Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
  • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4164—1,3-Diazoles
  • A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/08—Drugs for disorders of the urinary system of the prostate
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/10—Anti-acne agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • 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
  • C07D233/72—Two oxygen atoms, e.g. hydantoin
  • C07D233/76—Two oxygen atoms, e.g. hydantoin with substituted hydrocarbon radicals attached to the third ring carbon atom

Definitions

• the present invention relates to new fluorinated or hydroxylated phenylimidazolidines, their preparation process, the new intermediates obtained, their application as medicaments, their new use and the pharmaceutical compositions containing them.
• R- j _ and R 2> identical or different, are chosen from cyano, nitro, trifluoromethyl and halogen atoms
• R 3 represents an aryl, arylalkyl, alkyl, alkenyl or alkynyl radical, linear or branched, containing plus 10 carbon atoms and optionally substituted by one or more radicals chosen from halogen atoms and cyano, hydroxyl, alkoxy, carboxy, acyl and acyloxy radicals, in which, where appropriate, the alkyl, alkoxy and acyl radicals are linear or branched, containing at most 10 carbon atoms, the carboxy radical is free, salified, esterified or amidified and the hydroxy radical is free, esterified, etherified or protected
• R 4 and R 5 identical or different, represent a alkyl radical, linear or branched, containing at most 4 carbon atoms and optionally substituted by a halogen atom, or form with the carbon atom
• halogen designates fluorine, chlorine, bromine or iodine atoms. We prefer fluorine, chlorine or bromine atoms.
• linear or branched alkyl radical designates the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl and also heptyl, octyl, nonyl and decyl radicals as their linear or branched position isomers,
• alkyl radicals having at most 6 carbon atoms and in particular methyl, ethyl, propyl, isopropyl, n-butyl, n-pentyl and n-hexyl radicals,
• linear or branched alkenyl radical designates the vinyl, allyl, 1-propenyl, butenyl, 1-butenyl, pentenyl or hexenyl radicals as well as their linear or branched position isomers.
• alkenyl radicals the vinyl, allyl, n-butenyl or isobutenyl values are preferred, - the term alkynyl denotes a linear or branched radical having at most 12 carbon atoms such as, for example, ethyl, propargyl, butynyl, pentynyl or hexynyl.
• alkynyl radicals those with 4 carbon atoms are preferred, and in particular the propargyl radical.
• linear or branched alkoxy radical designates the methoxy, ethoxy, propoxy, isopropoxy, linear, secondary or tertiary butoxy, pentoxy or hexoxy radicals as well as their linear or branched position isomers, -
• cyclic radical consisting of 3 to 7 members and possibly containing one or more identical or different heteroatoms, chosen from oxygen, sulfur or nitrogen atoms designates on the one hand a cycloalkyl radical which designates itself- even in particular the cyclobutyl, cyclopentyl and cyclohexyl radicals and, on the other hand, a carbon cyclic radical interrupted by one or more heteroatoms chosen from oxygen, nitrogen or sulfur atoms such as very particularly the heterocyclic monocyclic radicals saturated such as for example the oxetannyl, oxolannyl, dioxany
• acyl radical preferably designates the formyl, acetyl, propionyl, butyryl and benzoyl radicals, but also the valeryl, hexanoyl, acryloyl, crotalkyl and carbamoyl radicals,
• acyloxy radical denotes the radicals in which the acyl radicals have the meaning indicated above and for example the acetoxy or propionyloxy radicals,
• aryl designates carbocyclic aryl radicals such as phenyl or naphthyl and heterocyclic aryl monocyclic with 5 or 6 members or consisting of condensed rings, comprising one or more heteroatoms preferably chosen from oxygen, sulfur and nitrogen.
• 5-membered heterocyclic aryls mention may be made of the furyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, thiadiazolyl, pyrazolyl, isoxazolyl and tetrazolyl radiocals.
• 6-membered heterocyclic aryls mention may be made of the pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl radicals.
• Phenyl, tetrazolyl and pyri ⁇ dyl radicals are preferred.
• arylalkyl designates the radicals resulting from the combination of the alkyl radicals and the aryl radicals mentioned above.
• alkyl radicals substituted by one or more halogens we. may cite the monofluoro-, chloro- or bromo-methyl, difluoro-, dichloro- or dibromo-methyl and trifluoromethyl radio ⁇ cals.
• the carboxy radical (s) of the products of formula (I) can be free, salified, esterified or amidified by various groups known to those skilled in the art.
• carboxy radicals salified with mineral bases such as, for example, an equivalent of sodium, potassium, lithium, calcium, magnesium or ammonium or organic bases such as, for example, methylamine, propylamine, t ⁇ methylamine, diethylamine, triethylamine, N, N-dimethylethanolamine, tris (hydroxy-methyl) amino methane, 1 ethanolamine, pyridine, picico, dicyclohexylamine, morpholine, benzylamine, procaine, lysine, arginine, histidine, N-methyl-glucamine.
• mineral bases such as, for example, an equivalent of sodium, potassium, lithium, calcium, magnesium or ammonium or organic bases such as, for example, methylamine, propylamine, t ⁇ methylamine, diethylamine, triethylamine, N, N-dimethylethanolamine, tris (hydroxy-methyl) amino methane, 1 ethanolamine, pyridine, picico, dicyclohexylamine,
• Sodium or potassium salts are preferred.
• alkyl radicals esterified by the alkyl radicals to form alkoxy carbonyl groups such as, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxy-, isobutoxy- and tert-butoxy-carbonyl or benzyloxycarbonyl
• these alkyl radicals possibly being substituted by radicals chosen, for example, from halogen atoms, hydroxyl, alkoxy, acyl, acyloxy, alkylthio, amino or aryl radicals, such as, for example, in chloromethyl, hydroxypropyl, methoxymethyl, propionyloxymethyl, methylthiomethyl, dimethylaminoethyl groups , benzyl or phenethyl.
• radicals formed with easily cleavable ester residues such as the methoxymethyl and ethoxymethyl radicals; acyloxyalkyl radicals such as pivaloyloxymethyl, pivaloyloxyethyl, acetoxy- methyl or acetoxyethyl; alkylalkylcarbonyloxyalkyl radicals such as methoxycarbonyloxy methyl or ethyl radicals, isopropyloxycarbonyloxy methyl or ethyl radicals.
• ester radicals can be found, for example, in European patent EP 0 034 536.
• Amidified carboxy means groups of the type -CON (Rg) (R 7 ) in which the radicals Rg and R 7, which are identical or different, represent a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl radicals.
• radical -N (Rg) (R 7 ) represents the amino, mono or dimethylamino radical are preferred.
• the radical N (Rg) (R 7 ) can also represent a heterocycle which may or may not include an additional heteroatom. Mention may be made of the pyrrolyl, imidazolyl, indolyl, piperidino, morpholino, piperazinyl radicals. The piperidino or morpholino radicals are preferred.
• esterified, etherified or protected hydroxyl radical means the radicals -0-C- ⁇ lr ⁇ ⁇ -Oo ⁇ or -OP respectively,
• O formed from a hydroxyl radical -OH, according to the usual methods known to those skilled in the art and in which P represents a protective group, a- ⁇ , # 2 and ⁇ 3 represent in particular an alkyl, alkaline radical - nyl, alkynyl, aryl or arylalkyl, having at most 12 carbon atoms and optionally substituted as defined above in particular for R 3 .
• protective group P as well as the formation of the protected hydroxyl radical, are given in particular in the usual book of those skilled in the art: Protective Groups in Organic Synthesis, Theodora W. Greene, Harvard University, printed in 1981 by Wiley- Interscience Publishers, John Wiley Se Sons.
• the hydroxyl radical protection group which P can represent can be chosen from the list below: for example formyl, acetyl, chloroacetyl, bromoacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, metho-xyacetyl, phenoxyacetyl, benzoyl, b.enzoylformyl, p-nitro-benzoyl.
• the addition salts with mineral or organic acids of the products of formula (I) can be, for example, the salts formed with hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, propionic, acetic, formic acids, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, ascorbic, alkylmonosulfonic acids such as for example methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, such as alkoyldisulfonic acids for example methanedisulfonic acid, alpha, beta-ethanedisulfonic acid, arylmonosulfonic acids such as benzenesulfonic acid and aryldisulfonic acids.
• stereoisomerism can be defined as the isomery of compounds having the same developed formulas, but the different groups of which are arranged differently in space, such as in particular in the boat and chair forms of cyclohexane and of monosubstituted cyclohexanes, the substituent of which may be in the axial or equatorial position, and the various possible rotational conformations of the ethane derivatives.
• stereoisomerism due to the different spatial arrangements of fixed substituents, either on double bonds or on rings, which is often called geometric isomery or cis-trans isomery.
• the term stereoisomers is used in the present application in its broadest sense and therefore relates to all of the compounds indicated above.
• the hydrogen atoms which contain the optionally substituted alkyl or alkenyl radicals which may represent R 3 , can be deuterium atoms,
• the fluorine atoms which can represent the halogen atoms, can be a 1 fiF atom useful for medical imaging.
• a subject of the present invention is thus the products of formula (I) as defined above, in which: R- ⁇ and R 2 both represent a chlorine atom, or else identical or different are chosen from cyano radicals, nitro and trifluoromethyl, R 3 represents a phenyl, pyridyl, phenylalkyl, pyridylalkyl, alkyl, alkenyl or alkynyl radical, linear or branched, containing at most 4 carbon atoms and optionally substituted by one or more radicals chosen from atoms halogen and the cyano, hydroxyl, alkoxy, acyl and acyloxy radicals, in which where appropriate, the acyl and alkoxy radicals are linear or branched, containing at most 6 carbon atoms and the hydroxyl radical is free, esterified or protected, R 4 and R 5 , identical or different, represent a radical methyl optionally substituted by a halogen atom, or form, with the carbon atom
• W represents an oxygen or sulfur atom or the radical -NH
• X and Y identical or different, represent an oxygen or sulfur atom, said products of formula (I) being in all the racemic isomeric, enantiomeric and diastereoisomeric forms possible, as well as the addition salts with acids mineral and organic or with the mineral and organic bases of said products of formula (I).
• the radical represents in particular the radical
• R 1 j and R 2 represent a cyano radical and a trifluoromethyl radical
• R 3 represents an alkyl, alkenyl or alkynyl radical, linear or branched, containing at most 4 carbon atoms and optionally substituted by one or more radicals chosen from halogen atoms, the cyano radical and the free, esterified or protected hydroxyl radical ,
• R 4 and R 5 identical or different, represent a methyl radical optionally substituted by a fluorine atom, or form with the carbon atom to which they are attached a cyclohexyl radical
• X and Y represent an oxygen atom, said products of formula (I) being in all the racemic isomeric, enantiomeric and diastereoisomeric forms possible, as well as the addition moieties with mineral and organic acids or with mineral bases and organic of said products of formula (I).
• the present invention also relates to a process for preparing the products of formula (I), as defined above, characterized in that a product of formula (II) is made to act in the presence of a tertiary base:
• the operation is carried out in the presence of a tertiary base such as triethylamine or else pyridine or methylethylpyridine.
• a tertiary base such as triethylamine or else pyridine or methylethylpyridine.
• the possible reactive functions which are optionally protected can in particular be the hydroxy or amino functions.
• usual protective groups are used. Mention may be made, for example, of the following protecting groups for the amino radical: tert-butyl, tert-amyl, trichloroacetyl, chloroacetyl, benzhydryl, trityl, formyl, benzyloxycarbonyl, terbutyloxy- carbonyl.
• protecting group for the hydroxy radical mention may, for example, be made of tetrahydropyrannyl, trime ⁇ thylsilyl, triphenylmethyl or tert-butyl dimethylsilyl radicals. It is understood that the above list is not exhaustive and that other protective groups, for example known in the chemistry of peptides can be used. A list of such protective groups can be found, for example, in French patent BF 2,499,995, the content of which is incorporated here by reference.
• R 4 and R 5 can form a cyclic radical with the carbon atom which carries them such as in particular a cyclohexyl radical.
• R 4 and Rc can or can carry a hydroxyl radical which can be protected in particular in -O-tetrahydropyrannyle (OTHP).
• reaction of the product of formula (II) as defined above with a product of formula (III) as defined above to give the corresponding product of formula (IV) can then be carried out in particular in the presence of chloride of methylene at a temperature of about -30 ° C.
• the possible reactions for removing protective groups are carried out according to the usual methods known to those skilled in the art or, for example, as indicated in patent BF 2,499,995.
• the preferred mode of elimination is acid hydrolysis using the acids chosen from hydrochloric, benzene sulfonic or para-toluene sulfonic, formic or trifluoroacetic acids. Hydrochloric acid is preferred.
• the transformation of the OH radical into a halogen radical can be carried out under the usual conditions known to those skilled in the art, such as in particular in a solvent such as, for example, tetrahydrofuran and the action of a halogen derivative, such as in particular, when the atom d halogen is a fluorine atom, diethylaminosulfide trifluoride (DAST).
• a solvent such as, for example, tetrahydrofuran
• a halogen derivative such as in particular, when the atom d halogen is a fluorine atom, diethylaminosulfide trifluoride (DAST).
• DAST diethylaminosulfide trifluoride
• Triflic anhydride can also be made to act beforehand to obtain the corresponding triflate which is then exchanged with the corresponding fluoride as described below in the examples and in particular by the action of tetrabutylammonium fluoride.
• halogen atom is a bromine, chlorine or iodine atom
• Hal preferably designates the chlorine atom, but can also represent a bromine or iodine atom.
• the reaction conditions of such a process are in particular those described in EP 0494819.
• the products which are the subject of the present invention have interesting pharmacological properties, in particular they are bind to the androgen receptor and they exhibit anti-androgenic activity.
• adenomas and neoplasias of the prostate as well as benign hypertrophy of the prostate, alone or in combination with analogues of LHRH. They can also be used in the treatment of benign or malignant tumors possessing androgen receptors and more particularly cancers of the breast, the skin, the ovaries, the bladder, the lymphatic system, the kidney and the liver,
• radioactive form in radioactive form (tritium, carbon 14, iodine 125 or fluorine 18) can also be used as specific markers for androgen receptors. They can also be used in diagnostic medical imaging.
• the products of formula (I) as defined above can also be used in the veterinary field for the treatment of behavioral disorders such as aggression, and androgen-dependent disorders, such as the circum analum in dogs and tumors with androgen receptors. They can also be used to cause chemical castration in animals.
• a subject of the invention is therefore the application, as medicaments, of products of formula (I) as defined above, said products of formula (I) being in all the possible isomeric forms, racemic or optically active, as well as addition salts with mineral or organic acids or with pharmaceutically acceptable mineral and organic bases of said products of formula (I).
• R 1 and R 2 represent a cyano radical and a trifluoromethyl radical
• R 3 represents an alkyl, alkenyl or alkynyl radical, linear or branched, containing at most 4 carbon atoms and optionally substituted by one or more radicals chosen from halogen atoms, the cyano radical and the free, salified or protected hydroxyl radical ,
• R 4 and R 5 either, identical or different, represent a methyl radical optionally substituted by a fluorine atom, or form with the carbon atom to which they are attached a cyclohexyl radical
• X and Y represent an oxygen atom, said products of formula (I) being in all the racemic isomeric, enantiomeric and diastereoisomeric forms possible, as well as the addition salts with mineral and organic acids or with mineral bases and pharmacologically acceptable organic, of said products of formula (I).
• the subject of the invention is also the application, as medicaments, of the following products:
• the products can be administered parenterally, buccally, perlingually, rectally or topically.
• a subject of the invention is also the pharmaceutical compositions, characterized in that they contain, as active principle, at least one of the medicaments of formula (I), as defined above.
• compositions can be presented in the form of solutions or injectable suspensions, tablets, coated tablets, capsules, syrups, suppositories, creams, ointments and lotions.
• These pharmaceutical forms are prepared according to the usual methods.
• the active principle can be incorporated into excipients usually employed in these compositions, such as aqueous vehicles or not, talc, gum arabic, lactose, starch, magnesium stearate, butter cocoa, fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, various wetting agents, dispersants or emulsifiers, preservatives.
• the usual dose which varies depending on the subject treated and the condition in question, can be, for example, from 10 mg to 500 mg per day in humans, orally.
• the subject of the invention is also, as new industrial products and in particular as new industrial products which can be used as intermediates for the preparation of the products of formula (I), as defined above, the products of formulas (IV) and (V) as defined above and in particular the products of formula (V) in which R 4 and R 5 represent an alkyl radical substituted by a free, esterified, etherified or protected hydroxyl radical.
• the present invention also relates to the use of the products of formula (I) as defined above, for the preparation of pharmaceutical compositions intended for the treatment of adenomas and neoplasias of the prostate as well as benign hypertrophy of the prostate, alone or in combination with LHRH analogues, for the treatment of skin conditions such as acne, hyperseborrhea, alopecia or hirsutism or in diagnostic medical imaging.
• Aromatics 1616-1575-1505 b) Hydrolysis of tetrahydropyrannic ethers
• STAGE 7 4- (4,4-bis (fluoromethyl) -2, 5-dioxo-3- (2-fluoroethyl) -1-imidazolidinyl) -2- (trifluoromethyl) -benzonitrile
• 1 ml of tetrahydrofuran is introduced, cools to -50 ° C and adds dropwise over - 1 min, 0.66 ml of diethylamino trifluorosulfide and then in 5 min at this temperature, 375 mg of the product obtained in stage 6 above and 4 ml of tetrahydrofuran. Rinse with 0.5 ml of tetrahydro- furan and wears at ⁇ 30 ° C.
• Aromatics 1610-1574-1504 STAGE 3 5, 5-bis (fluoromethyl) -3- (4-cyano-3- (trifluoro ⁇ methyl) phenyl) -2, 4-dioxo-1-imidazolidineacetonitrile
• EXAMPLE 3 4- (2,5-di ⁇ xo-4,4-bis (fluoromethyl) -3-ethyl-1- imidazolidinyl) -2- (trifluoromethyl) -benzonitrile
• STAGE 1 4- (4,4-bis (hydroxymethyl ) -2,5-dioxo-3-ethyl-1-imidazolidinyl) -2- (trifluoromethyl) -benzonitrile
• the procedure is as in a) and b) of stage 6 of Example 1 from 110 mg of hydride of sodium 50%, 1 g of the product obtained in stage 5 of Example 1, 5 ml of dimethylformamide and 0.24 ml of ethyl iodide.
• STAGE 2 4- (2,5-dioxo-4,4-bis (fluoromethyl) -3-ethyl-1-imida-zolidinyl) -2- (trifluoromethyl) -benzonitrile The procedure is carried out as in stage 7 of Example 1 , from
• stage 6 of example 1 The procedure is as in a) and b) of stage 6 of example 1 starting from 110 mg of sodium hydride 50%, 1 g of the product obtained in stage 5 of example 1, 5.5 ml of dimethyl sulfoxide and 0.3 ml isopropyl iodide. 1.1 g of product are obtained which is taken up in 12 ml of methanol and 4 ml of 2N hydrochloric acid. 574 mg of expected product is thus obtained
• Aromatics 1618-1575-1508 STAGE 2 4- (4, 4-bis (fluoromethyl) -2, 5-dioxo-3- (1-methyl-ethyl) -1-imidazolidinyl) -2- (trifluoromethyl) -benzonitrile
• stage 6 of example 1 The procedure is as in a) and b) of stage 6 of example 1 starting from 420 mg of sodium hydride at 50%, 3.86 g of the product obtained in stage 5 of example 1, 15 ml of dimethylforamide and 1.30 g of propargyl bromide, in 2 ml of dimethylformamide. 3.872 g of product are obtained which is taken up in 18 ml of methanol and 6 ml of hydrochloric acid.
• STAGE 4 4- (4, 4-bis (fluoromethyl) -2, 5-dioxo-3- (4-hydroxy-2-butyn-1-yl) -1-imidazolidinyl) -2- (trifluoromethyl) -benzo- nitrile
• Aromatics 1617-1580-1505 EXAMPLE 8: 4- (3- (4-hydroxy-2-butyn-1-yl) -4,4-dimethyl-2, 5-dione-1-imidazolidinyl) -2- (trifluoromethyl) -benzonitrile a) Condensation of the 4-tertbutyldimethylsiloxy- 2-butyne chain
• Aromatics 1615-1575-1505 are Aromatics 1615-1575-1505.
• B / T max % of the tritiated hormone bound for an incubation of this tritiated hormone at the concentration (T).
• B / T min % of the tritiated hormone bound for an incubation of this tritiated hormone at the concentration (T) in the presence of a large excess of cold hormone (2500.10 "9 M).
• the local (topical) activity of an antiandrogen is determined by the reduction it brings about on the surface of the costovertebral gland of the hamster (hereinafter GCV), androgen-dependent organ located on the sides of the animal.
• the animals are male hamsters weighing about 140 g, 14 weeks old coming from the Charles River breeding (USA), they are maintained in long photoperiod (16 h of light, 8 h of darkness). Animals are treated daily, except weekends, for 3 weeks (14 administrations).
• the product to be tested is applied, topically, to the G. VS . V. right, the left serving as a witness. The surface of the gland being previously shaved.
• the animals are sacrificed by carotid bleeding 24 h after the last treatment.
• the GCVs are taken, measured and weighed.
• the local activity of a product is determined by the% decrease in the surface area of the GCV which it induces compared to the 1st day of the experiment and compared to the animals treated with the solvent
• the systemic activity of an antiandrogen is determined by the reduction in the weight of the prostate it causes in a whole animal.
• the animals used are male rats of Sprague Dawley strain weighing approximately 200 g, 7 weeks old, from the Iffa Credo farm (France). The experience takes place over two weeks, except for the weekend.
• the product can be administered orally, subcutaneously or percutaneously.
• the solvents used are then: orally: 0.5% aqueous methylcellulose solution in a volume of 5 ml / kg, subcutaneously: corn germ oil 10% ethanol in a volume of 0.2 ml / kg, and percutaneously: ethanol in a volume of 50 ⁇ l on previously shaved skin.
• the treatment is carried out from day 0 to day 4 then (after the weekend) from day 7 to day 10.
• the animals are sacrificed the day after the last treatment by carotid bleeding, the prostates are removed and fixed in water demineralized containing 10% formalin for 72 h. They are then dissected and weighed. The blood is taken in order to determine, by radioimmunological assay, the level of serum testosterone.
• the antiandrogenic activity of the product is expressed in% reduction in the weight of prostates and in% variation in testosterone levels compared to animals treated with the solvent alone.

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• 1995
  • 1995-11-22 FR FR9513836A patent/FR2741342B1/fr not_active Expired - Fee Related
• 1996
  • 1996-11-21 WO PCT/FR1996/001846 patent/WO1997019064A1/fr not_active Application Discontinuation
  • 1996-11-21 JP JP9519453A patent/JP2000502053A/ja not_active Ceased
  • 1996-11-21 AU AU76984/96A patent/AU7698496A/en not_active Abandoned
  • 1996-11-21 US US09/077,223 patent/US6087509A/en not_active Expired - Fee Related
  • 1996-11-21 EP EP96939961A patent/EP0862559A1/de not_active Ceased
  • 1996-11-22 ZA ZA9609820A patent/ZA969820B/xx unknown

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