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
  • C07D295/14—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 carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D295/145—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 carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
  • C07D295/15—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 carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
  • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
  • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
  • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
  • C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring 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 atoms of the carbocyclic ring
  • C07D317/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Definitions

• the present invention relates to new ⁇ -(1-piperazinyl)acetamido arenecarboxylic acid derivatives which are useful in the treatment of diabetes.
• Ar is selected from
• - a mono-, bi- or tricyclic aryl group having from 6 to 14 carbon atoms, - a heteroaromatic group selected from the pyridyl, pyrimidinyl, pyrrolyl, furyl, thienyl, quinolyl, indolyl, benzothienyl, benzofuryl, benzopyranyl, benzothiopyranyl, dibenzofuryl, carbazolyl and benzothiazinyl groups, it being possible for the Ar group to carry 1 to 3 substituents selected from a C ⁇ -C 8 alkyl, (C 3 -C 8 )cycloalkyl(C ⁇ -C 6 )alkyl, d-C 8 alkoxy, (C 3 - C 8 )cycloalkyloxy(C 1 -C 6 )alkyl, (C3-C 8 )cycloalkyl(C ⁇ -C 6 )alkoxy(C ⁇ -C 6 )alkyl, (
• R 4 , R 5 and R 6 are selected, independently of one another, from
• the C ⁇ -C 8 alkyl groups can be linear or branched Mention may be ⁇ made, as examples, of the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert- butyl and pentyl groups
• the C ⁇ -C 8 alkoxy groups can likewise be linear or branched Mention may be made, as examples, of the methoxy ethoxy, propoxy isopropoxy, butoxy and isobutoxy groups 0
• the halogens can be selected from fluorine, chlorine, bromine and iodine
• heteroaryl groups in the definition of R ⁇ R 2 and R 3 may be defined in particular as defined for the heteroaromatic groups in the definition of Ar
• the invention also relates to the tautomeric forms and to the enantiomers, diastereoisomers and epimers of the compounds of general formula (I)
• the compounds of general formula (I) possess a carboxylic acid functional group and can be sa fied, then existing in the form of salts with bases o Examples of salts with bases of the compounds of general formula
• (I) include the pharmacologically acceptable salts, such as the sodium salts potassium salts, calcium salts and other salts of the same type
• the compounds of general formula (I) can also be sahfied with amines in order to form pharmaceutically acceptable salts
• the compounds of general formula (I) could be sahfied with glucamine, N- methylglucamine, N,N-d ⁇ methylglucam ⁇ ne, ethanolamme, morpholine N-methylmorpholine or lysine
• the compounds of general formula (I) possess basic nitrogen atoms and can be monosalified or disalified with inorganic or organic acids )
• salts with acids of the compounds of general formula (I) include the pharmaceutically acceptable salts, such as, and non-exhaustively, the hydrochlonde, the hydrobromide, the sulphate, the succmate, maleate, fumarate malate or tartrate and the sulphonates, such as the methanesulphonate, the be ⁇ zenesulphonate or the toluenesulphonate.
• the invention also relates to a process for the preparation of the compounds of general formula (I).
• a preparation process according to the invention comprises the reaction of an aromatic amine of general formula (II):
• R 7 is a hydrogen atom, a d-C 6 alkyl group or a benzyl group, with a haloacyl halide of general formula (III):
• Hal represents a chlorine or bromine atom, in order to form a compound of general formula (IV):
• R 7 is an alkyl group
• the compound of general formula (VI) can be hydrolysed by conventional acidic or basic means in order to give the compound of general formula (I)
• the compound of general formula (VI) can be hydrogenolysed in the presence of a catalyst, such as palladium-on-charcoal, in order to give the compound of general formula (I)
• the compounds of formula (V) can be prepared as described by R Ratouis et al (J Med Chem , 8, 104, 1965) or by Prelog et al (Collection 0 Czechoslov Chem Communications, 6, 211 , 1934)
• the compound (VI), in which R 7 is an alkyl group can by hydrolysed in the presence of a basic agent, such as dilute sodium hydroxide
• a basic agent such as dilute sodium hydroxide
• the enantiomers of the compounds of formula (I) can be separated by successive recrystallization of the salt of the acid (I) with an optically active base in solvents such as acetone, ethyl acetate or isopropanol and then displacement from the salt into an optically active acid by an inorganic or organic acid, according to a conventional method
• the compounds according to the present invention can be used in the treatment of diabetes, in particular of non-insu n-dependent diabetes, because of their hypoglycaemic effect and of their absence of toxicity at the active doses
• Another subject of the present invention is thus pharmaceutical compositions comprising an effective amount of a compound according to the invention
• compositions according to the invention can be presented in forms intended for parenteral, oral rectal, permucosal or 5 percutaneous administration
• excipients which are suitable for such administrations are derivatives of cellulose or microcrystalhne cellulose, alkaline-earth metal carbonates, magnesium phosphate, starches, modified starches or lactose for the solid forms Cocoa butter or polyethylene glycol stearates are the preferred excipients for rectal use
• the dosage can vary within wide limits depending on the o therapeutic indication and the administration route, as well as the age and weight of the patient.
• the following examples illustrate the preparation of the compounds of formula (I) and of the intermediates of formulae (II) and (IV).
• the apparatus is placed under a hydrogen atmosphere and agitated at room temperature for 3 hours.
• the anti-diabetic activity of the compounds of formula (I) by the oral route was determined with respect to an experimental model of non-insu n- dependent diabetes induced in the rat by streptozotocm
• the non-insulm-dependent diabetes model is obtained in the rat by a neonatal (the day of birth) injection of streptozotocm
• the diabetic rats used are 8 weeks old The animals are kept, from the day of their birth to the day of the experiment, in an animal house at a temperature regulated from 21 to 22°C and subject to a fixed cycle of light (from 7 h to 19 h) and of darkness (from 19 h to 7 h)
• Their feeding consisted of a maintenance diet, water and food was supplied "ad libitum", except for fasting for 2 hours before the test when the food is withdrawn (post-absorptive state)
• the rats are treated orally during the day with the test product Two hours after the final administration of the product and 30 minutes after anaesthetizing the animals with sodium pentobarbital (Nembutal ), a 300 ⁇ l blood sample is taken from the end of the tail

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

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Cited By (11)

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Citations (5)

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• 1997
  • 1997-05-13 FR FR9705849A patent/FR2763334A1/fr not_active Withdrawn
• 1998
  • 1998-06-08 BR BR9816021-4A patent/BR9816021A/pt not_active IP Right Cessation
  • 1998-06-08 WO PCT/EP1998/003431 patent/WO1999064407A1/en not_active Application Discontinuation
  • 1998-06-08 CN CN98814107A patent/CN1119338C/zh not_active Expired - Fee Related

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