Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
  • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
  • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
  • C07D295/092—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings with aromatic radicals attached to the chain
• • 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
  • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives

Definitions

• AryL-1 (4-o-alkoxyphenyl-1-piperazinyl) -2, -3 or -4 alkanols, process for their preparation and their use for the preparation of medicaments.
• the present invention relates to aryl-1- (o-alkoxy-phen l-4-piperazin 1-1) -2, -3 or -4 alkanols, their preparation process and their use for the preparation of medicaments, intended in particular to the treatment of dysuria in particular Linked to a urethral hypertonia, or to a benign enlargement of the Prostate.
• the compounds of formula I below have very interesting pharmacological properties and a sufficiently low toxicity to allow their use in therapy.
• the original pharmacological profile of these compounds makes it possible to envisage their use for the preparation of medicaments intended for the treatment of dysuria in particular linked to urethral hypertonia, or to benign enlargement of the prostate.
• R. and R 2 , R ? identical or different are chosen from a hydrogen atom, a hydroxy group, a methoxy group;
• - R. is chosen from a hydrogen atom, a group
• - n is an integer varying from 1 to 3.
• alkyl group is understood to mean a linear or branched hydrocarbon chain.
• An alkyl group having from 1 to 5 carbon atoms is for example a methyl, ethyl, propyl, isopro- pyle, butyle, isobutyle, tertiobut Le, pentyle.
• it will be an ethyl or isopropyl group.
• the compounds of formula I can also be in the form of addition salts, in particular with a pharmaceutically acceptable acid, mineral, for example hydrochloric acid or sulfuric acid, or organic, for example citric, tartaric, malic, maleic, fumaric or methane sulfonic acid.
• a pharmaceutically acceptable acid for example hydrochloric acid or sulfuric acid
• organic for example citric, tartaric, malic, maleic, fumaric or methane sulfonic acid.
• the compounds of formula I having an asymmetric carbon atom may be in the form of an individual enanti ere, or in the form of a racemic.
• R- represents a hydrogen atom and the other a hydrogen atom or a methoxy group; R represents a lower alkoxy group and n is equal to 3.
• EP 0395312, EP 0479546 and EP 0395313 is the derivative corresponding to formula I in which R .., R-, and R, simultaneously represent a hydrogen atom and R, represents an ethyl radical Consequently and according to a first aspect, the present invention aims to cover, as new products, the compounds of formula I mentioned above, in which R., R ? , R ,, R, and n have the meaning indicated above, on the condition however that when n is equal to 1 and R represents a hydrogen atom, R.
• R and R do not simultaneously represent a hydroxy group respectively in position 3 and 4 on the phenyl ring, when R., R_ and R, simultaneously represent a hydrogen atom R, does not represent a methyl radical, and when n equal to 3, at least one of R .. and R-, represents a hydroxy group.
• FR-2 073 326, EP 0395312, EP 0395313 and EP 0479546 are only presented as synthesis intermediates useful for the preparation of arylketone derivatives.
• the present invention aims to cover the above-mentioned compounds of formula I in which R,., R- ,, R- ,, R, and n have the meaning mentioned above. , provided, however, that when n is equal to 1, R. and R-, do not simultaneously represent a hydroxy group in positions 3 and 4 respectively on the phenyl ring.
• the invention also relates to medicaments, in particular useful in the field of urology in particular for the treatment of dysurias linked to urethral hypertonia or to benign prostatic hypertrophy, characterized in that they contain, as a principle active, at least one compound of the above formula (IA ) or One of its pharmaceutically acceptable salts, in combination with a pharmaceutically acceptable vehicle, excipient or support.
• medicaments in particular useful in the field of urology in particular for the treatment of dysurias linked to urethral hypertonia or to benign prostatic hypertrophy, characterized in that they contain, as a principle active, at least one compound of the above formula (IA ) or One of its pharmaceutically acceptable salts, in combination with a pharmaceutically acceptable vehicle, excipient or support.
• the pharmaceutically acceptable salts of the compounds of formula ( IA ) can be obtained in known manner by bringing a solution of a compound of formula (IA ) into contact with a mineral or organic acid.
• a hydrochloride by adding a titrated solution hydrochloric acid in an alcohol, to a solution of a compound of formula (IA).
• addition salts can comprise 1 or 2 moles of salifying acid per mole of compound of formula ( IA).
• the invention also relates to a process for the preparation of medicaments, in particular useful in the field of urology and in particular in the treatment of dysurias linked to urethral hypertonia or to benign prostatic hypertrophy, characterized in that it consists to incorporate, as active principle, at least one compound of formula (IA) above or one of its pharmaceu ⁇ tically acceptable salts, in a pharmaceutically acceptable vehicle, excipient or support.
• a reducing agent such as for example sodium borohydride in a solvent such as for example ethanol.
• X represents a halogen atom, preferably bromine or chlorine, on an o-alkoxy-phenyl-piperazine of formula (IV): in which
• R has the same meaning as indicated above.
• This reaction will preferably be carried out in the presence of a hydracid acceptor such as triethylamine in a solvent such as tetrahydrofuran.
• a hydracid acceptor such as triethylamine
• a solvent such as tetrahydrofuran.
• X represents a halogen atom, preferably bromine or chlorine on an o-alkoxy-phenyl-piperazine of formula (IV)
• This reaction will preferably be carried out in the presence of a hydracid acceptor such as a tertiary enzyme, in particular triethylamine in a solvent such as THF, benzene or toluene, or in the absence of solvent, in non-racemic conditions.
• a hydracid acceptor such as a tertiary enzyme, in particular triethylamine in a solvent such as THF, benzene or toluene, or in the absence of solvent, in non-racemic conditions.
• X represents a halogen atom, preferably bromine or chlorine, for example according to the reaction scheme and the following reference:
• the homogeneous medium is brought to reflux for 20 min, then cooled to 50 C. 615 g ( 5 mol ) of 2-bromo-propane are then added dropwise over 55 min and the reaction medium is maintained at reflux for 2 h.
• the salts formed are filtered and washed with ethanol.
• the alcoholic phase is evaporated under vacuum.
• the reaction mixture is heated at reflux for 1 h.
• the solubi Lization of the organic compound is noted.
• the infrared spectrum conforms to the proposed structure.
• reaction medium is poured onto ice, acidified with acetic acid, neutralized with sodium bicarbonate and then extracted with ethyl acetate; The organic phase is washed with water, dried over sodium sulfate and concentrated in vacuo.
• the white crystals are recrystallized from a mixture of heptane and isopropanol (55/45).
• reaction mixture is taken up in 100 ml of ethyl ether.
• crystals formed are discarded, then the ethereal phase is acidified.
• the precipitate formed is filtered, washed with ethyl ether and dried under vacuum.
• the crystals are recrystallized from a mixture of ethyl acetate and methanol (100/35).
• the recrystallization yield is 99% for a product which melts at 210-215 ° C. and which is a single spot in TLC on SiO-, (CH 2 Cl 2 / Me0H 95/5)
• the temperature is maintained at 20 C by an ice water bath. Shake for 8 h.
• the limpid yellow medium becomes whitish; the appearance of a white precipitate is noted. Leave to stir for 1 hour.
• the quality of the bromine alcohol obtained is checked by TLC on SiO 3, with CHCl, for eluent.
• Enantiomeric excess is evaluated by H.P.L.C. on a chiral column (DA ⁇ CEL).
• the white crystals which have precipitated are drained, washed with ethyl acetate and dried in an oven under vacuum over phosphoric anhydride.
• This monohydrochloride melts at 178-179 C and is monotache in
• the purity determined by argentimetry is 100%.
• the infrared spectrum and the NMR spectrum conform to the proposed structure.
• the rotary power is:
• R-, 4-methoxy
• This compound is obtained using experimental processes analogous to those described in Example 20, using the COREY chiralite auxiliary, R - (+) - 2-methyl-CBS-oxazaborolidine.
• the crude formula, the molecular weight, the melting point and the AgNO titer are given in Table I.
• mice were administered orally at a single dose in mice. Mortality was recorded for a period of 14 days. The results are expressed in the form of a lethal dose 50 (LD 50) in mg.kg "1.
• LD 50 lethal dose 50
• the products of the invention can therefore be used in human or veterinary medicine, in particular in the treatment of dysuria in particular linked to urethral hypertonia.
• the products can be administered by general route (parenteral, oral, rectal) or topically in combination with a pharmaceutically acceptable vehicle, can be solid or liquid and can be presented, for example, in the form of injections, tablets, capsules, granules.
• the dosage can vary within wide limits, in particular according to the type and severity of the condition to be treated and according to the method of administration.
• compositions constitute an object of the invention.
• Their preparation process is another. It consists in mixing with suitable excipients an effective dose of a compound of formula I.
• the invention relates to the use of the compounds of formula I for the preparation of medicaments useful for the treatment of dysuria, in particular related to a benign enlargement of the prostate, or to urethral hypertonia.

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• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Pharmacology & Pharmacy (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
• Veterinary Medicine (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Urology & Nephrology (AREA)
• Endocrinology (AREA)
• Reproductive Health (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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• 1992
  • 1992-06-24 FR FR9207750A patent/FR2692894B1/fr not_active Expired - Fee Related
• 1993
  • 1993-06-24 EP EP93913186A patent/EP0647221A1/de not_active Withdrawn
  • 1993-06-24 CA CA002139116A patent/CA2139116A1/fr not_active Abandoned
  • 1993-06-24 WO PCT/FR1993/000633 patent/WO1994000442A1/fr not_active Ceased
  • 1993-06-24 JP JP6502107A patent/JPH07508728A/ja active Pending

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