Classifications

• • 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
  • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
  • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
  • C07C311/18—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms, not being part of nitro or nitroso groups
• • 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
  • C07D213/60—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 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
  • C07D213/72—Nitrogen atoms
  • C07D213/73—Unsubstituted amino or imino radicals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • 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]
• • 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
  • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
  • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
  • C07C311/19—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
• • 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
  • C07D211/26—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 with hydrocarbon radicals, substituted by nitrogen atoms
• • 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
  • C07D213/60—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 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
  • C07D213/72—Nitrogen atoms
  • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
• • 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
  • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
  • C07D233/06—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring carbon atoms
  • C07D233/08—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring carbon atoms with alkyl radicals, containing more than four carbon atoms, directly attached to ring carbon atoms
  • C07D233/12—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring carbon atoms with alkyl radicals, containing more than four carbon atoms, directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
  • C07D233/16—Radicals substituted by nitrogen atoms
• • 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
  • C07D233/64—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 substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
• • 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
  • C07D295/12—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 or doubly bound nitrogen atoms
  • C07D295/125—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 or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
  • C07D295/13—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 or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen 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
  • 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

Definitions

• the present invention relates to new N- (phenylsulfonyl) glycine compounds, their preparation process and their use for obtaining pharmaceutical compositions.
• EP 558 961 also suggests the use of compounds of the arylsulfonamide type of substituted amino acids for the treatment of thrombosis due to anticoagulant properties.
• WO 92/16549 A1 describes phenylalanine derivatives comprising an arylsulfonamide group, which are proteinase inhibitors, in particular thrombin inhibitors.
• WO 00/34313 describes peptides which may contain an arylsulfonyl group at the chain end and which are claimed for their ability to inhibit procollagen-C-proteinase. Also known from the publication 1 Chem. Soc., Perkin Trans. 1 (1986), (9) p 1655-64, compounds of similar structure which are presented as inhibitors of porcine pancreatic elastase. Object of the invention:
• the invention relates to new compounds comprising the substituted N- (arylsulfonyl) glycyl-glycine chain, said compounds being in particular useful as active principles of medicaments intended for the treatment of pain, particularly hyperalgesia and major algesia.
• a compound of N- (phenylsulfonyl) glycine characterized in that it is chosen from the group consisting of i) the compounds of formula
• W represents a chlorine atom
• X represents a hydrogen atom, a methyl group or a chlorine atom
• Y and Z each independently represent a hydrogen atom or a chlorine atom, or
• X and W or X and Y together form, with the carbon atoms to which they are attached, a phenyl ring
• R represents a hydrogen atom, an allyl group or a C 1 -C 4 alkyl group which is unsubstituted or substituted by a phenyl group, methoxy group, pyridinyl group, carboxamide group or N-methylcarboxamide group,
• R 1 represents a hydrogen atom, a C 1 alkyl group or a group (CH 2 ) m -R 2 n and m each independently represent 1, 2, 3 or 4,
• R 2 and R ' 2 each independently represent a group
• R 3 represents a hydrogen atom or a C 1 -C alkyl group
• R 4 represents a hydrogen atom, a COCH 3 group, a COOCH 3 group, or a C 1 -C alkyl group
• R 5 represents a hydrogen atom or a C ⁇ -C 4 alkyl group, unsubstituted or substituted by a phenyl group,
• Re represents a hydrogen atom or a group CONHC 2 H 5
• R 7 represents a hydrogen atom, a group
• a CONHCH 3 Rs group represents a hydrogen atom, an NH 2 group, or a C ⁇ -C 4 alkyl group
• a method is also recommended for the preparation of the compounds of formula I as well as their addition salts.
• the use of a substance chosen from the compounds of formula I and their non-toxic addition salts is also recommended for the preparation of a medicament, useful in human or animal therapy, intended for the prevention or treatment of related pathologies. pain, especially hyperalgesia following an inflammatory condition or major pain relievers linked to other medical conditions such as, for example, cancer. detailed description
• C1-C alkyl group means a hydrocarbon chain having from 1 to 4 carbon atoms, linear or branched, or alternatively cyclic.
• a CC 4 alkyl group is for example a methyl, ethyl, propyl, butyl, 1-methyl-ethyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl or cyclopropylmethyl group.
• C x -C 4 alkyl group substituted by a phenyl group means a C ⁇ -C 4 alkyl group in which one of the hydrogen atoms is substituted by a phenyl group.
• a group is for example a phenylmethyl group, a 2- (phenyl) ethyl group, 1- (phenyl) ethyl group, phenylpropyl group or phenylbutyl group.
• R 2 or R ′ 2 represent a piperidine ring, optionally substituted with a group R 3 , the binding positions on this cycle can be made by any of the substitutable vertices.
• R 2 or R ′ 2 represent a pyridine ring, optionally substituted with an Rs group
• the binding and substitution positions can be carried out on any of the carbons of the ring.
• R 2 or R ′ 2 represent a phenyl ring substituted by an R 7 group different from H
• the relative position of the substituents can be ortho, meta or para, with a preference for the para position.
• addition salts is meant the addition salts obtained by reaction of a compound of formula I containing at least one basic function in its non-salified form, with a mineral or organic acid.
• these will be pharmaceutically acceptable addition salts.
• mineral acids suitable for salifying a basic compound of formula I hydrochloric, hydrobromic, phosphoric and sulfuric acids are preferred.
• organic acids suitable for salifying a basic compound of formula I methanesulfonic, benzenesulfonic, toluenesulfonic, maleic, fumaric, oxalic, citric, tartaric, lactic and trifluoroacetic acids are preferred.
• amino acid group includes, for example, amidine, 2-imidazolyl or 4,5-dihydro-2-imidazolyl groups.
• Ra represents a hydrogen atom or a group (CH 2 ) m R'b in which m represents 1, 2, 3 or 4
• Rb and R'b each independently represent a hydrogen atom, a group A
• 1 ⁇ is an amino-protecting group, COCH 3, COOCH 3, or an alkyl group Ci-G, and R 5 represents an alkyl group C ⁇ -C 4 alkyl optionally substituted by phenyl; a group
• R 3 represents an aminoprotective group or a C 1-6 alkyl group; a group
• R 8 represents H, C ⁇ -C 4 alkyl or NHRc in which Rc represents an aminoprotective group
• R 3 represents a CC 4 alkyl group or an aminoprotective group; a group
• R. represents H or COIMHC 2 H s ; or a group
• R 7 represents H, CN or CONHCH 3 in a solvent such as for example dichloromethane, in the presence of at least one coupling agent such as l- (3-dimethylaminopropyl) -3-ethyl-carbodiimide (EDCI) or l-hydroxy-7-azabenzotriazole (HOAT), to obtain the glycinamide of formula VIII
• Ru and R n each independently represent a hydrogen atom or a C ⁇ -C 4 alkyl group, or together form a C ⁇ -C 3 alkylene chain
• x represents 2 or 3
• y represents 0 or 1
• R i3 represents an aminoprotective group, such as for example an Fmoc group, on a polystyrenic resin functionalized using a chloro-trityl group represented by the formula:
• n 1, 2, 3 or 4 and Rb represents a
• R 5 represents an alkyl group in -G, optionally substituted by a phenyl group; a group
• R 3 represents an aminoprotective group or a C 4 alkyl group a group
• R_> represents a hydrogen atom, COCH 3 , COOCH 3 , or a C ⁇ -C 4 alkyl group and R 5 represents a C ⁇ -C 4 alkyl group optionally substituted by a phenyl group; a group
• R 3 represents a hydrogen atom or a C ⁇ -C 4 alkyl group a group
• R 8 represents a hydrogen atom, a C 4 -C 4 alkyl group or NH 2 a group
• R 3 represents a hydrogen atom, a C ⁇ -C 4 alkyl group.
• certain compounds according to the invention can be prepared by carrying out the steps consisting in: a) reacting a grafted resin of formula XII obtained according to step (b) of the method described below above, with an acid of formula
• DIAD diisopropylazodicarboxylate
• HOBT 1-hydroxybenzotriazole hydrate
• the solid support (resin) is, unless otherwise indicated, a styrenic polymer (PS) crosslinked using 1% of divinylbenzene and functionalized with a chlorotrityl group.
• PS styrenic polymer
• PS represents the polystyrene support
• the stirring devices are always agitators with orbital movement, without agitator inside the reaction vessel.
• the identification and the purity of the new compounds prepared in solid phase are determined by means of an analysis by LC / MS coupling.
• HP1100 equipped with a 50x4.6 mm column filled with stationary phase of the C18 grafted silica type, 3.5 or 5 ⁇ m (for example referenced SYMMETRY from WATERS).
• the column is thermostatically controlled at 30 ° C.
• the mobile phase adjusted to a flow rate of 0.4 or 1 ml / min, is a gradient of the following solvents A and B:
• A distilled water containing 0.05% trifluoroacetic acid
• B acetonitrile containing 0.05% trifluoroacetic acid
• the different gradient conditions used for the analyzes are as follows (the values indicated in the table are the proportion in% of solvent B in the mixture A + B).
• the mass spectrograph is a PERKIN.ELMER SCIEX API 150 MCA device with detection by APCI + positive ionization.
• mM millimole (10 "3 mole).
• a solution of 0.4 g (0.871 mM) of the acid obtained according to Preparation III is prepared in 20 ml of dichloromethane, 0.18 g (0.958 mM) of 1- (3-dimethylaminopropyl) hydrochloride is added. 3-ethyl-carbodiimide (EDCI), then 0.13 g (0.958 mM) of 1-hydroxy-7-azabenzotriazole (HOAT). The reaction mixture is stirred at room temperature for 20 minutes and then 0.1 g (1 mM) of triethylamine and 0.29 g (0.958 mM) of the amine obtained according to preparation V are added. The mixture is stirred for 48 hours at room temperature and then poured over water.
• EDCI 3-ethyl-carbodiimide
• HOAT 1-hydroxy-7-azabenzotriazole
• a solution of 0.45 g (0.604 mM) of the compound obtained according to preparation VI is prepared in 10 ml of DMSO and 0.15 g (2.1 mM) of hydroxylamine hydrochloride and 0.427 g (4, 4) are added. 2 mM) of triethylamine.
• the reaction mixture is stirred for 24 hours at room temperature.
• 0.15 g of hydroxylamine hydrochloride and 0.427 g of triethylamine are again added and the mixture is stirred for 24 hours.
• F 102 ° C
• a solution of 1.96 g (15.3 mM) of 1- (3-aminopropyl) pyrrolidine in 25 ml of toluene is prepared and 2 g (15.3 mM) of 4-cyanobenzaldehyde are added.
• the solution is heated to reflux with stirring and the water formed by the reaction is removed using a Dean-Stark apparatus. The reaction takes about 6 hours. The solvent is then removed under reduced pressure and the residue is taken up in solution in 25 ml of methanol.
• 0.58 g (15.3 mM) of sodium borohydride is added and the reaction medium is stirred for 20 hours at room temperature.
• a solution of 5.36 g (25 mM) of the 1,1-dimethylethyl ester of 4- (aminomethyl) -1-piperidinecarboxylic acid in 60 ml of dichloromethane is prepared and a solution of 6.66 g is added.
• the reaction mixture is stirred for 18 hours at room temperature and then washed successively with a 0.1 N solution of hydrochloric acid, a saturated solution of sodium bicarbonate and with pure water.
• 1,1-dimethylethyl ester a) a solution of 0.444 g (1 mM) of the compound obtained according to preparation XXIX is prepared in 5 ml of dimethylformamide. 0.48 g (2 mM) of 4-iodobutyl acetate and 0.69 g (5 mM) of potassium carbonate are added. The reaction mixture is stirred for 24 hours at room temperature then diluted with 50 ml of ethyl acetate and washed successively with a 0.1 N solution of hydrochloric acid, a saturated solution of sodium bicarbonate and then with water. The organic phase is dried over sodium sulfate and then concentrated under pressure scaled down.
• Example 28 4 - [[[2 - [[2 - [[(2,4-dichloro-3-methylphenyl) sulfonyl] (2-phenylethyl) - amino] acetyl] amino] acetyl] [3- (1-pyrrolidinyl) propyl] amino] methyl] -N- methyl-benzamide
• a suspension of 0.73 g (2.94 mM) of the compound obtained according to preparation XXXVII is prepared in 50 ml of dichloromethane. 10.3 ml (20.6 mM) of a 2M solution of borane / dimethyl sulfide complex in tetrahydrofuran are added dropwise. The reaction mixture is stirred for 24 hours at room temperature. 15 ml of a 5N hydrochloric acid solution are added, then 15 ml of water, then 100 ml of methanol. The mixture is stirred for 20 hours at room temperature and then concentrated under reduced pressure.
• a solution of 8.66 g (40.5 mM) of 4- (aminomethyl) -1-Boc-piperidine in 100 ml of DCM is prepared. 5.26 g (40.5 mM) of DIPEA and a solution of 10.47 g (40.5 mM) of 9r / -fluoren-9-yl chloroformate (or Fmoc-CI) in 50 ml of DCM are added . The reaction mixture is stirred at room temperature for 1 hour, washed with a saturated solution of potassium hydrogen sulfate then with water until neutral. The organic phase is dried and then concentrated under reduced pressure. 16.9 g of the expected compound are thus obtained which is used without further purification for the following step.
• a suspension of 5.36 g of functionalized resin is prepared (1% styrene copolymer of divinylbenzene functionalized with a chlorotrityl group, charged with 2.05 mM / g of active chlorine obtained from the company Novabiochem), ie 11 mM, in 40 ml from DCM. 5.69 g (44 mM) of DIPEA are added, then a solution of 7.43 g (16.5 mM) of the compound obtained according to preparation XLIV. The reaction mixture is stirred using an orbital shaker for 18 hours at room temperature.
• the resin is separated by filtration and rinsed successively with 10 ml of DMF, 10 ml of methanol, 10 ml of DCM, 10 ml of methanol, 10 ml of DCM and 10 ml of ethyl ether. After drying, the resin is used directly to carry out the next step.
• the resin is washed successively with 3 ml of DMF, 3 ml of DCM, then 3 ml of DMF, and resuspended in 5 ml of DMF. 0.155 g (1.2 mM) of DIPEA is then added, 0.138 g (0.6 mM) of N-Boc-2-piperidinecarboxylic acid, 0.076 g (0.6 mM) of HOBT and 0.075 g (0.6 mM) of DIC. The mixture is stirred for 22 hours at room temperature and then filtered.
• the resin is washed successively with 3 ml of DMF, 3 ml of methanol, 3 ml of THF, 3 ml of methanol, 3 ml of THF and 5 ml of DCM, then dried.
• the dry resin is used directly for the next step.
• a 0.2 mM suspension of the resin obtained according to preparation XLVI is prepared in 2 ml of THF and 0.083 g (0.8 mM) of trimethyl borate is added, followed by 2 ml of a 2M solution of the borane / sulfide complex. dimethyl in ethyl ether. The mixture is stirred at room temperature for 23 hours.
• the resin is separated by filtration, washed with 3 ml of DCM, then 3 ml of THF and reacted in the presence of 2 ml of THF, 0.083 g (0.8 mM) of trimethylborate and 2 ml of the 2M solution of the complex borane / dimethyl sulfide in ether, for 72 hours at room temperature.
• the resin is separated by filtration, washed with 3 ml of DCM, then with 3 ml of THF and stirred in the presence of
• a solution of 0.081 g (0.6 mM) is added of HOBT in 1 ml of DMF, 0.076 g (0.6 mM) of DIC, 0.159 g (1.2 mM) of DIPEA then a solution of 0.276 g of the acid obtained according to preparation III in 1 ml of DMF.
• the reaction mixture is stirred for 12 hours at 50 ° C and then 10 hours at room temperature.
• the resin is separated by filtration and washed successively with 4 ml of DMF, 4 ml of DCM then 4 ml of DMF.
• the resin is then subjected to a new coupling cycle with the acid, under the same conditions, then washed with 4 ml of DMF, 4 ml of methanol, 4 ml of THF, 4 ml of methanol, 4 ml of THF and 4 ml of DCM and dried.
• a 0.2 mM suspension of the resin obtained according to preparation XLVIII is prepared in 4 ml of DCM and 0.4 ml of trifluoroacetic acid is added. The mixture is stirred for 1.5 hours at room temperature, then the resin is filtered and rinsed with 5 ml of DCM and then 5 ml of methanol. The combined filtrates are concentrated under a nitrogen flow and the evaporation residue is purified by preparative HPLC chromatography, using a 250 ⁇ 20 mm column loaded with INERTSIL PREP stationary phase. ODS obtained from the company G.L. Sciences Inc., and eluting using a gradient water / acetonitrile mixture and in the presence of 0.05% trifluoroacetic acid. 117 mg of the expected product are thus obtained. LC / MS (Grad. C): 2.32 min
• a 0.2 mM suspension of the resin obtained according to preparation IL in 1 ml of THF is prepared and 0.52 g (2 mM) of triphenylphosphine in solution in 2 ml of THF is added, then a solution of 0.46 g (2 mM) of 1,1-dimethylethyl ester of 4- (2-hydroxyethyl) -1-piperidinecarboxylic acid in 1 ml of THF, then 0.20 g (1 mM) of DIAD. The mixture is stirred for 30 min at room temperature and again 0.20 g (1 mM) of DIAD is added. The mixture is stirred at room temperature for 20 hours.
• the resin is filtered, washed with 2 ml of DCM then 2 ml of THF and subjected to a new alkylation cycle in the same conditions.
• the resin is then separated and washed successively with 2 ml of DMF, methanol, THF, methanol, THF and DCM each time.
• the grafted resin thus obtained is used in the next step.
• a 0.2 mM suspension of the resin obtained according to Preparation L is prepared in 5 ml of DMF. 0.22 g (2 mM) of thiophenol is added and then 0.12 g (1.2 mM) of triethylamine is added. The reaction mixture is stirred for 22 hours at room temperature, then the resin is separated by filtration and rinsed successively with 2 ml of DMF, methanol and THF each time. It is subjected a second time to the reaction cycle described above and it is washed on a filter successively with 2 ml of DMF, methanol, THF, methanol, THF and DCM each time. The resin thus obtained is used for the next step.
• Example 50 2 - [[(2,4-dichloro-3-methylphenyl) sulfonyl] (2-phenylethyl) amino] -N- [2- oxo-2 - [[2- (4-piperidinyl) ethyl] (4- piperidinylmethyl) amino] ethyl] - acetamide, bis trifluoroacetate
• Example 54 2 - [[(2,4-dichloro-3-methylphenyl) sulfonyl] (2-phenylethyl) amino] -N- [2- [[(1-methyl-3-piperidinyl) methyl] (4-piperidinylmethyl) amino] -2-oxoethyl] acetamide, bis trifluoroacetate
• Example 60 [[(2,4-dichloro-3-methylphenyl) sulfonyl] (2-phenylethyl) amino] -N- [2- oxo-2 - [(4-piperidinylmethyl) (4-pyridinylmethyl! Amino] ethyl] -acetamide, bis trifluoroacetate
• a suspension of 7.32 g (15 mM) of functionalized resin (analogous to that used for the XLV preparation) is prepared in 60 ml of DCM. 3.88 g (30 mM) of DIPEA and 2.65 g (30 mM) of 1,4-butanediamine are added. The reaction mixture is stirred for 18 hours at room temperature then the resin is filtered and washed successively with 15 ml of DCM, methanol, DCM and ethyl ether each time. It is then used for the next step.
• Example 80 N- [2 - [(4-aminobutyl) (3-aminopropyl) amino] -2-oxoethyl] -2 - [[(2,4-dichloro-3-methylphenyl) sulfonyl] (2-phenylethyl) amino] acetamide, bis trifluoroacetate
• a solution of 1.84 g (4 mM) of the acid obtained according to preparation III in 20 ml of acetonitrile is prepared and a solution of 1.97 g (4 mM) of the amine obtained is added to preparation LV in 20 ml of acetonitrile, then 1.67 g (4.4 mM) of HBTU (0-benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium hexafluoro phosphate) then 0.59 g ( 4.4 mM) of HOBT and 0.57 g (4.4 mM) of diisopropylethylamine.
• the reaction mixture is stirred for 20 hours at room temperature, then concentrated under reduced pressure.
• Example 100 2 - [[(2,3,4-trichlorophenyl) sulfonyl] methylamino] -N- [2 - [[[4- (4,5- d.hydro-ltf-imidazol-2-yl) phenyl] methyl ] methylamino] -2- oxoethyl] acetamide, trifluoroacetate
• Example 103 [[(2,4-dichloro-3-methylphenyl) sulfonyl] 2-propenylamino] -N- [2 - [[[4- (4,5-dihydro-1H-imid3zol-2-yl) phenyl ] methyl] methylamino] -2-oxoethyl] acetamide, hydrochloride
• the compounds of the present invention were evaluated for their analgesic property in the formaldehyde-induced pain test in mice (Shibata, M., Ohkubo, T., Takahashi, H. & R. Inoki. Modified formalin test: characteristic biphasic pain response. Pain, 38, 347-352).
• an administration of formaldehyde (0.92% in physiological saline) is carried out in the hind paw and the duration of licking, which reflects the intensity of the pain, is recorded from 0 to 5 min ( 1st phase) and 15 to 30 min (2 nd phase) after injection.
• the percentage of inhibition of the second phase of licking induced by formaldehyde is given, for a few compounds according to the invention, in the following table:
• ip intraperitoneal sc: subcutaneous
• the cord is dissected in Krebs solution in order to clear the umbilical vein.
• the vein is cleaned of any adherent tissue and cut into small rings of 3-4 mm wide.
• the endothelium is carefully removed by introducing a thin No. 1 catheter into the lumen of the vessel, made slightly abrasive.
• the vein segments are incubated at 37 ° C. in a 25 ml tank for 16 hours in a EMEM culture medium oxygenated with a 95% 0 2 + 5% C0 2 mixture to which antibiotics are added: penicillin 10,000 IU / ml and streptomycin 10,000 UG / ml.
• the vein rings are mounted on a stainless steel support, connected to an isometric sensor and placed in an 8 ml insulated organ tank thermostatically controlled at 37 ° C, containing Krebs solution oxygenated by a 95% mixture. 0 2 + 5% C0 2 .
• the vein is gradually subjected to a tension of 1 g.
• KPSS hyperpotassium solution
• Mepyramine (1 ⁇ M)
• Atropine (1 ⁇ M)
• Indometacin 3 ⁇ M
• LNA 30 ⁇ M
• Captopril 10 ⁇ M
• DL-Thiorphan 1 ⁇ M
• Nifedipine 0.1 ⁇ M
• the molecule to be tested or the solvent for the molecule is added to the isolated organ bath.
• the molecules are studied at 10 ⁇ M; if a molecule has a sufficient degree of activity, it is studied at lower concentrations (ex: 1 - 0.1 - 0.01 ⁇ M).
• the vein segments are contracted by the addition of increasing concentrations of des-Arg 10 -Kallidin (0.1 nM to 30,000 nM) in the tank.
• the EC 50 (effective concentrations of agonist required to produce 50% of the maximum response obtained with the KPSS) are calculated by the method of least squares.
• K B [A] / (concentration ratio- 1) where [A] is the concentration of antagonist and the (concentration ratio) represents the ratio between the EC 50 in the presence of antagonist, and the EC 50 in l absence of antagonist.
• the compounds according to the invention cited in the description have a pK B of between 7 and 9.
• the compounds of the present invention are useful for the treatment of various forms of pain such as inflammatory hyperalgesia, allodynia, neuropathic pain associated, for example, with diabetes, with neuropathies (constriction of the sciatic nerve, low back pain), any form of trauma, surgery (tooth extraction, removal of tonsils), interstitial cystitis, inflammatory colon disease, cancer.
• the compounds of the present invention can also be useful for treating any pathology associated with recruitment of neutrophils such as, for example, acute respiratory distress syndrome, psoriasis, chronic pulmonary obstructions, inflammatory colon diseases, rheumatoid arthritis.
• the use of the compounds defined by formula I, as well as their salts with non-toxic acids, is recommended as active principles of medicaments intended for treatment in mammals, in particular in humans, with regard to pain or certain diseases generally characterized by a massive migration of neutrophils.
• inflammatory hyperalgesia neuropathic pain, pain associated with trauma or cancer, inflammatory bowel disease, rheumatoid arthritis, psoriasis, chronic pulmonary obstructions or acute respiratory distress syndrome.
• the dose of active ingredient depends on the mode of administration and the type of pathology; it is generally between 0.05 and 10 mg / kg.
• the compounds of formula I or their salts may be combined with other active ingredients, and will be formulated with commonly used excipients.
• the mode of administration of the medicament will preferably be by injection, for example by intramuscular or subcutaneous route.

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