Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
  • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
  • C07D221/20—Spiro-condensed ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • 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
  • A61P3/08—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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/54—Spiro-condensed
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/56—Ring systems containing three or more rings
  • C07D209/58—[b]- or [c]-condensed
  • C07D209/72—4,7-Endo-alkylene-iso-indoles
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
  • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D211/74—Oxygen atoms
  • C07D211/76—Oxygen atoms attached in position 2 or 6
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
  • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
  • C07D263/04—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
• • 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
  • C07D295/16—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 acylated on ring nitrogen atoms
  • C07D295/18—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 acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
  • C07D295/182—Radicals derived from carboxylic acids
  • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/10—Spiro-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
  • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D495/10—Spiro-condensed systems

Definitions

• the present invention relates to azacydoalkane derivatives, their preparation and their therapeutic use, in particular in the treatment of diabetes, obesity, hyperglycemia and inflammation.
• R 1 represents a hydrogen atom, hydroxyl, a group C, ⁇ alkyl, C, ⁇ hydroxyalkyle, C 4 . 7 cycloalkyl, C, ⁇ alkyloxy C 1 ⁇ alkyl, an aminocarbonyl group, a benzyl, a heterocycloalkyl or heteroaryl group comprising from 4 to 5 carbon atoms and a heteroatom, such as nitrogen, sulfur or oxygen, heterocycloalkyl or heteroaryl group being optionally substituted by one or two substituents such as a hydroxyl, a C 1 ⁇ t alkyl group or a halogen;
• R 2 , R 3 and R 4 which may be equal or different, represent independently of each other, a hydrogen atom, a C 1 _ alkyl group, a C 4 group. 7 cycloalkyl, a hydroxyl group, an aminocarbonyl group, or a heteroaryl group comprising from 4 to 5 carbon atoms and a heteroatom such as nitrogen, sulfur or oxygen, the heteroaryl group being optionally substituted with one or two substituents such as a hydroxyl group, a C, alkyl group or a halogen;
• R 1 and R 2 together form a group C 3 . 6 alkylene, a group C 2 . 3 alkylene dioxy, a group C 2 _3 alkylene dithio, - (O 2 ) SC 2 . 3 alkylene-S (0 2 ) - or a group -CH 2 NHC (0) CH 2 -;
• R 2 and R 3 together form a propylene or butylene group, a C, alkylene dioxy group, a carbonyldioxy group or a 2-butenylene; or R 2 and R 3 form together with the atoms carrying them a norbomane or a 5-norbornene, or a bond to give a double bond between the atoms carrying them, X being a carbon atom;
• R 5 represents a hydrogen atom, a hydroxyl group or, when R 6 represents a hydrogen, a 1-indanyl group;
• R 6 represents an aromatic group chosen from the following groups:
• R 2 and R together form a group C 1 . 3 alkylene dioxy or carbonyldioxy, a benzyl optionally substituted by one or two substituents such as a halogen or a C 1 ⁇ alkyl group, or R 6 represents a hydrogen, when R 5 represents a 1-indanyl group;
• R 7 represents a hydrogen atom or a C 1 ⁇ alkyl group
• R 8 represents a hydrogen, an acetyl, a benzoyl, a group C, ⁇ alkyl, optionally substituted by a hydroxyl; or a C 1-2 alkyl phenyl group, optionally substituted on the alkyl group by a hydroxyl,
• X represents a carbon, nitrogen, oxygen, sulfur atom or a sulfonyl group
• Y represents an oxygen or sulfur atom
• n 1 or 2; I is equal to 1 and m is equal to 0 when X represents a nitrogen atom; I and m are equal to 0 when X represents a sulfur, oxygen atom or a sulfonyl; they are equal to 1 when X represents a carbon atom.
• a C 4 alkyl group represents a carbon chain of 1 to 4 carbon atoms, linear or branched, more particularly a methyl, ethyl, propyl, isopropyl radical, butyl, isobutyl and tertbutyl, the term C xy alkylene denoting a divalent C xy alkyl group;
• C x . y alkenyl an aliphatic group, linear or branched, comprising from x to y carbon atoms and 1 or 2 ethylenic unsaturations, the term C x . y alkenylene denoting a group C x . y divalent alkenyl;
• - heteroaryl a pyrrolyl, pyridyl, thyenyl, furyl, pyranyl group, preferably pyrrolyl;
• heterocycloalkyl a pyrrolidinyl, piperidyl, tetrahydrofuranyl and tetrahydropyranyl group, preferably tetrahydrofuranyl.
• the compounds of formula (I) can form with the pharmaceutically acceptable acids and bases salts which are part of the invention.
• the compounds for which R 7 is hydrogen can form with the bases of the salts.
• the preferred base salts are, in this case, the sodium and calcium salts, which are such that R 7 represents a sodium or calcium atom.
• the compounds of formula (I) have one or more asymmetric carbon atoms, they can be in the form of enantiomers, diastereoisomers or mixtures of these different forms, including racemic mixtures which form part of the invention.
• R 2 , R 3 and R 4 when they are not linked together, represent, independently of each other, a hydrogen atom, a C group, ⁇ alkyl or a hydroxyl group, and / or the compounds for which R 8 represents a hydrogen.
• the compounds for which R 4 represents a hydrogen are particularly preferred and in particular those for which R 5 represents a hydrogen.
• R 6 represents an aromatic group other than a benzyl, more especially, an indanyl are also preferred and in particular those comprising the preferred groups mentioned above.
• R 1 and R 2 preferably form a group C 3 . 6 alkylene plus especially C 4 alkylene.
• the compounds of formula (I) can be prepared according to the process represented in scheme 1.
• R 7 represents a group C, ⁇ alkyl
• R 5 and R 6 are defined as in formula (I)
• R 9 represents a halogen atom, such as for example a chlorine or a bromine, or a hydroxyl group
• an aprotic solvent such as dichloromethane
• an agent activating the acid function such as isobutyl chloroformate or carbonyldiimidazole.
• the compounds of the invention of formula (I), for which Y is a sulfur atom and R 7 represents a C 1 ⁇ alkyl group, can be obtained by reaction of the compounds (I), previously obtained, with a thiation agent such as Lawesson's reagent.
• the compounds of the invention of formula (I), for which R 7 is a hydrogen atom can be obtained by hydrolysis of the compounds (I), in which R 7 represents a C 1 ⁇ alkyl group, according to known methods skilled in the art, for example sodium hydroxide or hydrochloric acid.
• the compounds of formula (II) can be prepared according to well methods known to those skilled in the art, or by methods described in the literature, such as for example in Boll. Chim. Farm., 121 (1), 16-26 (1982), in J. Med. Chem., 33, 62-69 (1990) or in J. Heterocyl. Chem., 30, 1357-59 (1993).
• the compounds of formula (III) can be prepared according to methods described in the literature, such as for example in J. Am. Chem. Soc, 90, 3495-3502 (1968) or in J. Med. Chem., 36, 2788-2797 (1993).
• the mixture is stirred for 16 h at room temperature, poured into 400 ml of cold water; stirred for 15 min and then extracted with 3 times 150 ml of ethyl acetate; the combined organic phases are washed successively with 150 ml of saturated sodium hydrogen carbonate solution, with 150 ml of a 5% aqueous solution of citric acid, then with brine, dried with sodium sulphate and evaporated to dryness .
• the mixture is concentrated, 200 ml of water are added, the solution obtained is washed with twice 150 ml of diethyl ether, then acidified at 0 ° C with 6 M hydrochloric acid to pH 2 and 1 'is extracted with 2 times 250 ml of dichloromethane; the organic phases are washed with brine, dried with sodium sulfate and evaporated to dryness.
• This compound was prepared according to the method described in Example 1, using (R) -2,3-dihydro-1 H-indene-1-ethyl acetate as starting material.
• HHHOH 160 (R * , R * )
• Ph represents a phenyl carried out in dimethylsulfoxide
• the compounds of the invention have been tested in various biological tests.
• hypoglycaemic activity test in rats. This test is carried out on rats fasted for 20 h.
• the products to be tested are administered orally; blood samples are taken from the tail 0.5; 1, 2, 3, 5 and 7 h after administration of the product, according to the method described by H. OHNOTA in The Journal of Pharmacology and Experimental Therapeutics, 269, n ° 2, 489-495 (1994).
• the compounds of the invention reduce the basal glycemia by 30 to 40% at doses between 0.1 and 10 mg / kg.
• mice were also subjected to an antihyperglycemic activity test in mice, according to the method described by R.S. HO et al. in Arch. Int. Pharmacodyn. 237, 98 (1979).
• This test is carried out on mice kept fasting for 20 h.
• the test products are administered orally 30 min before the administration of a glucose overload (1.5 g / kg).
• the animals are sacrificed by decapitation 30 min. after glucose overload and their blood sugar is determined as before.
• the Effective Doses 50 (ED 50 ) of the compounds of the invention are between 0.1 and 10 mg / kg.
• the reference compound KAD1229 has an Effective Dose 50 of 1.5 mg / kg.
• the in vivo activity of the compounds of the present invention was studied in an experimental model of plantar inflammation in the rat.
• CAR carrageenan
• the compounds of the invention are given orally 1 hour before the injection of CAR.
• a 1% solution of CAR in saline is injected s.c. into the sub-plantar part of the right hind paw of the rat.
• the volume of the inflammatory reaction is measured by plethysmography after 1.5; 3 and 4.5 hours of CAR injection. 19
• the compounds of the invention at doses between 0.5 and 10 mg / kg orally, confer a lasting inhibition of the induced inflammation (between 1, 5; 3 and 4.5 hours after the injection of CAR .) between 20 and 90% compared to the control.
• the compounds of the invention have "in vivo" hypo and antihyperglycemic properties, and anti-inflammatory properties. They can therefore be used in the treatment of hyperglycemia, diabetes, obesity and / or inflammation. In the case of inflammation, they can be used more particularly in diabetic neuropathies, polyarthritis, arthritis, low back pain, trauma pain, inflammation in the ENT area.
• the compounds of the invention may be presented, in combination with any suitable excipient, in any form suitable for oral or parenteral administration, for example, in the form of tablets, capsules, dragees, or oral or injectable solutions. .
• the compounds of the invention can be administered at daily doses of between approximately 1 and 100 mg in adults by the oral route, or between approximately 0.1 and 100 mg by the parenteral route.

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• Organic Chemistry (AREA)
• Chemical & Material Sciences (AREA)
• Health & Medical Sciences (AREA)
• Diabetes (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Pharmacology & Pharmacy (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Veterinary Medicine (AREA)
• Obesity (AREA)
• Hematology (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
• Pain & Pain Management (AREA)
• Emergency Medicine (AREA)
• Child & Adolescent Psychology (AREA)
• Endocrinology (AREA)
• Rheumatology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)
• Other In-Based Heterocyclic Compounds (AREA)
• Hydrogenated Pyridines (AREA)
• Plural Heterocyclic Compounds (AREA)
• Pyrrole Compounds (AREA)
• Indole Compounds (AREA)

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• 1998
  • 1998-04-15 FR FR9804653A patent/FR2777566B1/fr not_active Expired - Fee Related
• 1999
  • 1999-04-13 EP EP99913392A patent/EP1071666A1/de not_active Withdrawn
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  • 1999-04-13 WO PCT/FR1999/000851 patent/WO1999052876A1/fr not_active Application Discontinuation
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