EP1546111A2 - 2-thiohydantoin-verbindungen und deren verwendung zur behandlung von diabetis - Google Patents

2-thiohydantoin-verbindungen und deren verwendung zur behandlung von diabetis

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Publication number
EP1546111A2
EP1546111A2 EP03772390A EP03772390A EP1546111A2 EP 1546111 A2 EP1546111 A2 EP 1546111A2 EP 03772390 A EP03772390 A EP 03772390A EP 03772390 A EP03772390 A EP 03772390A EP 1546111 A2 EP1546111 A2 EP 1546111A2
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EP
European Patent Office
Prior art keywords
group
phenyl
formula
alkoxy
compounds
Prior art date
Legal status (The legal status 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 status listed.)
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Application number
EP03772390A
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English (en)
French (fr)
Inventor
Jean Binet
Benaissa Boubia
Evelyne Chaput
Alan Edgar
Khan Ou
Philippe Ratel
Soth Samreth
Didier Thomas
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Laboratories Fournier SAS
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Laboratories Fournier SAS
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Priority claimed from FR0212368A external-priority patent/FR2845383B1/fr
Priority claimed from FR0212370A external-priority patent/FR2845385B1/fr
Priority claimed from FR0212369A external-priority patent/FR2845384B1/fr
Application filed by Laboratories Fournier SAS filed Critical Laboratories Fournier SAS
Publication of EP1546111A2 publication Critical patent/EP1546111A2/de
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • A61P3/06—Antihyperlipidemics
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members 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 ring carbon atoms
    • C07D233/86—Oxygen and sulfur atoms, e.g. thiohydantoin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to new compounds derived from 2-tiiiohydantorne (or 2-thioxo-_midazolidin-4-one) 5 their manufacturing process and their use as active ingredients for the preparation of medicaments intended in particular for the treatment of diabetes.
  • Prior art 2-tiiiohydantorne (or 2-thioxo-_midazolidin-4-one) 5 their manufacturing process and their use as active ingredients for the preparation of medicaments intended in particular for the treatment of diabetes.
  • 3244-3254 describes the inhibition of aldose reductases by compounds of the 1- (phenylsulfonyl) -2-thiohydantoin type; Il Farmaco, Ed. Scientifîco, 1983, Vol. 38, n ° 6, p.
  • 383-390 provides 3-dialkylaminopropyl-2-thiohydantoins as antiarrhythmic agents;
  • WO 96/04248 describes amide or sulfonamide derivatives of 2-thiohydantoin Fangiotensin II antagonists;
  • WO 97/19932 claims the use of 2-thiohydantoin derivatives to increase HDL levels;
  • WO 98/33776 cites a "bank” of compounds obtained by combinatorial chemistry and tested for their antimicrobial or analgesic properties;
  • WO 93/18057 and EP 584 694 describe acids or esters comprising a 2-thiohydantoin ring and inhibitors of platelet aggregation;
  • EP 580 459 and WO 97/00071 propose N-phenyl-thiohydantoins having an anti-androgenic activity.
  • the present invention relates to novel compounds comprising in their structure Fhcherrocycle 2-thi ⁇ hydanto ⁇ ne (or 2-thioxo-imidazolidin-4-one) and 'process for their preparation and their use in therapy, in particular for the preparation of a medicament for the treatment of diabetes, diseases due to hyperglycemia, hypertriglyceridaemia, dyslipidaemia or obesity.
  • Fhcherrocycle 2-thi ⁇ hydanto ⁇ ne or 2-thioxo-imidazolidin-4-one
  • new compounds comprising the 2-thioxo-imidazolin-4-one (or 2-tbiohydan toin) ring chosen from: a) the compounds of formula
  • Ri or R 2 each independently represent - a linear, branched or cyclic -Cs alkyl group
  • Ar represents a phenyl or pyridinyl aromatic ring, unsubstituted or substituted by one or more atoms or groups of atoms chosen from halogens, C ⁇ -C alkyl, hydroxy, nitro, C 3 alkoxy, methylenedioxy , SCH 3 , free or esterified carboxylic acid, trifluoromethyl, trifluoromethoxy, cyano, morpholinyl or
  • A represents O, S, CH 2 , OCH 2 or CH 2 O
  • X represents CH or N
  • R 5 represents a hydrogen atom, a halogen atom, an N, N-dialkylamino group, a C 4 -C alkyl group, a C 1 -C 3 alkoxy group > a free or esterified hydroxy group with an amino acid or a carboxyl or alkoxy (C ⁇ -C 4 ) carbonyl group
  • R 3 represents a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C1-C6 alkoxy group, a hydroxy group, a phenyl group, or a benzyl group
  • R represents a hydrogen atom, a halogen atom or a C ⁇ -C 4 alkyl group, with the condition that at least one of the substituents R 1 and R 2 comprises in its structure 2 aromatic rings chosen from phenyl or pyridinyl groups, the dibenzofuranyl group, and b) the addition salts of the compounds of formula (I) with a non-
  • dibenzofuranyl group is considered to comprise two aromatic rings.
  • a family of preferred compounds according to the invention are the compounds of formula (I):
  • - Ar represents a phenyl or pyridinyl aromatic ring, unsubstituted or substituted by one or more atoms or groups of atoms chosen from halogens, C ⁇ -C 4 alkyl, hydroxy, nitro, C] -C 3 alkoxy, methylenedioxy, ester, trifluoromethyl, trifluoromethoxy, cyano, morpholinyl or the group
  • R 5 represents a hydrogen atom, a halogen atom, an N, N-dialkylamino group, a -C 3 ⁇ alkoxy group or a free or esterified hydroxy group with an amino acid,
  • R 3 represents a hydrogen atom, a halogen atom, a C 1 -C alkyl group, a C 1 -C 6 alkoxy group, a hydroxy group, a phenyl group or a benzyl group,
  • R 4 represents a hydrogen atom, a halogen atom or a C ⁇ -C 4 alkyl group, with the condition that at least one of the substituents Rj and R includes in its structure 2 aromatic rings chosen from phenyl or pyridinyl groups , or represents the dibenzofuranyl group; and the addition salts of the compounds of formula (I) with a non-toxic acid when said compounds of formula (I) comprise a basic salifiable function.
  • n 0 or 1
  • Ar represents a phenyl or pyridinyl aromatic ring, unsubstituted or substituted by one or more of the atoms or groups of atoms chosen from: halogens, C ⁇ -C 4 alkyl, nitro, C ⁇ -C 3 alkoxy, alkoxyalkyl C 3 -C, or the group
  • R 5 represents a hydrogen atom, a halogen atom, an N, N-di (C ⁇ -C 3 ) alkylamino group, a C ⁇ -C 3 alkoxy group ; or a free hydroxy group or esterified by an amino acid, •
  • R 2 represents
  • Y represents O or N-CH3
  • Ar represents a phenyl or pyridinyl aromatic ring, unsubstituted or substituted by one or more atoms or groups of atoms chosen from halogens, C 1 -C 4 alkyl, hydroxy, nitro, C ⁇ -C 3 alkoxy groups , methylenedioxy, ester, trifluoromethyl, trifluoromethoxy, cyano, morpholinyl or the group
  • B represents O or S
  • R 3 represents a hydrogen atom, a halogen atom, a - C 4 alkyl group, a C ⁇ -C 4 alkoxy group, a hydroxy group, a phenyl group or a benzyl group,
  • R. represents a hydrogen atom, a halogen atom or a C1-C4 alkyl group, with the condition that at least one of the substituents Ri and R 2 includes in its structure 2 aromatic rings chosen from the groups phenyl or pyridinyl or that Ri represents the dibenzofuranyl group.
  • Another family of preferred compounds according to the invention are the compounds of formula (I):
  • Ar represents a phenyl ring, unsubstituted or substituted by one or more atoms or groups of atoms chosen from halogens, alkyl groups -, nitro, C ⁇ -C 3 alkoxy, methylenedioxy, carboxyl or alkoxy (C ⁇ -C 4 ) carbonyl, or
  • A represents CH 2 O or OCH 2
  • R 5 represents a hydrogen atom, a halogen atom, a C 1 -C 4 alkyl group, a C ⁇ -C 3 alkoxy group , or a carboxyl or alkoxy (C ⁇ -C 4 ) carbonyl group, • R 3 and each independently represent a hydrogen atom or a C 1 -C 4 alkyl group, with the condition that at least one of the substituents R 1 and R 2 comprises in its structure 2 aromatic rings.
  • Ri represents - a C 3 -C 4 alkenyl group, - a group - (CH) n - Ar in which n represents 0 or 1, and
  • Ar represents a phenyl ring, unsubstituted or substituted by one or more atoms or groups of atoms chosen from halogens, C 4 alkyl groups, nitro, C 1 -C 3 alkoxy, carboxyl or alkoxy (C ⁇ - C 4 ) carbonyl, or
  • A represents CH 2 O or OCH 2 .
  • R 5 represents a hydrogen atom, a halogen atom, a C ⁇ -C 4 alkyl group, a C ⁇ -C 3 alkoxy group, or a carboxyl or alkoxy (C ⁇ -C 4 ) carbonyl group
  • R 2 represented a C 1 -C 5 alkyl group, a C 3 -C 4 alkenyl group, a group -Ar, in which
  • Ar represents a phenyl nucleus, unsubstituted or substituted by one or more atoms or groups of atoms chosen from halogen, C 1 -C 4 alkyl, nitro, C ⁇ -C 3 alkoxy, methylenedioxy, carboxyl or alkoxy (C ⁇ -C 4 ) carbonyl, or
  • B represents CH 2 O, or OCH 2 ;
  • R 3 and R 4 each independently represent a hydrogen atom or a C 1 -C 4 alkyl group, with the condition that at least one of the substituents Ri and R 2 comprises in its structure 2 aromatic rings.
  • Another family of preferred compounds according to the invention are the compounds of formula I:
  • Ri and R 2 independently of each other, represent - a C 1 -C 5 alkyl group
  • a C 2 -C 3 hydroxyalkyl group or one of its precursors, such as the (tetrahydro-2H-pyran-2-yl) oxy (C 2 -C 3 ) alkyl group,
  • a C 3 -C 5 alkoxyalkyl group a (CH 2 ) P -Ar group, in which p represents 0 or 1, and Ar represents a phenyl or pyridinyl aromatic ring, unsubstituted or substituted by one or more atoms or groups of atoms chosen from halogens, hydroxy, nitro, cyano, C ⁇ -C 3 alkoxy, carboxyl, alkoxy ( C ⁇ -C 4 ) carbonyl, methylthio, methylenedioxy or
  • X represents CH or N
  • R 3 and R 4 represent, each independently, a hydrogen atom or a C ⁇ alkyl group -C > with the condition that at least one of the substituents Ri and R includes in its structure 2 aromatic rings chosen from phenyl or pyridinyl groups.
  • Ri represents - a C 3 -C alkenyl group, - a group (CH 2 ) n -Ar in which n represents 0 or 1
  • n represents 0 or 1
  • Ar represents a phenyl aromatic ring, unsubstituted or substituted by one or more atoms or groups of atoms chosen from halogens, C-alkoxy groups, nitro, or the group in which
  • X represents CH or N
  • R 5 represents a hydrogen atom, a halogen atom, a C ⁇ -C 3 alkoxy group ; or a hydroxy group,
  • a C 2 -C 3 hydroxyalkyl group or one of its precursors, such as the (tetrahydro-2H-pyran-2-yl) oxy (C 2 -C 3 ) alkyl group,
  • Ar represents a phenyl or pyridinyl aromatic ring, unsubstituted or substituted by one or more atoms or groups of atoms chosen from halogens, hydroxy, nitro, cyano, C ⁇ -C 3 alkoxy, carboxyl, alkoxy ( C ⁇ -C 4 ) carbonyl, methylthio, methylenedioxy or
  • R 3 and t represent, each independently, a hydrogen atom or a C ⁇ -C 4 alkyl group ; with the condition that at least one of the substituents Ri and R 2 comprises in its structure 2 aromatic rings chosen from the phenyl or pyridinyl groups.
  • Particularly preferred compounds according to the invention are the compounds of formula (I) in which one of the radicals R 1 or R 2 represents the phenoxyphenyl, phenylthiophenyl, (phenylmethoxy) phenyl or
  • R 3 represents a methyl group and R 4 represents a hydrogen atom or a methyl group.
  • the invention also includes, when the substituents R 3 and are different, the compounds of configuration R, the compounds of configuration S and their mixtures.
  • the invention also includes the salts of the compounds of formula (I) when these include in their structure a basic salifiable function, such as for example an amino function, a pyridine group or a morpholine group.
  • a basic salifiable function such as for example an amino function, a pyridine group or a morpholine group.
  • These salts can be obtained with non-toxic mineral or organic acids which are acceptable in therapy, in particular hydrochloric, sulfuric, phosphoric, methanesulfonic, citric, maleic, fumaric, oxalic and trifluoroacetic acids.
  • the invention also relates to the compounds of formula (I) for their use as a pharmacologically active substance.
  • the invention relates to the use of at least one compound according to formula (I) above as an active principle for the preparation of a medicament intended for use in therapy, in particular for combating diseases due to hyperglycemia, diabetes, hypertriglyceridemia, dyslipidemia or obesity.
  • C 1 -C 4 alkyl group is understood to mean a hydrocarbon chain having from 1 to 4 carbon atoms, linear or branched, or alternatively cyclic.
  • Examples of C ⁇ -C 4 alkyl groups include methyl, ethyl, propyl, butyl, 1-methylethyl, 1-methylpropyl, 2-methylpropyl and 1,1-dimethylethyl groups.
  • C 1 -C 5 alkyl group is intended to mean a hydrocarbon chain having from 1 to 5 carbon atoms, linear or branched, or alternatively cyclic.
  • C 1 -C 5 alkyl groups include the groups mentioned above as well as the pentyl, isopentyl and cyclopentyl groups.
  • the substituent may be in the ortho, meta or para position, the para position being preferred.
  • linear or branched -C 3 alkoxy group is meant the methoxy, ethoxy, propoxy and 1-methylethoxy groups.
  • Halogen atom includes fluorine, chlorine, bromine and iodine atoms, fluorine and chlorine atoms being preferred.
  • N-di (C ⁇ -C 3 ) alkylamino denotes in particular the groups dimethylamino, diethyla ino, dipropylamino and diisopropylamino.
  • N-di (C ⁇ -C 3 ) alkylamino (C ⁇ -C 3 ) alkyl denotes in particular the dimethylaminoethyl, diethylaminoethyl and dimethylaminopropyl groups.
  • C 3 -C alkenyl group is meant a hydrocarbon chain comprising 3 or 4 carbon atoms comprising in its structure an ethylenic bond between 2 carbons.
  • C 3 -C 4 alkoxyalkyl group is meant a hydrocarbon chain having 3 or 4 carbon atoms interrupted by an oxygen atom, in particular the methoxyethyl and ethoxyethyl groups.
  • precursor group of a hydroxyalkyl group means a group capable of easily generating the hydroxyalkyl group either by means of a conventional chemical reaction (for example hydrolysis) or a biological reaction (for example enzymatic hydrolysis).
  • a conventional chemical reaction for example hydrolysis
  • a biological reaction for example enzymatic hydrolysis
  • An example of such a precursor group is a hydroxyalkyl group protected by a tetrahy dro-2H-pyran-2-yl group, which can be hydrolyzed in an acid medium to yield the corresponding hydroxylated derivative.
  • the compounds of formula (I) can be prepared according to a first general process A comprising the steps consisting in:
  • R 3 represents H, C 1 -C 4 alkyl, phenyl or benzyl and * represents H or alkyl, with an isothiocyanate of formula
  • R _ ⁇ N c s (l ⁇ ) in which R 2 represents a group as defined above for the compounds of formula (I), in a solvent such as for example ethanol, at a temperature between 20 ° C and the boiling point of the solvent, in presence of an aprotic base such as for example triethylamine and for 1 to 20 hours, to obtain the compound of formula (I)
  • Ri, R 3 and R 4 are as defined in process A and R represents a C ⁇ -C 4 alkyl group, preferably a methyl, ethyl or isopropyl group, which is reacted with an isothiocyanate of formula ( III)
  • the compounds of formula (I) in which R 3 represents a halogen atom, in particular the fluorine atom can be obtained from compounds of formula (I) in which R 3 is a hydrogen atom by successive action d a halogenating agent, such as N-bromosuccinimide, water (which makes it possible to obtain the compound of formula (I) in which R 3 represents a hydroxy group) then a halogenating agent, such as N, N-sulfur diethylamino-trifluoride which leads to the compound of formula (I) in which R 3 represents a fluorine atom.
  • a halogenating agent such as N-bromosuccinimide, water
  • the compounds of formula (I) in which R 3 represents a C ⁇ -C 4 alkoxy group can be obtained from the compounds of formula (I) in which R 3 is a hydrogen atom, by the action of a halogenating agent , such as N-bromo succinimide, then action of an aliphatic alcohol in C ⁇ -C 4 .
  • a halogenating agent such as N-bromo succinimide
  • the compounds of formula (II) are generally known products or can be prepared according to methods known to those skilled in the art, for example by reaction of an aliphatic or aromatic primary amine of formula
  • Hal represents a halogen atom, and R 3 and are as defined above, preferably in the absence of solvent, in the presence of a weak base such as for example sodium bicarbonate and at a temperature between 60 and 150 ° C, for 0.5 to 10 hours.
  • a weak base such as for example sodium bicarbonate
  • an ⁇ -brominated acid is used.
  • the compounds of formula (IN) are generally known products or can be prepared according to methods known to those skilled in the art, for example by reaction of an aliphatic or aromatic primary amine of formula
  • Hal represents a halogen atom
  • R 3 and * are as defined above and R represents an alkyl group, in particular methyl or ethyl, preferably in the absence of solvent, in the presence of a weak base such as for example sodium bicarbonate or a tertiary amine, and at a temperature between 60 and 150 ° C, for 0.5 to 10 hours.
  • a weak base such as for example sodium bicarbonate or a tertiary amine
  • an ⁇ -brominated ester is used.
  • the compounds of formula (III) are generally known products or can be prepared according to methods known to those skilled in the art, for example by reaction of an aliphatic or aromatic primary amine of formula R 2 - NH 2 with the thiophosgene in presence of a tertiary amine or with 1,1 '- thiocarbonyldiimidazole.
  • the following examples of preparation of compounds according to formula (I) will make it possible to better understand the invention.
  • “preparation” designates the examples describing the synthesis of intermediate compounds and “examples” those describing the synthesis of compounds of formula (I) according to the invention.
  • the melting points are measured on a Kofler bench and the spectral values of Nuclear Magnetic Resonance are characterized by the chemical shift calculated with respect to the TMS, by the number of protons associated with the signal and by the shape of the signal (s for singlet, d for doublet, t for triplet, q for quadruplet, m for multiplet).
  • the working frequency and the solvent used are indicated for each compound. If the compounds include an asymmetric carbon, the absence of any particular indication means that the compound is in its racemic form, and the presence of the sign of chirality (R or S) means that the compound is in its chiral form.
  • a mixture of 2.17 g (7.3 mmol) of 4-phenoxy-iodobenzene, 1.02 g (6.2 mmol) of phenylalanine, 0.48 g of bis (tri-o-tolyl palladium dichloride) is prepared. ), 125 mg of copper iodide, 240 mg of benzyltriethylammomum chloride and 876 mg of potassium carbonate in 12 ml of dimethylformamide, 1.2 ml of water and 2.4 ml of triethylamine. This reaction medium is kept stirring at 100 ° C for 24 h and then cooled. 50 ml of toluene are added and concentrated under reduced pressure.
  • a solution of 0.8 g (3.64 mmol) of 4- (3-chlorophenoxy) aniline in 10 ml of dimethoxyethane is prepared and oh 0.328 ml (3.64 mmol) of 2-bromopropanoic acid and 0.5 are added. ml of triethylamine.
  • the reaction medium is kept stirring for 24 h at 50 ° C then cooled and poured into 50 ml of water.
  • the mixture is brought to basic pH by addition of a sodium hydroxide solution and extracted with 50 ml of ethyl acetate.
  • the aqueous phase is then acidified with a hydrochloric acid solution to pH 4 and extracted with 2 times 70 ml of ethyl ether.
  • Acid 1 [(4-phenoxyphenyl) amino] cyclopropanecarboxylic acid, ethyl ester a)
  • a suspension of 6.15 g of 1-aminocyclopropane carboxylic acid in 100 ml of ethanol is prepared and 6.5 ml of chlorine chloride are added slowly thionyl.
  • the reaction mixture is heated at gentle reflux for 8 hours then concentrated under reduced pressure, adding toluene to remove the ethanol. 10 g of the hydrochloride of the ethyl ester of the starting acid are thus obtained.
  • a solution of 15 g (63.6 mmol) of 4- (phenylmethoxy) aniline hydrochloride in 200 ml of dimethylformamide is prepared and 13.8 g (76.4 mmol) of ethyl 2-bromopropanoate are added, followed by 8 , 9 ml (63.6 mmol) of triethylamine.
  • the reaction mixture is stirred for 24 h at 100 ° C, then cooled and poured into 200 ml of ice water.
  • the mixture is extracted with 2 times 200 ml of ethyl acetate and the combined organic phases are washed with water then dried over sodium sulfate and concentrated under reduced pressure.
  • EXAMPLE 1 5-methyl-1- (4-phenoxyphenyl) -3-phenyl-2-thioxo-4-imidazolidinone A mixture of 175 g (0.68 mole) of the compound obtained according to the preceding step and 104 ml is prepared. of triethylamine in 21 of ethanol. The solution obtained is filtered through sintered glass and 89.5 ml (0.75 mole) of phenyl isothiocyanate are added. The reaction mixture is stirred at room temperature for 18 hours. The white precipitate formed is separated by filtration and then taken up in solution in a dichloromethane / ethanol mixture. The solution is treated with activated carbon, filtered and partially reconcentrated in an evaporator under reduced pressure.
  • a solution of 50 mg of the racemic compound obtained according to Example 1 is prepared in 1 ml of a hexane / dichloromethane mixture. This solution is injected into a high pressure preparative chromatography device equipped with a 250 ⁇ 20 mm column, CHIRALPACK AD 10 ⁇ (supplied by DAICEL).
  • the eluent is a 75/25 hexane / isopropanol mixture, with a flow rate of 10 ml / min.
  • the configuration compound (S) has a retention time of the order of 21 to 26 min and the configuration compound (R) has a retention time of approximately 32 to 37 min.
  • the separate compounds, recovered in solution after chromatography, are obtained by evaporation of the solvent at low temperature.
  • the proof of the configuration of the two enantiomers was established by unequivocal synthesis, starting from (R) alanine and (S) alanine.
  • Example 4 5-methyl-1, 3-bis (4- ⁇ henoxyphenyl) -2-thioxo-4-imidazolidinone
  • a solution of 1.5 g (4.21 mmol) of the compound obtained according to Example 24 is prepared in 75 ml of dichloromethane.
  • the mixture is cooled to -70 ° C and 16.8 ml (16.8 mmol) of a normal solution of boron tribromide in dichloromethane are added.
  • the reaction medium is stirred at -70 ° C for 15 min then at 0 ° C for 2 h, and then poured into 500 ml of water.
  • the mixture obtained is extracted by
  • a solution of 0.27 g (0.656 mmol) of the compound obtained according to Example 26a is prepared in 20 ml of diethyl ether and 2 ml of ethanol and 0.7 ml of a normal solution of hydrogen chloride in ethyl ether. A white precipitate is formed. 25 ml of ethyl ether are added, then the precipitate is isolated by filtration. The solid is washed on the filter with 2 times 5 ml of ethyl ether and then dried.
  • Example 31 (4-phenoxyphenyl) -3-phenyl-2-thioxo-4-imidazolidinone
  • Example 36 1 - [4- (4-fluorophenoxy) phenyl] -3- (4-hydroxyphenyl) -5-methyl-2-thioxo-4-imidazolidinone
  • Example 40a 1- [4- [3- (dimethylamino) phenoxy] phenyl] -5-methyl-3-phenyl-2-thioxo-4-imidazolidinone
  • Table III shows the compounds described in Examples 138 to 148:
  • N- (alkyl) glycine in 25 ml of toluene and 0.5 g (2.2 mmol) of isothiocyanate obtained according to preparation XXXIII, and 2.2 ml of acetic acid are added.
  • the reaction mixture is heated with stirring at slight reflux of the solvent for
  • Example 196 1 - [4- (phenylmethyl) phenyl] -3- (2-propenyl) -2-thioxo-4-imidazolidinone
  • F 162 ° C
  • Example 197
  • Example 198 1- (4-chlorophenyl) -3- [4- (phenylmethyl) phenyl] -2-thioxo-4-imidazolidinone
  • Table VI brings together other compounds according to the invention, obtained by preparation methods analogous to those described for, Examples 185 to 201; in this table are indicated the melting points (F ° C), the yields of the preparation as well as the synthesis method used (A by analogy with the example
  • Example 235 this compound is obtained according to a process analogous to that of Example 229, from 2 - [(tetrahydro-2H-pyran-2-yl) oxy] ethanamine.
  • Example 208 1H NMR: (CDC1 3 , 300 MHz): 0.97 (t, 3H); 1.40 (m, 5H); 1.71 (m, 2H); 3.89 (t, 2H); 4.02 (s, 2H); 4.40 (q, 1H); 7.25 (m, 9H).
  • the compounds of formula (I) according to the invention have been subjected to pharmacological tests in order to evaluate their potential to decrease the level of glycemia in the blood.
  • the animals are housed in cages with a filter cover and have free access to standard i ⁇ adiated food as well as filtered drinking water. All the equipment used (cages, bottles, pipettes and shavings) is sterilized by autoclaving, irradiation or soaking in a disinfectant. The room temperature is maintained at 23 ⁇ 2 ° C. The light and dark cycle is 12 hrs.
  • each animal is marked using an electronic chip, the implantation of which is carried out under anesthesia by inhalation of a CO 2 / O mixture.
  • Groups of 8 to 10 mice are formed and treatments begin when the animals are 9 to 11 weeks old.
  • the products are suspended in 3% gum arabic and administered to the animals using a gavage cannula, for 10 days at the rate of two administrations per day, as well as in the morning of the eleventh day.
  • the products are tested at doses below 200 mg / kg, generally 10 mg / kg.
  • the animals in the control group receive the administration vehicle only.
  • a blood sample is taken before treatment, then four hours after the last administration of the product.
  • the animals are anesthetized by inhalation of a CO 2 / O 2 mixture, the blood is taken from the retroorbital sinus, collected in a dry tube and kept cold.
  • the serum is separated by centrifugation at 2800 g (15 minutes, 4 ° C) within one hour of collection.
  • the samples are stored at -20 ° C until analysis.
  • the serum glucose and triglyceride levels are determined on a Konélab 30 analyzer, using Konélab kits. Animals with a pre-treatment blood glucose lower than 3 g / 1 are systematically excluded from the study.
  • the average glucose and triglyceride levels after treatment are calculated and the results are expressed as a percentage change in these means compared to the control group, after checking the homogeneity of the means before treatment.
  • the compounds according to the invention can be used as active principle of a medicament intended for the treatment of diabetes in mammals and, more particularly, in humans. They can be used to combat hypertriglyceridemia and diseases caused by an excess of triglycerides in the blood, such as for example atherosclerosis.
  • they can be useful for the prevention or treatment of diseases associated with hyperglycemia or hypertriglyceridemia such as for example type II diabetes, hypertension, dyslipidemia, cardiovascular disease, and obesity; they are also useful for the treatment of diseases due to microvascular or macrovascular complications in diabetics, in particular in the renal or central nervous system, said complications being generally associated with metabolic syndrome X.
  • the compounds according to the invention are also useful for treating cerebral ischemia or stroke.
  • compositions incorporating the compounds according to the invention can be formulated in particular by association of these compounds with usual non-toxic excipients according to methods well known to those skilled in the art, preferably so as to obtain medicaments which can be administered orally, for example capsules or tablets.
  • the daily dosage in humans will preferably be between 5 and 500 mg.
  • formulations in the form of capsules or tablets are preferred for reasons of patient comfort, the compounds according to the invention can also be prescribed in other galenical forms, for example if the patient does not accept or n is unable to accept solid oral formulations or if the treatment requires very rapid bioavailability of the active ingredient.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Diabetes (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Endocrinology (AREA)
  • Emergency Medicine (AREA)
  • Child & Adolescent Psychology (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
EP03772390A 2002-10-04 2003-10-03 2-thiohydantoin-verbindungen und deren verwendung zur behandlung von diabetis Withdrawn EP1546111A2 (de)

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
FR0212368 2002-10-01
FR0212368A FR2845383B1 (fr) 2002-10-04 2002-10-04 Composes derives de la 2-thiohydantoine et leur utilisation en therapeutique
FR0212370A FR2845385B1 (fr) 2002-10-04 2002-10-04 Composes derives de la 2-thiohydantoine et leur utilisation en therapeutique
FR0212369 2002-10-04
FR0212370 2002-10-04
FR0212369A FR2845384B1 (fr) 2002-10-04 2002-10-04 Composes derives de la 2-thiohydantoine et leur utilisation en therapeutique
PCT/FR2003/002904 WO2004031160A2 (fr) 2002-10-04 2003-10-03 Composes derives de la 2-thiohydantoïne et leur utilisation pour le traitement du diabete

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DE10322108B4 (de) * 2003-05-09 2008-12-11 Bayer Schering Pharma Aktiengesellschaft Antiandrogene Pyrrolidine mit tumorhemmender Wirksamkeit
DE602004031881D1 (de) 2003-12-19 2011-04-28 Univ California Verfahren und materialien zur beurteilung von prostatakrebstherapien
AU2005232526B2 (en) 2004-02-24 2011-06-23 The Regents Of The University Of California Methods and materials for assessing prostate cancer therapies and compounds
TW200621723A (en) 2004-09-09 2006-07-01 Chugai Pharmaceutical Co Ltd Novel imidazolidine derivative and use thereof
US7709517B2 (en) 2005-05-13 2010-05-04 The Regents Of The University Of California Diarylhydantoin compounds
SI1893196T2 (sl) 2005-05-13 2015-10-30 The Regents Of The University Of California Diarilhidantoinska spojina
DK2004181T6 (da) * 2006-03-27 2023-08-21 Univ California Androgen receptormodulator til behandling af prostatacancer og androgen receptor-associerede sygdomme
JP5350217B2 (ja) 2006-03-29 2013-11-27 ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア ジアリールチオヒダントイン化合物
TW200831080A (en) 2006-12-15 2008-08-01 Irm Llc Compounds and compositions as inhibitors of cannabinoid receptor 1 activity
EP2620432A3 (de) 2007-10-26 2013-12-18 The Regents Of the University of California Diarylhydantoinverbindungen
WO2009097998A1 (de) * 2008-02-07 2009-08-13 Sanofi-Aventis Arylchalcogeno-arylalkyl-substituierte imidazolidin-2,4-dione, verfahren zu ihrer herstellung, diese verbindungen enthaltende arzneimittel und ihre verwendung
CN101817787B (zh) * 2009-02-26 2013-07-24 童友之 抗前列腺癌的雄性激素受体拮抗剂
WO2010118354A1 (en) * 2009-04-09 2010-10-14 Medivation Prostate Therapeutics, Inc. Substituted di-arylhydantoin and di-arylthiohydantoin compounds and methods for use thereof
WO2011029392A1 (en) * 2009-09-10 2011-03-17 Youzhi Tong Androgen receptor antagonists and uses thereof
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EP2654440B1 (de) * 2010-12-23 2014-10-29 DuPont Nutrition Biosciences ApS Mikrobizide zusammensetzung
JP5833681B2 (ja) 2011-03-10 2015-12-16 蘇州開拓薬業有限公司Ｓｕｚｈｏｕｋｉｎｔｏｒ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ， Ｉｎｃ． アンドロゲン受容体アンタゴニストおよびその使用
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WO2004031160A2 (fr) 2004-04-15
US20060025589A1 (en) 2006-02-02
CA2500977A1 (en) 2004-04-15
WO2004031160A3 (fr) 2004-05-27
AU2003279442A8 (en) 2004-04-23
AU2003279442A1 (en) 2004-04-23

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