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WO1995024406A1 - NOUVEAU DERIVE de 2-(IMIDAZOLYLMETHYL)THIAZOLE ET COMPOSITION MEDICALE ISSUE DE CE DERIVE - Google Patents

NOUVEAU DERIVE de 2-(IMIDAZOLYLMETHYL)THIAZOLE ET COMPOSITION MEDICALE ISSUE DE CE DERIVE Download PDF

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Publication number
WO1995024406A1
WO1995024406A1 PCT/JP1995/000386 JP9500386W WO9524406A1 WO 1995024406 A1 WO1995024406 A1 WO 1995024406A1 JP 9500386 W JP9500386 W JP 9500386W WO 9524406 A1 WO9524406 A1 WO 9524406A1
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WO
WIPO (PCT)
Prior art keywords
group
imidazolylmethyl
thiazole
salt
atom
Prior art date
Application number
PCT/JP1995/000386
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English (en)
Japanese (ja)
Inventor
Kiyoshi Iwaoka
Kenichi Kazuta
Shinya Nagashima
Hiroyuki Ito
Keiji Miyata
Mitsuaki Ohta
Original Assignee
Yamanouchi Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Yamanouchi Pharmaceutical Co., Ltd. filed Critical Yamanouchi Pharmaceutical Co., Ltd.
Priority to AU18623/95A priority Critical patent/AU1862395A/en
Publication of WO1995024406A1 publication Critical patent/WO1995024406A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to a pharmaceutical, particularly a 2- (imidazolylmethyl) thiazole derivative or a salt thereof useful as a 5-HT 3 receptor agonist, and a pharmaceutical composition containing the same as an active ingredient.
  • the compounds of the present invention act as effective and selective agonists of neuronal serotonin (5-HT) receptors located on the primary afferent nerves of the intestinal nervous system or central nervous system. This type of receptor is now considered a 5-HT 3 receptor.
  • the compounds of the present invention exert their action by releasing acetylcholine from efferent nerve endings. Stimulation of acetylcholine receptors in the gastrointestinal tract is known to increase gastrointestinal motility and improve gastrointestinal dysfunction [Go o dman and G i 1 man's The Ph Ph a r a c m a c e B 8 thedition, p 125, (1 990), Pergamon press].
  • 5-HT 3 receptor is located at the presynaptic site in the central nervous system and suppresses neural activity by its stimulation [J. Neurosci., 11, 1881 (1992) 1)]. Therefore, 5-HT 3 receptor agonists are considered to be particularly useful for digestive disorders.
  • Previously 5- ⁇ 3 compounds having selective agonist activity for the receptor has been not been found, the present inventors have, WO 92/07 84 9 2-position UNA I disclosed in the ⁇ "Vx — (X is-NH—, one NHCONH-, one CONH— or
  • 5-HT S relates agonistic activity of the receptor, promoting further research, Vo n B ezol d- J ariseh reflection [AS which is an index of conventionally 5-HT 3 receptor agonistic activity P aintaletal., Phy siol. R e v., 5 3, 1 59 (1 973)] indicators independent 5-HT 3 receptor agonistic activity and, namely via the 5-HT S receptors 5- Focusing on the contractile action of HT on the isolated guinea pig colon, we proceeded with synthetic studies and found that a new 2- (imidazolylmethyl) thiazole derivative has a selective 5-HT 3 receptor agonist activity. Completed the present invention.
  • 5-HT S has a high affinity for receptors, having 5-HT 3 receptor work movement activity It is characterized by the following.
  • H e t a) at least one atom selected from nitrogen, oxygen, and sulfur
  • R a hydrogen atom, a lower alkyl group, a lower alkenyl group, a cycloalkyl group, a halogeno lower alkyl group, an optionally substituted aryl group or an optionally substituted aralkyl group]
  • Preferred compounds according to the present invention include, in the above general formula (I), Het containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, an optionally substituted, 5-membered 2-((imidazolylmethyl) thiazole derivative or salt thereof which is a saturated heterocyclic group.
  • the 5-membered unsaturated heterocyclic group may contain 1 to 4 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and may be substituted.
  • a 2- (imidazolylmethyl) thiazole derivative or a salt thereof More preferably, it is a 2-((imidazolylmethyl) thiazole derivative or a salt thereof, which is an optionally substituted, 5-membered unsaturated heterocyclic group containing one or two selected atoms.
  • an object of the present invention is to provide a 2- (imidazolylmethyl) thiazole derivative represented by the above general formula (I) or a salt thereof.
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising the above-mentioned 2- (imidazolylmethyl) thiazole derivative (I) or a salt thereof, and a pharmaceutically acceptable carrier.
  • the “lower alkyl group” represented by (R) specifically means a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group.
  • lower alkenyl group examples include a vinyl group, an aryl group (a 1 y 1 group), a 1-propenyl group and a 2-butenyl group.
  • cycloalkyl group examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and the like.
  • halogeno lower alkyl group is a lower alkyl group substituted with a halogen atom such as a chloro atom, a bromo atom, a fluorine atom and a chloro atom, and is a chloromethyl group, a bromomethyl group, a trifluoromethyl group, a 2 — Chloroethyl, 3-bromopropyl, 2,2,2-trifluoroethyl, etc.
  • aryl group of the “optionally substituted aryl group” examples include a phenyl group and a naphthyl group.
  • Examples of the aralkyl group in the “optionally substituted aralkyl group” include a benzyl group, a phenethyl group, a diphenylmethyl group, and a naphthylmethyl group.
  • Preferable specific examples of the substituent of the aryl group or the aralkyl group include a lower alkyl group (having 1 to 6 carbon atoms), a halogen atom, a nitro group, a hydroxyl group, an amino group, a mono- or di-lower alkylamino group.
  • a carboxy group a cyano group, a carbamoyl group, a lower alkoxy group, a lower alkoxycarbonyl group, a formyl group and the like.
  • a lower alkyl group, a halogen atom, a nitro group and an amino group are particularly preferred.
  • Preferred specific examples include the following groups.
  • benzofuran ring group and “benzothiophene ring group” include the following groups. No People, Each of the above-mentioned ring groups may have 1 to 3 substituents at any position.
  • the substituent includes a carbon substituent bonded to a carbon atom constituting the ring and a nitrogen substituent bonded to a nitrogen atom.
  • Preferred specific examples of the carbon substituent include a low alkyl group (1 carbon atom).
  • a halogen atom a nitro group, a hydroxyl group, an amino group, a mono- or di-lower alkylamino group, a carboxy group, a cyano group, a carbamoyl group, a lower alkoxy group, a lower alkoxycarbonyl group, and a formyl group.
  • a lower alkyl group, a halogen atom and a nitro group are particularly preferred.
  • the nitrogen substituent examples include a benzenesulfonyl group, a p-toluenesulfonyl group, a benzoyl group, a benzyl group, a trifluoromethyl group, and a lower alkyl group.
  • a benzenesulfonyl group is particularly preferable. preferable.
  • the compound (I) of the present invention forms an acid addition salt.
  • such salts include mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, and fumaric acid.
  • Organic acids such as monocarboxylic acid, maleic acid, lactic acid, lingoic acid, tartaric acid, citric acid, methanesulfonic acid and ethanesulfonic acid, and acid addition salts with acidic amino acids such as aspartic acid and glutamic acid. Are listed.
  • the compound of the present invention has 1 H and 3 H tautomers based on the presence of an imidazole ring. Also, some types of groups may contain asymmetric carbon atoms.
  • the present invention includes isolated isomers of various isomers and mixtures thereof.
  • the present invention also includes hydrates, various solvates and polymorphic substances of the compound (I) of the present invention.
  • the compound of the present invention is not limited to the compounds exemplified above, but includes all of the compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof. .
  • the compound (I) of the present invention and a pharmaceutically acceptable salt thereof can be produced by applying various synthetic methods utilizing characteristics based on the basic skeleton or the type of the substituent.
  • the amino group (including imidazole nitrogen), carboxy group, and hydroxyl group of the compound of the present invention are appropriately protected as necessary, that is, the amino group (imidazole)
  • Examples of such a protecting group include the protecting groups described in Greene and Wuts, 2nd edition of 'Proactive Grupsin Oranic Synthesis', which may be appropriately used depending on the reaction conditions. Can be used.
  • functional groups other than the above-mentioned protecting groups that can be easily converted to amino groups, carboxy groups, and hydroxyl groups can be used in the same manner as the protecting groups.
  • H et ' is the same group as H et which may have a protecting group
  • H et and R have the above-mentioned meaning
  • Z means a halogen atom.
  • the compound (I) of the present invention can be produced by reacting a perhalogenoketone derivative represented by the general formula (I) with an imidazolylthioacetamide represented by the formula (II) or a salt thereof.
  • a perhalogenoketone derivative represented by the general formula (I) with an imidazolylthioacetamide represented by the formula (II) or a salt thereof.
  • examples of the halogen atom represented by Z include an iodine atom, a bromine atom, and a chlorine atom.
  • This reaction is carried out in an alcoholic solvent such as isopropanol, methanol, ethanol, or the like, under heating, preferably under reflux, with the compound of formula (H) and the compound of formula ( ⁇ ) being equimolar or slightly in excess of one. It is desirable.
  • an alcoholic solvent such as isopropanol, methanol, ethanol, or the like
  • the removal of the protecting group depends on the type of the protecting group.
  • the protecting group of the amino group is a substituted or unsubstituted benzyloxycarbonyl group
  • catalytic reduction is preferable.
  • acid treatment with hydrobromic acid Z-acetic acid, hydrobromic acid Z-trifluoroacetic acid, hydrofluoric acid, or the like is used.
  • Other urethane-type protecting groups such as a tert-butoxycarbonyl group are advantageously treated with an acid such as hydrobromic acid / acetic acid, trifluoroacetic acid, hydrochloric acid, hydrochloric acid acetic acid, hydrochloric acid dioxane, or the like.
  • the protecting group of the carboxy group is a methyl group or an ethyl group
  • the benzyl group or various substituted benzyl groups are subjected to catalytic reduction or genogenation, and the tert-butyl group is converted to the same acid as described above.
  • the trimethylsilyl groups are each easily removed by contact with water.
  • Hydroxyl protecting groups can be mostly removed by treatment with sodium liquid ammonia or hydrofluoric acid, or, depending on the type of protecting group (for example, 0-benzyl, 0-benzyloxycarbonyl), catalytic reduction can be applied. Further, when it is an acyl-type protecting group such as a benzoyl group or an acetyl group, it can be removed by hydrolysis in the presence of an acid or alcohol.
  • Z ′ represents a halogen atom, a sulfonate or a quaternary ammonium, and Het ′, Het and R have the above-mentioned meanings.
  • the compound (I) of the present invention or a salt thereof may be a thiazole derivative optionally having a protecting group represented by the general formula (IV) and a imidazole derivative represented by the general formula (V) or a protecting group at the imidazole nitrogen.
  • a protecting group represented by the general formula (IV) and a imidazole derivative represented by the general formula (V) or a protecting group at the imidazole nitrogen By reacting the compound with an imidazole derivative and then removing the protecting group, if desired. The reaction is carried out using a reaction-corresponding amount of the compound (IV) and the compound (V), or one of them as an excess mole, and using dimethylformamide, dimethylsulfoxide, ether, tetrahydrofuran, dioxane, acetone, methylethylketone.
  • reaction-if necessary Methanol, ethanol, methylene chloride, dichloroethane, chloroform, and other solvents inert to the reaction-if necessary, pyridine, picoline, dimethylaniline, N-methylmorpholine-trimethylamine, tridimethylamine, hydrogen It is advantageous to carry out the reaction in the presence of a base such as sodium bromide, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, hydrating power, etc., at a low temperature or under heating, or under heating to reflux.
  • a base such as sodium bromide, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, hydrating power, etc.
  • a non-protonic solvent inert to the reaction such as ether, tetrahydrofuran, dioxane, etc.
  • hexamethylphosphoramide and hexamethylphosphorous triamide Tetramethylethylenediamine, etc.
  • bases such as n-butyllithium, sec-butyllithium, t-butyllithium, lithium diisopropylamide, potassium-t-butoxide, and sodium hydride are required.
  • the compound (V) can be used as an alkali metal salt to react the compound (W) at a low temperature to room temperature such as ⁇ 100.
  • the removal of the protecting group is the same as in the first production method.
  • a trityl group or a benzhydryl group is used as a protecting group for imidazole nitrogen, it can be easily removed by acid or catalytic reduction.
  • the acid hydrochloric acid, sulfuric acid, trifluoroacetic acid or a mixture of these acids and dioxane is used.
  • the catalytic reduction is performed in the presence of a catalyst such as palladium carbon, palladium oxide, palladium hydroxide, platinum, platinum oxide, Raney nickel, etc. Can be.
  • the compound (I) of the present invention contains a nitro group, it can be reduced to produce a compound containing an amino group.
  • a conventional method for reducing an aromatic compound can be applied, particularly an alcoholic solvent such as methanol, ethanol, or isopropanol, or a solvent inert to the reaction such as water or hydrous alcohol.
  • an alcoholic solvent such as methanol, ethanol, or isopropanol
  • a solvent inert such as water or hydrous alcohol.
  • Fourth production method conversion between target compounds ⁇
  • the compound (I) of the present invention can be produced by reacting the compound (la) with the compound (VI), and then optionally removing the protecting group.
  • the reaction is carried out by using the reaction-corresponding amounts of the compound (la) and the compound (VI) or one of them as an excess mole, and using dimethylformamide, dimethylsulfoxide, ether, tetrahydrofuran, dioxane, acetate, methylethylketone, methanol, In a solvent inert to the reaction, such as ethanol, methylene chloride, dichloroethane, and chloroform, if necessary, pyridine, picoline, dimethylaniline, N-methylmorpholine, trimethylamine, triethylamine, sodium hydride, carbonic acid It is advantageous to carry out the reaction in the presence of a base such as lime, sodium carbonate, sodium hydrogencarbonate, sodium hydroxide, or hydration-bearing lime, at a low temperature or under heating, or under heating to reflux.
  • a base such as lime, sodium carbonate, sodium hydrogencarbonate, sodium hydroxide, or hydration-bearing lime, at a
  • the removal of the protecting group can be performed in the same manner as in the first production method.
  • the target compound is obtained as a mixture of the substituents at the 1- and 3-positions of the imidazole ring in this production method
  • the respective substituents may be separated by a conventional purification method such as column chromatography. It is possible.
  • the compound (I) of the present invention thus produced is isolated and purified as a free compound, a salt, a hydrate, a solvate and the like.
  • the pharmaceutically acceptable salt of the compound (I) of the present invention can also be produced by a usual salt-forming reaction.
  • Isolation and purification are performed by applying ordinary chemical operations such as extraction, fractional crystallization, recrystallization, and various types of fractional chromatography.
  • Tautomers can be separated by utilizing the difference in physicochemical properties between isomers.
  • a racemic compound can be obtained by a general racemic resolving method [for example, a method of deriving a diastereomer monosalt with a general optically active acid (tartaric acid, etc.) and performing optical resolution], or by using an appropriate optically active raw material compound Can lead to stereochemically pure isomers.
  • the mixture of diastereomers can be separated by a conventional method, for example, fractional crystallization or chromatography.
  • INDUSTRIAL APPLICABILITY The compounds of the present invention shows a marked effect 5-HT 3 receptor agonistic activity, especially in guinea pig isolated colonic contracting action. The effect is described below together with the measurement method.
  • the distal colon of a Hart1ey male guinea pig (500 to 800 g) was excised and cut into approximately 20 mm sections.
  • the suspension was suspended in the direction of the longitudinal muscle in the Magnus tube, and the contraction response was measured isometrically.
  • 5-HT caused a dose-dependent contractile response at a concentration of 0.1 to 30 // M, and showed a maximum response at a concentration of 10 to 30 mm.
  • 5-action of Itatau is through the 5-Itatau 3 receptors:... J. Ph a rma col Exp Th e r, 259. 1 5 - 2 1, 1 99 1) effects of compounds, in each specimen It is shown as a relative value by comparison with the action of 5- ⁇ .
  • Max.response was expressed as a percentage of the maximum response of the compound when the maximum contractile response due to 5-HT was 100%.
  • Relative potency was a relative value of the EC 60 value of the compound when the EC 50 value of 5-HT was used as a reference (1).
  • the compound of the present invention showed a concentration-dependent guinea pig isolated colonic contractile action at 300 M or less.
  • the compounds of the present invention include those that show an action of 80% or more of the maximum response of 5-HT and those that show a contractile action at a dose of 1 to 2 to 10 to 10 or less of 5-HT.
  • the compounds of the present invention have been shown to be potent 5-HT 3 receptor agonists.
  • V on B ezold- J arisch reflections are an indicator of conventionally 5-HT 3 receptor agonistic activity (S. P aintaleta 1., Phy siol . Rev., 53, 159 (1973)) is a compound with almost no 5-HT 3 receptor agonistic activity.
  • the compound of Example 5 showed a significant stool excretion enhancing effect.
  • the compound (I) of the present invention or a salt, solvate or hydrate thereof can be used as a neuron for enteric nerves.
  • Gastrointestinal disorders by acting specifically on 5-HT 3 receptors, ie senile, flaccid, rectal, constipation, acute / chronic gastritis, stomach / duodenal ulcer, gastric god Gastrointestinal dysfunction, gastrointestinal dysfunction, gastrointestinal dysfunction, gastrointestinal dysfunction, gastrointestinal obstruction, non-ulcer dyspepsia, abdominal indefinite complaints, gastrointestinal dysmotility due to diabetes, stomach dysfunction after anesthesia It is useful for treatment of poor and bloating. It can also be used for the treatment of diseases associated with dysfunction, such as fat malabsorption.
  • the compounds of the present invention are also useful in treating conditions such as neuropathy (eg, schizophrenia and depression), anxiety, memory disorders, dementia, and extrapyramidal disorders.
  • neuropathy eg, schizophrenia and depression
  • anxiety eg, anxiety, memory disorders, dementia, and extrapyramidal disorders.
  • the compounds of the present invention are also useful in treating dysuria associated with urinary tract obstruction, ureteral stones, or prostatic hypertrophy.
  • the compound (I) of the present invention can be prepared from tablets, powders, fine granules and capsules by using a pharmaceutically acceptable carrier, a carrier and other additives which are usually used. Or pills, solutions, injections, suppositories, ointments, patches, etc., and are administered orally (including sublingually) or parenterally.
  • the carrier or excipient for the preparation includes solid or liquid non-toxic pharmaceutical substances. These include, for example, lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, acacia, olive oil, sesame oil, cocoa butter, ethylene glycol and the like and other commonly used ones.
  • the clinical dose of the compound of the present invention is appropriately determined in consideration of the symptoms, body weight, age, sex, etc. of the patient to which the compound is applied, and is usually 1 to 10 mg orally per adult daily. Yes, this is administered once or in several divided doses.
  • the compound of the present invention (100 g), lactose (375 g), and corn starch (80 g) were uniformly mixed using a fluidized-granulation coating device. This was sprayed with 25 g of a 10% hydroxypropyl cellulose solution and granulated. After drying, pass through a 20 mesh sieve, add 19 g of calcium carboxymethylcellulose and 3.5 g of magnesium stearate, mix and use a 7 mm x 8.4 R mortar and punch with a rotary tableting machine. 12 Omg per tablet.
  • the starting compounds of the compound of the present invention also include novel compounds, and production examples of these compounds will be described as reference examples.
  • Raw material compound 4- (2-furyl) -12- (4-imidazolylmethyl) thiazole, p-toluenesulfonic acid 2,2,2-trifluoroethyl ester

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Dérivé de 2-(imidazolylméthyl)thiazole représenté par la formule générale (I), présentant une utilité comme agoniste de récepteur 5-HT3, et composition médicale issue de ce dérivé, dans laquelle Het représente (a) un groupe hétérocyclique insaturé à cinq éléments qui renferme au moins un atome choisi parmi l'azote, l'oxygène et le soufre et qui peut être substituté, ou (b) un groupe liaison benzofurane ou benzothiophène; et R représente l'hydrogène, un alkyle inférieur, un alcényl inférieur, un clycloalkyle, un alkyle inférieur halogéné, un aryle ou un aralkyle à substitution facultative.
PCT/JP1995/000386 1994-03-10 1995-03-09 NOUVEAU DERIVE de 2-(IMIDAZOLYLMETHYL)THIAZOLE ET COMPOSITION MEDICALE ISSUE DE CE DERIVE WO1995024406A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU18623/95A AU1862395A (en) 1994-03-10 1995-03-09 Novel 2-(imidazolylmethyl)thiazole derivative and medicinal comp osition thereof

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP4015894 1994-03-10
JP4014394 1994-03-10
JP6/40158 1994-03-10
JP6/40143 1994-03-10

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WO1995024406A1 true WO1995024406A1 (fr) 1995-09-14

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0749966A1 (fr) * 1994-03-11 1996-12-27 Yamanouchi Pharmaceutical Co. Ltd. Agoniste de recepteur 5-ht 3, nouveau derive de thiazole et intermediaire destine a son obtention
WO2001087878A1 (fr) * 2000-05-18 2001-11-22 Daiichi Pharmaceutical Co., Ltd. Nouveaux dérivés de benzothiophène

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH032180A (ja) * 1989-05-09 1991-01-08 Pfizer Inc ５ｈｔ↓３拮抗剤としてのアリールチアゾリルイミダゾール類

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH032180A (ja) * 1989-05-09 1991-01-08 Pfizer Inc ５ｈｔ↓３拮抗剤としてのアリールチアゾリルイミダゾール類

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0749966A1 (fr) * 1994-03-11 1996-12-27 Yamanouchi Pharmaceutical Co. Ltd. Agoniste de recepteur 5-ht 3, nouveau derive de thiazole et intermediaire destine a son obtention
EP0749966A4 (fr) * 1994-03-11 1997-07-02 Yamanouchi Pharma Co Ltd Agoniste de recepteur 5-ht 3, nouveau derive de thiazole et intermediaire destine a son obtention
US5834499A (en) * 1994-03-11 1998-11-10 Yamanouchi Pharmaceutical Co., Ltd. 5-HT3 receptor agonist, novel thiazole derivative and intermediate thereof
WO2001087878A1 (fr) * 2000-05-18 2001-11-22 Daiichi Pharmaceutical Co., Ltd. Nouveaux dérivés de benzothiophène

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