WO2005012282A1 - Nouveaux derives du benzothiofene 2-thiosubstitues, leur procede de preparation et les compositions pharmaceutiques qui les contiennent - Google Patents
Nouveaux derives du benzothiofene 2-thiosubstitues, leur procede de preparation et les compositions pharmaceutiques qui les contiennent Download PDFInfo
- Publication number
- WO2005012282A1 WO2005012282A1 PCT/FR2004/001676 FR2004001676W WO2005012282A1 WO 2005012282 A1 WO2005012282 A1 WO 2005012282A1 FR 2004001676 W FR2004001676 W FR 2004001676W WO 2005012282 A1 WO2005012282 A1 WO 2005012282A1
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- WO
- WIPO (PCT)
- Prior art keywords
- formula
- pharmaceutically acceptable
- addition salts
- compound
- base
- Prior art date
Links
- 0 *c1ccc2[s]c(S*)c(CBr)c2c1 Chemical compound *c1ccc2[s]c(S*)c(CBr)c2c1 0.000 description 2
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- 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
-
- 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
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
Definitions
- the present invention relates to new 2-thiosubstituted benzothiophene derivatives, their preparation process and the pharmaceutical compositions containing them.
- the compounds of the present invention are new and have very interesting pharmacological characteristics concerning the melatoninergic receptors.
- melatonin N-acetyl-5-methoxytryptamine
- melatonin N-acetyl-5-methoxytryptamine
- it has a fairly short half-life due to rapid metabolism. It is therefore very interesting to be able to provide the clinician with analogues of melatonin, metabolically more stable and having an agonist or antagonist character, from which one can expect a therapeutic effect greater than that of the hormone itself.
- the ligands of the melatoninergic system have interesting pharmacological properties on the central nervous system, in particular anxiolytics and antipsychotics (Neuropharmacology of Pineal Secretions, 1990, 8 (3-4), pp. 264-272), analgesics (Pharmacopsychiat., 1987, 20, pp. 222-223) , as well as for the treatment of diseases of
- Parkinson J. Neurosurg. 1985, 63, pp. 321-341
- Alzheimer's Brain Research, 1990, 528, pp. 170-174
- these compounds have shown activity on certain cancers (Melatonin - Clinical Perspectives, Oxford University Press, 1988, pp. 164-165), on ovulation (Science 1987, 227, pp. 714-720), on diabetes (Clinical Endocrinology, 1986, 24, pp. 359-364), and in the treatment of obesity (International Journal of Eating
- melatonin receptors Molecular biology studies have shown the existence of several sub- receptor types that can bind this hormone (Trends Pharmacol. Sci., 1995, 16, p. 50; WO 97.04094). Some of these receptors could be located and characterized for different species, including mammals. In order to be able to better understand the physiological functions of these receptors, it is of great interest to have selective ligands. In addition, such compounds, by interacting selectively with one or the other of these receptors, can be, for the clinician, excellent drugs for the treatment of pathologies linked to the melatoninergic system, some of which have been mentioned previously.
- the compounds of the present invention in addition to their novelty, show a very strong affinity for the melatonin receptors and / or a selectivity for one or the other of the melatoninergic binding sites.
- the present invention relates more particularly to the compounds of formula (I):
- R 1 represents a halogen atom, an alkyl group (C ⁇ -C 6 ) linear or branched, or an alkoxy group (C ⁇ -C 6 ) linear or branched
- R 2 represents a phenyl group unsubstituted or substituted by one to three groups chosen from hydroxy, linear or branched (C] -C 6 ) alkyl, linear or branched alkoxy (C ⁇ -C 6 ), carboxy, formyl, nitro, cyano, linear or branched polyhaloalkyl (C ⁇ -C 6 ) and d atoms 'halogen,
- R represents an alkyl (C ⁇ -C6) linear or branched substituted or unsubstituted alkenyl, (C ⁇ -C6) linear or branched substituted or unsubstituted cycloalkyl (C -C 8 ), or cycloalkyl (C -C 8 ) alkyl (C ⁇ -C 6 ), the alkyl part of which can be linear or branched, it being understood that:
- substituted applied to “alkyl” and “alkenyl” means that these groups are substituted by one or more halogen atoms, or by one or more groups chosen from linear and branched hydroxy and alkoxy (C ⁇ -C 6 ),
- hydrochloric hydrobromic, sulfuric, phosphonic, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, oxalic, methane acids. sulfonic, camphoric, etc.
- the preferred compounds of the invention are the compounds of formula (I) for which
- R 1 represents a halogen atom such as fluorine, chlorine or bromine.
- R advantageously represents a phenyl group substituted by a halogen atom.
- the preferred group R is alkyl, for example the methyl, ethyl, "-propyl or" -butyl groups, as well as the alkyl group substituted by a halogen atom, such as, for example, the bromomethyl, bromoethyl, bromopropyl or bromobutyl groups.
- the invention relates to N- (2- ⁇ 5-bromo-2 - [(4-bromophenyl) thio] -l -benzothien-3-yl ⁇ ethyl) acetamide, 2-bromo-N- ( 2- ⁇ 5-fluoro-2 - [(4-fluorophenyl) thio] - 1 -benzothien-3-yl ⁇ ethyl) acetamide, N- (2- ⁇ 5-fluoro-2 - [(4-fluoro- phenyl) thio] -1-benzothien-3-yl ⁇ ethyl) cyclobutanecarboxamide, N- (2- ⁇ 5-fluoro-2 - [(4-fluorophenyl) thio] - 1 -benzothien-3-yl ⁇ ethyl) propanamide .
- the invention also extends to the process for preparing the compounds of formula (I) characterized in that the compound of formula (II) is used as starting material:
- the pharmacological study of the derivatives of the invention has shown that they are non-toxic, endowed with a strong selective affinity for the melatonin receptors and possess important activities on the central nervous system and, in particular, it has been noted therapeutic properties for sleep disorders, antidepressant, anxiolytic, antipsychotic, analgesic properties as well as for microcirculation, which make it possible to establish that the products of the invention are useful in the treatment of stress, sleep disorders, anxiety, seasonal depressions or major depression, cardiovascular pathologies, pathologies of the digestive system, insomnia and fatigue due to jetlag, schizophrenia, panic attacks, melancholy, disorders of the appetite, obesity, insomnia, psychotic disorders, epilepsy, diabetes, Parkinson's disease, senile dementia, various disorders related to normal or pathological aging, migraine, memory loss, Alzheimer 's disease, as well as in disorders of the cerebral circulation.
- the products of the invention can be used in sexual dysfunctions, that they have properties of inhibitors of ovulation, of immunomodulators and that they are likely to be used in the treatment of cancer.
- the compounds will preferably be used in the treatment of major depression, seasonal depressions, sleep disorders, cardiovascular pathologies, pathologies of the digestive system, insomnia and fatigue due to jet lag, appetite disorders and obesity.
- the compounds will be used in the treatment of major depression, seasonal depressions and sleep disturbances.
- the present invention also relates to pharmaceutical compositions containing at least one compound of formula (I) alone or in combination with one or more pharmaceutically acceptable excipients.
- compositions according to the invention there may be mentioned, more particularly those which are suitable for oral, parenteral, nasal, per or transcutaneous, rectal, perlingual, ocular or respiratory administration and in particular simple or coated tablets, sublingual tablets , sachets, packages, capsules, lollipops, tablets, suppositories, creams, ointments, dermal gels, and oral or injectable ampoules.
- the dosage varies according to the sex, age and weight of the patient, the route of administration, the nature of the therapeutic indication, or possibly associated treatments and ranges between 0.01 mg and 1 g per 24 hours in one or more takes.
- Acute toxicity was assessed after oral administration in groups of 8 mice (26 ⁇ 2 grams). The animals were observed at regular intervals during the first day and daily during the two weeks following the treatment. The LD 50, resulting in the death of 50% of the animals, was evaluated and showed the low toxicity of the compounds of the invention.
- the compounds of the invention are tested in a behavioral model, the forced swimming test.
- the device consists of a plexiglass cylinder filled with water. Animals are tested individually during a 6 minute session. At the start of each test, the animal is placed in the center of the cylinder. The downtime is recorded. Each animal is judged immobile when it stops struggling, and remains on the surface of the water, immobile, only making the movements allowing it to keep the head above water.
- the compounds of the invention significantly reduce the immobilization period attesting to their antidepressant activity.
- the binding experiments on the MT 3 sites are carried out on hamster brain membranes using 2- [ I25 I] iodomelatonin as radioligand.
- the membranes are incubated for 30 minutes with 2- [ 125 I] iodomelatonin at a temperature of 4 ° C. and different concentrations of the compounds to be tested. After incubation, the membranes are quickly filtered and then washed with cold buffer using a filtration system. The fixed radioactivity is measured by a scintillation counter.
- the IC 50 values concentration inhibiting the specific binding by 50%
- the compound of Example 4 has an IC 50 (MTi) of 8D0 "8 M and an IC 50 (MT 2 ) of 1D0 " 9 M.
- the affinity of the compounds for the human 5-HT 2 c receptor is evaluated on membrane preparations of CHO cells stably expressing this receptor. Incubation is carried out in 50 mM TRIS buffer, pH 7.4, containing 10 mM MgCl 2 and 0.1% BSA, in the presence of [ 3 H] Mesulergin (1 nM) and 25 fmol / ml of receiver. The non-specific binding is determined in the presence of 10 ⁇ M mianserin.
- the reaction is stopped by adding 50 mM TRIS buffer, pH 7.4 followed by a filtration step and 3 successive rinses: the radioactivity linked to the membranes remaining on the filters (GF / B pretreated with PEI 0.1%) is counted in liquid scintillation.
- the compounds of the invention are affine for the 5-HT 2 r receptor>
- the compound of Example 3 has a K, (5HT 2C ) of
- the rats receive a daily administration of the test molecule.
- the compounds of the invention are tested in a behavioral model, the test of light / dark cages, which makes it possible to reveal the anxiolytic activity of the molecules.
- the device consists of two polyvinyl boxes covered with Plexiglas. One of these boxes is obscure. A lamp is placed above the other box giving a light intensity in the center thereof of approximately 4000 lux. An opaque plastic tunnel separates the light box from the dark box. The animals are tested individually during a 5 min session. The floor of each box is cleaned between each session. At the start of each test, the mouse is placed in the tunnel, facing the dark box. The time spent by the mouse in the lit box and the number of transitions through the tunnel are recorded after the first entry in the dark box.
- the compounds of the invention significantly increase the time spent in the lighted cage as well as the number of transitions, which shows the anxiolytic activity of the derivatives of the invention.
- the compounds of the invention were tested in vitro on the rat caudal artery.
- Melatoninergic receptors are present on these vessels which makes them a significant pharmacological model for studying the activity of melatoninergic ligands. Stimulation of receptors can induce either vasoconstriction or vasodilation depending on the arterial segment studied. Protocol
- the caudal artery is isolated and maintained in a richly oxygenated environment.
- the arteries are then cannulated at both ends, suspended vertically in an organ chamber in an appropriate medium and perfused via their proximal end. Changes in pressure in the infusion rate allow the vasoconstrictor or vasodilator effect of the compounds to be assessed.
- the activity of the compounds is evaluated on segments pre-contracted by phenylephrine (1 ⁇ M).
- a concentration-response curve is determined in a non-cumulative manner by adding a concentration of the compound studied on the pre-contracted segment. When the observed effect has reached equilibrium, the medium is changed and the preparation left 20 minutes before the addition of the same concentration of phenylephrine and a new concentration of the compound studied.
- the compounds of the invention significantly modify the diameter of the caudal arteries preconstructed by phenylephrine.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Diabetes (AREA)
- Endocrinology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Emergency Medicine (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Anesthesiology (AREA)
- Reproductive Health (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR0308214A FR2857011B1 (fr) | 2003-07-04 | 2003-07-04 | Nouveaux derives du benzothiophene 2-thiosubstitues, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
FR03/08214 | 2003-07-04 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2005012282A1 true WO2005012282A1 (fr) | 2005-02-10 |
Family
ID=33522784
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/FR2004/001676 WO2005012282A1 (fr) | 2003-07-04 | 2004-06-30 | Nouveaux derives du benzothiofene 2-thiosubstitues, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
Country Status (3)
Country | Link |
---|---|
AR (1) | AR044996A1 (es) |
FR (1) | FR2857011B1 (es) |
WO (1) | WO2005012282A1 (es) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015066344A1 (en) | 2013-11-01 | 2015-05-07 | Arena Pharmaceuticals, Inc. | 5-ht2c receptor agonists and compositions and methods of use |
US9085198B2 (en) | 2008-08-29 | 2015-07-21 | Michelin Recherche Et Technique S.A. | 1-D tire apparatus |
WO2016135048A1 (en) | 2015-02-25 | 2016-09-01 | Palobiofarma, S.L. | Derivatives of 2-aminopyridine as adenosine a2b receptor antagonists and ligands of the melatonin mt3 receptors |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1997011056A1 (fr) * | 1995-09-18 | 1997-03-27 | Cemaf | Derives d'indole comme analogues melatonergiques |
EP0926145A1 (fr) * | 1997-12-24 | 1999-06-30 | Adir Et Compagnie | Composés naphtaléniques, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent |
WO1999058495A1 (fr) * | 1998-05-12 | 1999-11-18 | Adir Et Compagnie | Nouveaux composes cycliques substitues, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
-
2003
- 2003-07-04 FR FR0308214A patent/FR2857011B1/fr not_active Expired - Fee Related
-
2004
- 2004-06-30 WO PCT/FR2004/001676 patent/WO2005012282A1/fr active Application Filing
- 2004-07-02 AR ARP040102337A patent/AR044996A1/es unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1997011056A1 (fr) * | 1995-09-18 | 1997-03-27 | Cemaf | Derives d'indole comme analogues melatonergiques |
EP0926145A1 (fr) * | 1997-12-24 | 1999-06-30 | Adir Et Compagnie | Composés naphtaléniques, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent |
WO1999058495A1 (fr) * | 1998-05-12 | 1999-11-18 | Adir Et Compagnie | Nouveaux composes cycliques substitues, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9085198B2 (en) | 2008-08-29 | 2015-07-21 | Michelin Recherche Et Technique S.A. | 1-D tire apparatus |
US9333811B2 (en) | 2008-08-29 | 2016-05-10 | Compagnie Generale Des Etablissements Michelin | 1-D tire patch apparatus and methodology |
WO2015066344A1 (en) | 2013-11-01 | 2015-05-07 | Arena Pharmaceuticals, Inc. | 5-ht2c receptor agonists and compositions and methods of use |
WO2016135048A1 (en) | 2015-02-25 | 2016-09-01 | Palobiofarma, S.L. | Derivatives of 2-aminopyridine as adenosine a2b receptor antagonists and ligands of the melatonin mt3 receptors |
US10253017B2 (en) | 2015-02-25 | 2019-04-09 | Palobiofarma, S.L. | Derivatives of 2-aminopyridine as adenosine A2B receptor antagonists and ligands of the melatonin MT3 receptors |
Also Published As
Publication number | Publication date |
---|---|
AR044996A1 (es) | 2005-10-12 |
FR2857011A1 (fr) | 2005-01-07 |
FR2857011B1 (fr) | 2005-09-16 |
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