators |
US9611254B2 (en) | 2013-06-04 | 2017-04-04 | Acturum Life Science AB | Triazole compounds and their use as gamma secretase modulators |
US9718805B2 (en) | 2013-06-04 | 2017-08-01 | Acturum Life Science AB | Triazole compounds and their use as gamma secretase modulators |
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ITMI20030312A1 (it) | 2004-08-22 |
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