EP0946517A1 - Derives de n-(imidazolylbutyle) benzenesulfonamide ayant une activite antithrombotique - Google Patents
Derives de n-(imidazolylbutyle) benzenesulfonamide ayant une activite antithrombotiqueInfo
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- EP0946517A1 EP0946517A1 EP97947089A EP97947089A EP0946517A1 EP 0946517 A1 EP0946517 A1 EP 0946517A1 EP 97947089 A EP97947089 A EP 97947089A EP 97947089 A EP97947089 A EP 97947089A EP 0946517 A1 EP0946517 A1 EP 0946517A1
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Classifications
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- 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
-
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- 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
- C07D233/66—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 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
- C07D233/68—Halogen atoms
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- 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
- C07D401/06—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 carbon chain containing only aliphatic carbon 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
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- 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
-
- 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
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
Definitions
- the subject of the present invention is derivatives of 5 N- (imidazolylbutyl) benzenesulfonamide, their preparation and their therapeutic use.
- R ′ x each represent independently of one another, 0 either a hydrogen atom, or a halogen atom, or a (C -C j ) alkyl group
- R 2 represents either a p ⁇ dozensr ⁇ dm-1-yl group optionally substituted in position 4 by one or more groups chosen from hydroxy groups, (C 1 -C 4 ) straight or branched alkyl, 5 hydroxy (C 1 -C 4 ) alkyl, (C 1 -C 4) alkoxy (C 1 -C 4) alkyl,
- a group NOCH 3 , or a spiro group ((C 3 -C 6 ) cycloalkane- 1, 4 '-piperidin] -1-yle, or a group 1, 2, 3, 6-tetrahydropy-ridin-1-yle optionally substituted in position 4 by a (C 1 -C 4 ) straight or branched alkyl group (optionally substituted by one or more halogen atoms) or
- (C 3 -C 6 ) cycloalkyl, or a hexahydro-1H-azepin-1-yl group optionally substituted in position 4 by a trifluoromethyl group or CF 2 , or a heptahydroazocin-1-yl group, or an octahydro-1H group -azonin- 1-yle,
- A represents either a phenyl group optionally substituted by one or more substituents chosen from halogen atoms and (C -C j ) straight or branched alkyl groups, (Cx-C ⁇ straight or branched alkoxy, trifluoromethyl, trifluoromethoxy, formyl, -CH 2 OR 10 , -CH 2 OCOR 10 , -CH 2 OCONR 10 R 1; L , -COOR 10 , -CONR 10 R 1: I , nitro, -NR 10 R 1: L , -NHCOR 10 , and -NH (CH 2 ) q OR 10 with R 10 and R l each being independently of one another a hydrogen atom or a (C 1 -C 4 ) straight or branched alkyl group and q between 0 and 6, either a heterocycle chosen from pyridinyl, thienyl, furyl, pyrimidyl and thiazolyl groups, the said groups being
- R x and R'i each independently of one another represent either a hydrogen atom or a halogen atom or a (C 1 -C 4 ) alkyl group
- R 3 represents either a (C ⁇ -C ⁇ ) straight or branched alkyl group, or a -COR 5 group where R 5 is a (C x -C 4 ) straight or branched alkyl group, -CH 2 0 (C 2 H 4 0) n CH 3 , (CH 2 ) n 0H, (CH 2 ) n OCH 3 , i.e. a group -C0NHR 6 and
- A represents either a phenyl group optionally substituted by one or more substituents chosen from halogen atoms and (C 1 -C 4 ) straight or branched alkyl, (C 1 -C 4 ) straight or branched alkoxy, trifluoromethyl, trifluoromethoxy and -NR 10 R ⁇ ;
- the compounds of the invention may exist in the form of pure racemates or enantiomers or as a mixture of enantiomers. They can also exist in the form of free acid or base or of pharmaceutically acceptable addition salts. All these forms are part of the invention.
- the -CPh 3 group represents the t ⁇ phenylmethyl group.
- the compounds of formula (la) in which R 3 represents a group -COR 5 where R 5 is a (C 1 -C 4 ) straight or branched alkyl group or a group - (CH 2 ) n CF 3 ( n equal 1 to 4), can be synthesized according to scheme 1.
- R 5 is a (C 1 -C 4 ) straight or branched alkyl group or a group - (CH 2 ) n CF 3 ( n equal 1 to 4
- a compound of formula (II) can be reacted with a compound of formula (V) in which A represents either a substituted phenyl group as above, or a heterocycle chosen from the pyridmyl, thienyl, furyl, pynmidyl and thiazolyl groups, the said groups being able to be substituted as above, or a cyclo (C 5 -C 8 ) alkyl group, and R 4 and R 5 are as defined above, in an aprotic solvent such as dichloromethane in the presence of a base
- the process illustrated in diagram 3 can also be used.
- a compound of formula (VII) is reacted in which R ⁇ and R'i each represent either a hydrogen atom or a group ( C 1 -C 4 ) alkyl and R 2 , R 4 and R 5 are as defined above with a compound of formula (VIII) in which R represents a group (Ci-C ⁇ alkyl and A is as defined Diagram 2
- the corresponding compound of formula (la) in which R 4 is a hydrogen atom can be subjected to hydrogenolysis.
- the corresponding compound of formula (la) in which R ⁇ and / or R'represent a halogen atom then the corresponding compound of formula (la) in which R ⁇ and / or R' x represent is treated a hydrogen atom by a halogenating agent such as, for example, N-bromosuccinimide or N-chlorosuccinimide in a solvent such as dimethyl ormamide.
- a halogenating agent such as, for example, N-bromosuccinimide or N-chlorosuccinimide in a solvent such as dimethyl ormamide.
- R 3 represents either a group -C0R 5d is a group -S0 2 R 6 or a group -C0 ⁇ HR 6 or a -S0 2 N (R 6) 2 , 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 0P, P protecting group (n equal to 1 to 4) and R 6 is as defined previously, the method illustrated in diagram 4 is used.
- a compound of formula (II) is reacted with a compound of formula (X) in which A and R 4 are as defined above and a compound of formula (XI) is obtained which is reacted with a chloride of acid of formula R 5 C0C1 or an alkylisocyanate of formula R 6 NC0 or a sulfonyl chloride of formula R 6 S0 2 C1 or a sulfamoyl chloride of formula (R 6 ) 2 NS0 2 C1 and a compound of formula (XII is obtained) ) which are treated with a mixture of acetic acid: ethanol, acetic acid: water or acetic acid: tetrahydrofuran: water at reflux temperature.
- the starting compounds are commercially available or described in the literature or can be prepared according to methods which are described therein or which are known to those skilled in the art.
- N-cyclopentylformamide is described by Bossio R. et al., (1993), Synthesis, 8 . , 783-785.
- Examples 1 to 11 which follow illustrate the preparation of a few compounds of formula (II); Examples 12 to 27 illustrate the preparation of some compounds of formula (I) according to the invention.
- the reaction medium is concentrated under reduced pressure, the residue is taken up in 100 ml of ether and washed with 450 ml of an aqueous solution of 0.7 N hydrochloric acid.
- the phases are separated, the pH of the aqueous phase at 8-9 with a solution of 1 sodium hydrogen carbonate and 500 ml of ethyl acetate are extracted twice.
- the organic phases are combined, dried over sodium sulfate and concentrated under reduced pressure.
- the temperature of the mixture is allowed to return to ambient temperature and stirring is continued at this temperature for 24 hours.
- Evaporated under reduced pressure and the aqueous phase is acidified to pH 2 at 0 ° C with an aqueous solution of 1N hydrochloric acid before extracting twice with 300 ml of dichloromethane.
- the organic phases are combined, washed with 100 ml of a saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue is triturated in ether, filtered and dried under reduced pressure.
- the temperature of the mixture is allowed to return to ambient temperature, stirring is continued at this temperature for 18 hours and the reaction medium is concentrated under reduced pressure.
- the residue is taken up in 100 ml of ethyl acetate, washed successively with 50 ml of an aqueous solution of 1N hydrochloric acid, 50 ml of a saturated solution of sodium hydrogen carbonate, 50 ml of a solution saturated with sodium chloride, dried over sodium sulfate and concentrated under reduced pressure.
- the residue is purified by chromatography on a column of silica gel, eluting with a methanol: dichloromethane mixture (2:98).
- the reaction medium is poured onto 100 ml of a saturated ammonium chloride solution and extraction is carried out with 2 times 200 ml of ethyl acetate.
- the organic phases are combined, washed successively with 100 ml of water and 100 ml of a saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure.
- the temperature of the mixture is allowed to return to ambient temperature, stirring is continued at this temperature for 18 hours and the reaction medium is concentrated under reduced pressure.
- the residue is taken up in 100 ml of ethyl acetate, washed successively with 50 ml of an aqueous solution of 0.5N hydrochloric acid, 50 ml of a saturated solution of sodium hydrogen carbonate, 50 ml of 'A saturated solution of sodium chloride, dried over sodium sulfate and concentrated under reduced pressure.
- the residue is purified by chromatography on a column of silica gel, eluting with a methanol: dichloromethane mixture (2:98). 1.05 g of product are obtained in the form of a viscous oil.
- This compound is obtained from 4-methylenep ⁇ desperater ⁇ dme-l-carboxylate of 1, 1-dimethylethyl according to the method described in Example 3.1.3.
- Hydrogenation is carried out at 50 ° C. in a Parr apparatus under a pressure of 0.35 MPa (50 psi) 13 g (109 mmol) of 4-cyclopropylpyridme in solution in 150 ml of acetic acid in the presence of 0.7 g of 'platinum oxide (IV).
- the reaction medium is filtered on celite and the filtrate is concentrated under reduced pressure.
- the product is obtained in the form of a white powder.
- the residue is taken up in 200 ml of ethyl acetate and washed successively with twice 100 ml of an aqueous solution of 1N hydrochloric acid, 100 ml of water and 100 ml of a saturated solution of chloride sodium. It is dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on a silica gel column, eluting with ethyl acetate.
- the product is obtained in the form of an amorphous powder.
- the residue is taken up in 200 ml of ethyl acetate and washed successively with twice 100 ml of an aqueous solution of 0.1N hydrochloric acid, 100 ml of water and 100 ml of a saturated solution. in sodium chloride. It is dried over sodium sulfate and concentrated under reduced pressure.
- the residue is taken up in 100 ml of toluene and 15 ml of triethylamine, the mixture is heated for 18 hours at reflux temperature and concentrated under reduced pressure.
- the residue is purified by chromatography on a column of silica gel, eluting with an n-hexane: ether mixture (95: 5).
- the residue is taken up in 200 ml of ethyl acetate and washed successively with 3 times 30 ml of an aqueous solution of hydrochloric acid 1 ⁇ , 2 times 20 ml of a saturated solution of sodium hydrogenocarbonate then 20 ml saturated sodium chloride solution. It is dried over magnesium sulphate and concentrated under reduced pressure.
- the residue is purified by chromatography on a column of silica gel, eluting with a dichloromethane: methanol gradient (98: 2 to 97: 3).
- Example 12 (compound No. 67) ⁇ S) -N- [3- [[[4- (5-ethyl-1H- ⁇ m ⁇ dazol-4-yl) -1) hydrochloride -1- [(4-ethylp ⁇ dozensr ⁇ dm-1-yl) carbonyl] butyl] am o] sulfonyl] [1,1 '-biphenyl] -2-yl] propanamide (1: 1)
- the residue is taken up in 150 ml of ethyl acetate, washed successively with 50 ml of a saturated solution of sodium hydrogen carbonate and with 50 ml of a saturated solution of sodium chloride, dried over sodium sulfate and concentrated under reduced pressure.
- the residue is purified by chromatography on a column of silica gel, eluting with a methanol: dichloromethane mixture (4:96). 0.44 g of product is obtained in the form of the base, which is taken up in 10 ml of a solution of 0.1 ⁇ hydrochloric acid in isopropanol and concentrated under reduced pressure.
- Example 14 hydrochloride of (S) -N- [2 - [[[1- [(4-methoxypiperidin-1-yl) carbonyl] -4- (5-methyl-1H-imidazol -4- yl) butyl] amino] sulfonyl] - 6-thien-2-ylphenyl] propanamide (1: 1)
- the temperature of the mixture is allowed to return to ambient temperature, stirring is continued for 18 hours at this temperature and concentrated under reduced pressure.
- the residue is taken up in 100 ml of ethyl acetate, washed successively with 50 ml of an aqueous solution of 1N hydrochloric acid, 50 ml of a saturated solution of sodium hydrogen carbonate and 50 ml of a saturated sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure.
- the residue is taken up in 150 ml of ethyl acetate, washed successively with 50 ml of a saturated solution of sodium hydrogen carbonate and 50 ml of a saturated solution of sodium chloride, dried over sodium sulfate and concentrated under reduced pressure.
- the residue is purified by chromatography on a column of silica gel, eluting with a methanol: dichloromethane mixture (5:95). 0.43 g of product is obtained in the form of the base, which is taken up in 12 ml of a solution of 0.1N hydrochloric acid in isopropanol and concentrated under reduced pressure.
- the residue is purified by chromatography on a RP 18 column, eluting with an acetonitrile: water mixture (3: 7).
- Example 15 hydrochloride of (S) -N- [2- [[[4- (5-methyl-1H- ⁇ m ⁇ dazol-4-yl) -1- [(4-methylenep ⁇ peridm-1-yl) carbonyl] butyl] ammo] sulfonyl] -6- th ⁇ enyl-2-ylphenyl] propanamide (1: 1)
- Example 17 hydrochloride of (S) -N- [3 '- (ethylammo) -3 - [[[1- [(4-ethylp ⁇ - per ⁇ dm-1-yl) carbonyl] -4- (5 -methyl-1H- ⁇ m ⁇ dazol-4-yl) butyl] ammo] sulfonyl] [1, 1 '-biphenyl] -2 -yl] propanamide (2: 1)
- the residue is used as is in the next step.
- reaction medium is filtered on celite and the filtrate is concentrated under reduced pressure.
- residue is taken up in 100 ml of ethyl acetate, washed with 50 ml of a saturated solution of sodium hydrogen carbonate, dried over sodium sulfate and concentrated under reduced pressure.
- Example 18 hydrochloride of (S) -N- [3 - [[[1- [(4 -ethylp ⁇ dozensr ⁇ dm-1-yl) carbonyl] -4- (5-methyl-1H- ⁇ m ⁇ dazol-4- yl) butyl] ammo] sulfonyl] [1,1 '-biphenyl] -2-yl] -2- (2-methoxyethoxy) acetamide (1: 1)
- reaction medium is left under stirring at this temperature for 0.5 hour and then cooled by an ice bath.
- 100 ml of ethyl acetate and 100 ml of an aqueous hydrochloric acid solution 1 ⁇ are added and the organic phase is recovered. It is washed successively with 50 ml of a saturated solution of sodium hydrogen carbonate and 50 ml of a saturated solution of sodium chloride and then concentrated in vacuo.
- the residue is taken up in an acetic acid: water: tetrahydrofuran mixture (2: 1: 1), the mixture is heated for 3 hours at 80 ° C. and concentrated in vacuo.
- the residue is taken up in 100 ml of ethyl acetate, washed successively with 50 ml of a 1 ⁇ hydrochloric acid solution, 50 ml of a saturated solution of sodium hydrogen carbonate and 50 ml of a solution saturated with sodium chloride and then dried over magnesium sulfate. Finally, it is filtered and concentrated under vacuum. The residue is purified by chromatography on a column of silica gel, eluting with a dichloromethane: methanol mixture (98: 2 then 90:10).
- the hydrochloride is prepared in 10 ml of a solution of 0.1N hydrochloric acid in isopropanol. 0.57 g of product is obtained after lyophilization.
- Example 19 (compound no. 30) ⁇ S) -N- [2-cyclopentyl-6- [[[[1- [(4-ethylp ⁇ pec- ⁇ dm-1-yl) carbonyl) -4- (5-methyl-) hydrochloride 1H-imidazol -4 -yl) butyl] ammo] sulfonyl] phenyl] -N '-ethylurea (1: 1)
- the reaction medium is left under stirring for 5 hours at this temperature and then concentrated under reduced pressure.
- the residue is taken up in 100 ml of ethyl acetate, washed successively with 50 ml of a 1 ⁇ hydrochloric acid solution, 50 ml of a saturated solution of sodium hydrogen carbonate and 50 ml of a solution saturated with sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure.
- the residue is taken up in 200 ml of ethyl acetate, washed successively with 50 ml of a saturated solution of sodium hydrogen carbonate and 50 ml of a saturated solution of sodium chloride, dried over sodium sulfate and concentrated under reduced pressure.
- the residue is purified by chromatography on a column of silica gel, eluting with a methanol: dichloromethane mixture (5:95).
- the base is taken up in 15 ml of a solution of hydrochloric acid 0.1 ⁇ in isopropanol and concentrated under reduced pressure.
- the residue thus obtained is purified on a RP 18 column, eluting with an acetonitrile: water mixture (6: 4).
- the reaction medium is concentrated under reduced pressure and the residue is taken up in 150 ml of ethyl acetate. It is washed successively with 50 ml of a saturated solution of sodium hydrogenocarbonate and 50 ml of a saturated solution of sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel, eluting with a methanol: dichloromethane mixture (5:95).
- the base is taken up in 25 ml of a solution of hydrochloric acid 0.1 ⁇ in isopropanol and concentrated under reduced pressure.
- the residue thus obtained is purified on a RP 18 column, eluting with an acetonitrile: water mixture (6: 4).
- Example 22 (compound No. 22) ⁇ S) -N- [2 - [[[1- [(4-ethylpiperidin-1-yl) carbonyl) hydrochloride] -4- (5-methyl-1H-imidazol-4 - yl) butyl] amino] sulfonyl] - 4-fluoro-6-thien-2 -ylphenyl] propanamide (1: 1)
- the temperature of the reaction medium is allowed to slowly return to ambient temperature, stirring is continued at this temperature for 15 hours and concentrated under reduced pressure.
- the residue is taken up in 300 ml of ethyl acetate and washed successively with 300 ml of an aqueous solution of hydrochloric acid 1 ⁇ , 300 ml of a saturated solution of sodium hydrogen carbonate then 300 ml of a saturated sodium chloride solution. It is dried over sodium sulfate, filtered and concentrated under reduced pressure.
- the residue is heated for 12 hours in 225 ml of an acetic acid: water mixture (2: 1) and concentrated under reduced pressure.
- the residue is taken up in 400 ml of dichloromethane and washed successively with 200 ml of a saturated solution of sodium hydrogenocarbonate then 200 ml of a saturated solution of sodium chloride. It is dried over sodium sulfate, filtered and concentrated under reduced pressure.
- the residue thus obtained is purified by chromatography on a column of silica gel, eluting with a dichloromethane: methanol mixture (96: 4).
- the hydrochloride is prepared by adding 45.1 ml of a solution of 0.1 ⁇ hydrochloric acid in isopropanol to 2.5 g (4.5 mmol) of base.
- This product is prepared according to the procedure described in Example 19 from 0.81 g (1.36 mmol) of (S) -5-methyl- ⁇ - [[4- (difluoromethylene) piperidin-1 hydrochloride -yl] carbonyl] -1- (triphenylmethyl) -1H-imidazole-4 -butanamine and 0.47 g (1.36 mmol) of 2- [(1 -ehloropropylidene) amino] -3-thien-2 chloride -ylbenzenesulfonyl.
- Example 24 hydrochloride of (S) -N- [6-cyclopentyl-2- [[[[1- [(4 -ethylpiperidin-1-yl) carbonyl] -4- (5-methyl- 1H-imidazol-4 -yl) butyl] amino] sulfonyl] phenyl] propanamide (1: 1)
- Example 25 hydrochloride of (S) -N- [2- [[[4- (5-methyl-1H- ⁇ m ⁇ dazol-4-yl) -1- [(5-oxohexahydro-1H-1, 4-d ⁇ azépm-l-yl) carbonyl] butyl] ammo] sulfonyl] -6-thien-2 -ylphenyl] propanamide (1: 1)
- the mixture is heated overnight at 50 ° C., the medium is evaporated to dryness and the residue is taken up in 100 ml of dichloromethane. Wash with an aqueous solution of sodium hydrogen carbonate and dry over magnesium sulfate. The residue is filtered and purified by chromatography on a column of silica gel in eluting with a dichloromethane: methanol mixture (90:10). The base is dissolved in a solution of 0.1N hydrochloric acid in isopropanol and the product is purified by chromatography on a RP 18 silica column, eluting with an acetonitrile / water mixture.
- Example 26 (Compound No. 65) (S) -N-cyclopentyl -N, 5-dimethyl- ⁇ - [[[2- [(1- oxopropyl) ammo] -3-th ⁇ én-2-ylphenyl] sulfonyl]] hydrochloride ammo] - 1H- ⁇ m ⁇ dazole-4-pentanam ⁇ de (1: 1)
- the temperature of the reaction medium is allowed to return to ambient temperature and stirring is continued for 15 hours at this temperature.
- the reaction medium is concentrated under reduced pressure.
- the residue is taken up in 150 ml of ethyl acetate and washed successively with 50 ml of an aqueous solution of hydrochloric acid 1 ⁇ , 50 ml of a saturated solution of sodium hydrogen carbonate and then with 50 ml of saturated sodium chloride solution. Dried over sodium sulfate.
- the residue is purified by chromatography on a column of silica gel, eluting with a dichloromethane: methanol mixture (97: 3).
- the mixture is left for 10 hours with stirring and then 150 ml of ethyl acetate are added. Washed with 150 ml of water and then with 100 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 60 ml of ethyl acetate and 30 ml of water and then the mixture is heated at reflux temperature for 2 hours. 150 ml of dichloromethane are then added and the mixture is washed successively with 100 ml of a saturated solution of sodium hydrogen carbonate and 100 ml of a saturated solution of sodium chloride. It is dried over sodium sulfate, filtered and concentrated under reduced pressure.
- HCl corresponds to a hydrochloride and the ratio between brackets is the ratio (acid: base),
- the compounds of the invention have been the subject of pharmacological studies which have demonstrated their antithrombotic properties and their advantage as substances with therapeutic activity.
- the K ⁇ is determined by the Dixon method.
- the compounds of the invention are thrombin inhibitors and their K ⁇ is between 0.001 and 100 ⁇ M.
- 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;
- the compounds of the invention can be useful in all clinical indications linked to thrombosis or in those where thrombotic complications could occur.
- oral, parenteral or intravenous administration such as tablets, dragees, capsules, capsules, suspensions or oral or injectable solutions, etc. in combination with suitable excipients. All these forms are dosed to allow administration of 1 to 1000 mg per day per patient, in one or more doses.
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Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR9614309A FR2756285B1 (fr) | 1996-11-22 | 1996-11-22 | Derives de n-(imidazolylbutyle)benzenesulfonamide, leur preparation et leur application en therapeutique |
FR9614309 | 1996-11-22 | ||
PCT/FR1997/002079 WO1998022443A1 (fr) | 1996-11-22 | 1997-11-19 | Derives de n-(imidazolylbutyle) benzenesulfonamide ayant une activite antithrombotique |
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EP0946517A1 true EP0946517A1 (fr) | 1999-10-06 |
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EP97947089A Ceased EP0946517A1 (fr) | 1996-11-22 | 1997-11-19 | Derives de n-(imidazolylbutyle) benzenesulfonamide ayant une activite antithrombotique |
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EP (1) | EP0946517A1 (xx) |
JP (1) | JP2001504128A (xx) |
KR (1) | KR20000069063A (xx) |
CN (1) | CN1238765A (xx) |
AR (1) | AR009627A1 (xx) |
AU (1) | AU5226498A (xx) |
BG (1) | BG103414A (xx) |
BR (1) | BR9713291A (xx) |
CA (1) | CA2270478A1 (xx) |
CO (1) | CO4910158A1 (xx) |
CZ (1) | CZ178299A3 (xx) |
EE (1) | EE9900201A (xx) |
FR (1) | FR2756285B1 (xx) |
HU (1) | HUP9904599A2 (xx) |
IL (1) | IL129546A0 (xx) |
NO (1) | NO992436L (xx) |
SK (1) | SK66799A3 (xx) |
TR (1) | TR199901143T2 (xx) |
WO (1) | WO1998022443A1 (xx) |
ZA (1) | ZA9710515B (xx) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2783521B1 (fr) * | 1998-09-18 | 2002-04-26 | Synthelabo | Derives de n-(arginyl) benzenesulfonamide, leur preparation et leur application en therapeutique |
FR2806722B1 (fr) * | 2000-03-23 | 2002-05-17 | Sanofi Synthelabo | Derives de n-(heterocyclylbutyl) benzene-ou pyridine sulfonamide, leur preparation et leur application en therapeutique |
WO2016051420A1 (en) | 2014-09-29 | 2016-04-07 | Cellix Bio Private Limited | Compositions and methods for the treatment of multiple sclerosis |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
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FR2689130B1 (fr) * | 1992-03-30 | 1994-05-27 | Synthelabo | Derives de 1-[2 (arylsulfonylamino)ethyl-1-oxo] piperidine, leur preparation et leur application en therapeutique. |
FR2710066B1 (fr) * | 1993-09-14 | 1995-10-20 | Synthelabo | Dérivés de 1-[2-amino-5-[1-(triphénylméthyl-1H-imidazol-4-yl]-1-oxopentyl]piperidine, leur préparation et leur utilisation comme intermédiaires de synthèse. |
FR2727410B1 (fr) * | 1994-11-25 | 1996-12-20 | Synthelabo | Chlorures de sulfonyles, leur preparation et leur utilisation comme intermediaires de synthese |
FR2728570B1 (fr) * | 1994-12-23 | 1997-04-11 | Synthelabo | Derives de 1-oxo-2-(phenylsulfonylamino)pentylpiperidine, leur preparation et leur application en therapeutique |
DE19548797A1 (de) * | 1995-12-27 | 1997-07-03 | Thomae Gmbh Dr K | Substituierte 2-Amino-imidazole, ihre Herstellung und ihre Verwendung als Arzneimittel |
-
1996
- 1996-11-22 FR FR9614309A patent/FR2756285B1/fr not_active Expired - Fee Related
-
1997
- 1997-11-19 WO PCT/FR1997/002079 patent/WO1998022443A1/fr not_active Application Discontinuation
- 1997-11-19 CN CN97199986A patent/CN1238765A/zh active Pending
- 1997-11-19 EP EP97947089A patent/EP0946517A1/fr not_active Ceased
- 1997-11-19 KR KR1019997004485A patent/KR20000069063A/ko not_active Application Discontinuation
- 1997-11-19 BR BR9713291-8A patent/BR9713291A/pt not_active Application Discontinuation
- 1997-11-19 CO CO97067574A patent/CO4910158A1/es unknown
- 1997-11-19 CA CA002270478A patent/CA2270478A1/en not_active Abandoned
- 1997-11-19 EE EEP199900201A patent/EE9900201A/xx unknown
- 1997-11-19 CZ CZ991782A patent/CZ178299A3/cs unknown
- 1997-11-19 IL IL12954697A patent/IL129546A0/xx unknown
- 1997-11-19 HU HU9904599A patent/HUP9904599A2/hu unknown
- 1997-11-19 TR TR1999/01143T patent/TR199901143T2/xx unknown
- 1997-11-19 JP JP52328498A patent/JP2001504128A/ja active Pending
- 1997-11-19 SK SK667-99A patent/SK66799A3/sk unknown
- 1997-11-19 AU AU52264/98A patent/AU5226498A/en not_active Abandoned
- 1997-11-21 AR ARP970105455A patent/AR009627A1/es unknown
- 1997-11-21 ZA ZA9710515A patent/ZA9710515B/xx unknown
-
1999
- 1999-05-19 BG BG103414A patent/BG103414A/xx unknown
- 1999-05-20 NO NO992436A patent/NO992436L/no not_active Application Discontinuation
Non-Patent Citations (1)
Title |
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See references of WO9822443A1 * |
Also Published As
Publication number | Publication date |
---|---|
CZ178299A3 (cs) | 1999-08-11 |
NO992436D0 (no) | 1999-05-20 |
IL129546A0 (en) | 2000-02-29 |
BG103414A (en) | 2000-01-31 |
BR9713291A (pt) | 1999-10-26 |
FR2756285A1 (fr) | 1998-05-29 |
TR199901143T2 (xx) | 1999-08-23 |
FR2756285B1 (fr) | 1998-12-18 |
AU5226498A (en) | 1998-06-10 |
CN1238765A (zh) | 1999-12-15 |
EE9900201A (et) | 1999-12-15 |
NO992436L (no) | 1999-07-22 |
CA2270478A1 (en) | 1998-05-28 |
CO4910158A1 (es) | 2000-04-24 |
JP2001504128A (ja) | 2001-03-27 |
ZA9710515B (en) | 1998-06-10 |
WO1998022443A1 (fr) | 1998-05-28 |
AR009627A1 (es) | 2000-04-26 |
KR20000069063A (ko) | 2000-11-25 |
HUP9904599A2 (hu) | 2000-06-28 |
SK66799A3 (en) | 2000-02-14 |
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