Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
  • C07D213/40—Acylated substituent nitrogen atom
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
  • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
  • C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
  • C07C311/46—Y being a hydrogen or a carbon atom
• • 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
  • C07D211/06—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 no double bonds between ring members or between ring members and non-ring members
  • C07D211/08—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 no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
  • C07D211/18—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 no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
• • 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
  • C07D211/70—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• • 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
  • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
  • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
  • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
  • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
  • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
  • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
• • 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
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• the present invention relates to and derivatives of 5 N- (arginyl) benzenesulphonamide, their preparation and their therapeutic application.
• R 3 represents either a hydrogen atom or a (C 1 -C 5 ) straight or branched alkyl group, or a group -C0R 5 where R 5 is a (C 1 -C 4 ) straight or branched alkyl group, - (CH 2 ) n OCH 3 , -CH 2 0 (C 2 H 4 0) n CH 3; - (CH 2 ) n CF 3 , - (CH 2 ) n 0H (n equal 1 to 4), either a group -S0 2 R 6 , or a group -CONHR 6 , or a group
• the ratio (x: y) represents the ratio (acid: base).
• reaction medium The temperature of the reaction medium is allowed to return to ambient temperature and stirring is continued for 18 hours at this temperature. Evaporated under reduced pressure and the aqueous phase is extracted with 2 times 300 ml of ethyl acetate. The organic phases are combined and washed with 100 ml of a saturated sodium chloride solution. It is dried over sodium sulfate and concentrated under reduced pressure. The residue thus obtained is purified by chromatography on a column of silica gel, eluting with a cyclohexane: ethyl acetate mixture (9: 1).
• the residue is taken up in 150 ml of ethyl acetate and washed successively with 100 ml of an aqueous 0.1N hydrochloric acid solution, 50 ml of a saturated solution of sodium hydrogencarbonate and 50 ml of a saturated solution of sodium chloride. It is dried over sodium sulfate and concentrated under reduced pressure.
• the residue is purified by chromatography on a column of silica gel, eluting with a dichloromethane: methanol mixture (98: 2).
• the mixture is heated at 50 ° C. for 0.5 hour under a pressure of 0.35 MPa (50 psi) a mixture of 0.75 g (0.9 mmol) of (S) - [4- [(4-ethylpiperidin- l-yl) carbonyl] -4- [[[2 '-fluoro-2- [(1- oxopropyl) amino] [1,1' -biphenyl] -3-yl] sulfonyl] amino] butyl] [imino [[ (phenylmethoxy) carbonyl] amino] methyl] phenylmethyl carbamate and 0.8 g of 10% palladium on carbon in 10 ml of water and 10 ml of acetic acid.
• the temperature of the mixture is allowed to return to ambient temperature, it is stirred for 18 hours at this temperature and concentrated under reduced pressure.
• the residue is taken up in 100 ml of 7 ethyl acetate and washed successively with twice 50 ml of 0.5N hydrochloric acid, 50 ml of a saturated solution of sodium hydrogen carbonate and 50 ml of a saturated sodium chloride solution. It is dried over sodium sulfate, filtered and concentrated under reduced pressure.
• the residue is taken up in 50 ml of tetrahydrofuran and treated for 15 minutes at 0 ° C. with a stream of gaseous ammonia. The temperature is allowed to return to room temperature, stirring is continued for 2 hours and concentrated under reduced pressure.
• the temperature of the reaction medium is allowed to return to ambient temperature, stirring is continued for 15 hours at this temperature and concentration is carried out under reduced pressure.
• the residue is taken up in 100 ml of ethyl acetate, washed twice with 50 ml of 1N hydrochloric acid and then with 50 ml of a saturated solution of sodium chloride, dried over sodium sulfate, filtered. and concentrated under reduced pressure.
• the temperature of the reaction medium is allowed to return to ambient temperature, stirring is continued for 16 hours at this temperature and concentration is carried out under reduced pressure.
• the residue is taken up in 100 ml of ethyl acetate, washed successively with 30 ml of 1N hydrochloric acid, 20 ml of water, 30 ml of a saturated solution of sodium hydrogen carbonate and then with 20 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure.
• the temperature of the mixture is allowed to return to ambient temperature and stirring is continued for 18 hours at this temperature.
• the reaction medium is cooled to 0 ° C., acidified to pH 2 with a 12N aqueous hydrochloric acid solution and then neutralized with a solution of sodium hydrogencarbonate before adding 2.4 g (11 mmol) of bis (1, 1-dimethylethyl) dicarbonate dissolved in 15 ml of methanol.
• the temperature of the mixture is allowed to return to room temperature, stirring is continued for 18 hours at this temperature and concentrated under reduced pressure.
• the residue is taken up in 200 ml of ethyl acetate, washed with 50 ml of a saturated sodium chloride solution, dried over sodium sulphate and concentrated again under reduced pressure.
• the residue thus obtained is purified by chromatography on a column of silica gel, eluting with a cyclohexane: ethyl acetate mixture (7: 3).
• the reaction medium is left under stirring at this temperature for 6 hours and concentrated under reduced pressure.
• the residue is purified by chromatography on a column of silica gel, eluting with a cyclohexane: ethyl acetate mixture (1: 1).
• reaction medium The temperature of the reaction medium is allowed to return to ambient temperature, stirring is continued for 30 minutes at this temperature and evaporated to dryness.
• the residue is taken up in 250 ml of toluene and evaporated to dryness. It is taken up in 200 ml of toluene and evaporated to dryness.
• the residue is purified by chromatography on a column of silica gel, eluting with a dichloromethane: methanol mixture (99.5: 0.5).
• HC1 corresponds to a hydrochloride and the ratio between brackets is the ratio (help: base); the absence of any mention means that the compound is in the base form.
• - c 0.2; methanol except for compounds n ° 11, 12, 13, 14, 18, 19, 21, 23, 25, 30, 32, 33, 34, 41 and 42,
• mice Male CD rats weighing 150 to 200 g are treated with the test compound or with the vehicle, i.v., orally or subcutaneously. Then the animals are anesthetized with Nembutal TM (60 mg / kg; 0.1 ml / kg), the blood is taken on 3.8% trisodium citrate (1 vol / 9 vol of blood) at the retro sinus orbital and the plasma is prepared by centrifugation at 3600 g for 15 minutes at room temperature. 200 ⁇ l of plasma are then incubated at 37 ° C. with 200 ⁇ l of a human thrombin solution, the final concentration of human thrombin being 0.75 NIH units / ml and the coagulation time is noted. The anticoagulant effect is expressed by the dose which increases the coagulation time by 100%. They inhibit the coagulation of rat plasma at doses of 0.01 to 5 mg / kg i.v. They are also active by the oral and subcutaneous routes.
• Nembutal TM 60 mg / kg;

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Hydrogenated Pyridines (AREA)
• Plural Heterocyclic Compounds (AREA)

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• 1997
  • 1997-03-20 FR FR9703392A patent/FR2761065B1/fr not_active Expired - Fee Related
• 1998
  • 1998-03-17 WO PCT/FR1998/000532 patent/WO1998042700A1/fr not_active Application Discontinuation
  • 1998-03-17 AU AU69243/98A patent/AU6924398A/en not_active Abandoned
  • 1998-03-17 EP EP98914932A patent/EP0971916A1/de not_active Withdrawn
  • 1998-03-18 AR ARP980101211A patent/AR012096A1/es unknown
  • 1998-03-19 ZA ZA982355A patent/ZA982355B/xx unknown

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