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    • 专利摘要:
    PURPOSE: Provided are new benzothiophene, benzofuran and indole compounds, and pharmaceutical compositions containing them. The compounds have inhibition effect on the activity of PAI-1, and are thus therapeutically useful in the field of fibrinolysis and thrombosis. CONSTITUTION: The compound is represented by the formula(I), wherein X represents oxygen, sulphur, or NR3 wherein R3 is as defined in the description;Y represents oxygen, sulphur, NR3, or may represent single bond in certain cases;T represents nitrogen, carbon, or CH; A represents single bond, alkylene, arylene, cycloalkylene, heterocycloalkylene, heteroarylene, or -SO2-R4- wherein R4 is as defined in the description,W represents hydroxy, alkoxy, aryloxy, arylalkoxy, cycloalkyloxy, heterocycloalkyloxy or heteroaryloxy, or hydroxyamino; U1 represents hetero, or alkylene wherein one or more of carbon may optionally be replaced by one or more hetero atoms; V1 represents arylene, heteroarylene,or heterocycloalkylene; U2 represents single bond, hetero or alkylene wherein one or more carbon may optionally be replaced by one or more hetero atoms; V2 represents aryl, heteroaryl, or heterocycloalkyl, Ra, Rb, Rc, which may be identical or different; each independently of the others represents a group as defined in the description; R1 represents aryl substituted by from one to five substituents, 1,3-dihydro-2H-indol-2-one, 3,4-dihydro-2(1H)-quinolinone, 1-hydroxy-2(1H)-pyridinone group, or heteroaryl; R2 represents halogen, alkyl, aryl, arylalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.
    公开号:KR20010051018A
    申请号:KR1020000060286
    申请日:2000-10-13
    公开日:2001-06-25
    发明作者:길라움 드난토일；크리스틴 릴라；토니 버보이렝；알랭 루팽
    申请人:오딜 오스터만；아디르 에 꽁빠니；
    IPC主号:
    专利说明:

    Benzothiophene, benzofuran and indole compounds, methods for their preparation and pharmaceutical compositions containing them {NEW BENZOTHIOPHENE, BENZOFURAN AND INDOLE COMPOUNDS, A PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM}
    The present invention relates to novel benzothiophene, benzofuran and indole compounds, methods for their preparation and pharmaceutical compositions containing them. These novel compounds have the property of inhibiting the activity of PAI-1, and are thus therapeutically useful in the field of fibrin degradation and thrombosis.
    PAI-1 is a potent inhibitor of plasminogen activators (tissue plasminogen activators and urokinase). In vitro and in vivo, this inhibits the breakdown of fibrin masses formed by the action of thrombin on fibrinogen. Numerous infectious disease studies have suggested that high levels of PAI-1 are associated with frequent onset of thromboembolism in humans. In addition, in experimental models of thrombosis and thrombolysis, inhibition of PAI-1 activity by anti-PAI-1 monoclonal antibodies reduces the incidence of re-obstruction. As such, the therapeutic value of molecules that have the property of inhibiting the activity of PAI-1 in the formed or in the process of formation of fibrin mass is due to the degradation of PAI-1 at an early stage before complexing with factor XIIIa, resulting in high levels of PAI-1. Reduces the incidence of thromboembolism in patients with -1. Such compounds are useful for all diseases originating from thrombosis (eg myocardial infarction, angina pectoris, intermittent claudication, cerebrovascular accident, deep vein thrombosis or pulmonary embolism) and diseases that increase the risk of thrombosis (eg, hypertension, hypercholesterolemia, diabetes, obesity). It is therapeutically useful in hereditary clotting abnormalities (factor V Leiden, deficiency in proteins C and S) or acquired clotting abnormalities.
    The compounds of the invention are not only novel but also proved to be potent PAI-1 inhibitors than those described in the literature, and are potentially useful for the treatment of diseases that cause thrombosis, diseases originating from thrombosis and increased thrombosis risk. .
    Numerous antithrombotic agents have been described in the literature. This corresponds in particular to the compounds described in patent specifications WO 97/45424, WO 94/08962, EP 540 051 and GB 2225012.
    The object of the present invention is not only novel but also proved to be a potent PAI-1 inhibitor than those described in the literature, which are potentially useful for the treatment of thrombosis, diseases originating from thrombosis and diseases which lead to an increased risk of thrombosis In providing.
    The present invention specifically relates to compounds of formula (I), their isomers and addition salts thereof with pharmaceutically acceptable acids or bases:
    In the above formula,
    X is an oxygen atom, a sulfur atom or an NR 3 group, where R 3 is a hydrogen atom, a linear or branched (C 1 -C 6 ) alkyl group, a linear or branched (C 1 -C 6 ) acyl group, an acyl group , Aryl- (C 1 -C 6 ) alkyl group, wherein the alkyl moiety is in linear or branched form, or heteroaryl- (C 1 -C 6 ) alkyl group, wherein the alkyl moiety is in linear or branched form Is);
    Y is an oxygen atom, a sulfur atom or an NR 3 group, wherein R 3 is as defined above, or X is NR ' 3 (wherein R' 3 is a heteroaryl wherein the alkyl moiety is in linear or branched form) A (C 1 -C 6 ) alkyl group) can be a single bond;
    T is a nitrogen atom bonded to neighboring carbon atoms to form a single bond (-), or a single bond (-) or double bond (bonded to neighboring carbon atoms) Is a carbon atom or a CH group depending on whether
    A represents a single bond or (C 1 -C 6) alkylene group (the one or more linear or branched (C 1 -C 6) alkyl group, an aryl group, an aryl, alkyl moiety is linear or branched form - (C 1 -C 6 Substituted or unsubstituted with an alkyl group, a cycloalkyl group, a heterocycloalkyl group, or a heteroaryl group), arylene, cycloacylene, heterocycloalkylene, heteroarylene, and -SO 2 -R 4 groups, where SO 2 Moiety is bonded to T, and R 4 is linear or branched (C 1 -C 6 ) alkylene, arylene, aryl- (C 1 -C 6 ) alkylene, cyclo wherein the alkylene moiety is in linear or branched form A group selected from alkylene, heterocycloalkylene and heteroarylene);
    W is hydroxy, linear or branched (C 1 -C 6 ) alkoxy, aryloxy, aryl (C 1 -C 6 ) alkoxy, cycloalkyloxy, heterocycloalkyloxy, hetero, wherein the alkoxy moiety is in linear or branched form aryloxy, amino (itself a linear or branched (C 1 -C 6) alkyl, aryl, alkyl moiety is linear or branched in the form of aryl, each is (C 1 -C 6) selected from alkyl, and cycloalkyl May be substituted with one or two identical or different groups) and hydroxyamino;
    U 1 is an oxygen atom, a sulfur atom or a linear or branched (C 1 -C 6 ) alkylene chain, wherein one or more carbon atoms are unsubstituted or substituted by one or more atoms selected from oxygen, nitrogen and sulfur And alkylene may be unsubstituted or substituted by one or more identical or different groups selected from halogen, hydroxy, linear or branched (C 1 -C 6 ) alkyl and linear or branched (C 1 -C 6 ) alkoxy. Can be);
    V 1 is an arylene, heteroarylene or heterocycloalkylene group;
    U 2 is a single bond, oxygen atom, nitrogen atom, sulfur atom or a linear or branched (C 1 -C 6 ) alkylene chain, wherein at least one carbon atom is oxygen, sulfur or nitrogen atom (nitrogen atom is hydrogen and And may be unsubstituted or substituted by one or more identical or different groups selected from linear or branched (substituted with a group selected from (C 1 -C 6 ) alkyl)) and a SO 2 group;
    V 2 is an aryl, heteroaryl or heterocycloalkyl group;
    Ra, Rb and Rc are the same or different and each individually
    Hydrogen, halogen,
    Hydroxy, cyano, nitro,
    Linear or branched (C 1 -C 6 ) alkyl, linear or branched (C 1 -C 6 ) alkoxy, linear or branched (C 1 -C 6 ) acyl, carboxy, linear or (C 1 -C 6) Alkoxycarbonyl, linear or branched (C 1 -C 6 ) trihaloalkyl,
    -Amino (linear or branched (C 1 -C 6) alkyl, aryl, and the alkyl moiety is linear or branched in the form of aryl - (C 1 -C 6), each one individually selected from alkyl or two of the same or different Unsubstituted or substituted with a group),
    Aryloxy, aryl- (C 1 -C 6 ) alkoxy in which the alkoxy moiety is in linear or branched form, heteroaryloxy, heteroaryloxy- (C 1 -C 6 ) alkoxy in which the alkoxy moiety is in linear or branched form, And
    Or a group selected from the formula -U 1 -V 1 -U 2 -V 2 , wherein U 1 , U 2 , V 1 and V 2 are as defined above, or
    Two of them together are methylenedioxy or ethylenedioxy groups (each of which one or two linear or branched (C 1 -C 6 ) alkyl groups, aryl groups or alkyl moieties in linear or branched form; C 1 -C 6 ) alkyl group unsubstituted or substituted;
    R 1 is
    Halogen, hydroxy, cyano, nitro, carboxy, linear or branched (C 1 -C 6 ) alkyl, linear or branched (C 1 -C 6 ) alkoxy, linear or branched (C 1 -C 6 ) Acyl, linear or branched (C 1 -C 6 ) alkoxycarbonyl, linear or branched (C 1 -C 6 ) trihaloalkyl (with or without a substituted hydroxy group), linear or branched (C 1 -C 6 ) trihaloalkoxy, amino (substituted or unsubstituted with one or two linear or branched (C 1 -C 6 ) alkyl groups, of which alkyl groups are amino, linear or branched (C 1 -C 6 ) Alkylamino and alkyl moieties may or may not be substituted with groups selected from di- (C 1 -C 6 ) alkylamino in linear or branched form, respectively, and amino- (C 1 -C 6 ) alkoxy (alkoxy moieties In linear or branched form, the amino moiety being one or two identical or different linear or branched (C 1 -C 6 ) alkyl groups (C 1 -C 6 ) alkoxycarbonyl (C 1 -C 6 ) alkyl, linear or branched (C 1 -C 6 ), wherein the alkoxy and alkyl moieties are each substituted or unsubstituted ) alkylcarbonylamino, in which the alkyl portion is a linear or branched form aryl - (C 1 -C 6) alkyl, aryloxy, aryl-alkoxy part of the linear or branched form - (C 1 -C 6) alkoxy, aryl amino, the alkyl moiety is a linear or branched form aryl - (C 1 -C 6) alkylamino, aryl-isoquinoline, wherein the aryl alkyl moiety a linear or branched form - (C 1 -C 6) alkyl sulfanyl, heterocycloalkyl Aryl, heteroaryl- (C 1 -C 6 ) alkyl in which the alkyl moiety is in linear or branched form, heteroaryl- (C 1 -C 6 ) alkoxy, heteroaryl in which the alkoxy moiety is in linear or branched form Amino, heteroaryl- (C 1 -C 6 ) alkylamino, heteroarylsulfanyl, alkyl moiety linear or branched Or heteroaryl- (C 1 -C 6 ) alkylsulfanyl in branched form,
    A 1,3-dihydro-2H-indol-2-one, 3,4-dihydro-2 (1H) -quinolinone or 1-hydroxy-2 (1H) -pyridinone group, or
    -A substituted or unsubstituted heteroaryl group;
    R 2 is a hydrogen atom, a linear or branched (C 1 -C 6 ) alkyl group, an aryl group, an aryl- (C 1 -C 6 ) alkyl, group, cycloalkyl group, heterocycloalkyl group in which the alkyl moiety is in linear or branched form , a heterocycloalkyl of the alkyl moiety a linear or branched alkyl form - (C 1 -C 6) alkyl group, heteroaryl group, heteroalkyl portion are the linear or branched form aryl - (C 1 -C 6) alkyl group selected from Is;
    In the above,
    Aryl group means a phenyl, biphenyl, naphthyl, tetrahydronaphthyl or dihydronaphthyl group, each of which is halogen, hydroxy, cyano, nitro, linear or branched (C 1 -C 6 ) alkyl group ( Hydroxy, amino and alkyl moieties are each substituted or unsubstituted with one or more groups selected from mono- or di- (C 1 -C 6 ) alkylamino in linear or branched form), linear or branched (C 1- C 6 ) trihaloalkyl, linear or branched (C 1 -C 6 ) alkoxy, aryloxy, linear or branched (C 1 -C 6 ) acyl, carboxy, linear or branched (C 1 -C 6 ) May be unsubstituted or substituted with one or more identical or different groups selected from alkoxycarbonyl and amino (amino is substituted or unsubstituted with one or two identical or different linear or branched (C 1 -C 6 ) alkyl groups) ;
    -Cycloalkyl group means a single or bicyclic group of (C 3 -C 8 );
    Heterocycloalkyl group means a saturated or unsaturated non-aromatic single or double cyclic having 5 to 12 elements in one ring and containing one to three identical or different heteroatoms selected from oxygen, nitrogen or sulfur; Halogen, hydroxy, linear or branched (C 1 -C 6 ) alkyl, linear or branched (C 1 -C 6 ) trihaloalkyl, linear or branched (C 1 -C 6 ) alkoxy, aryl Oxy, alkoxy moiety is linear or branched aryl- (C 1 -C 6 ) alkoxy, amino (substituted or substituted with one or more linear or branched (C 1 -C 6 ) alkyl groups), linear or branched ( May be substituted or unsubstituted with one or more identical or different groups selected from C 1 -C 6 ) acyl, linear or branched (C 1 -C 6 ) alkoxycarbonyl, nitro and oxo,
    Heteroaryl group means a single or bicyclic heterocycloalkyl, as defined above, having aromatic character in at least one ring, and in the case of bicyclic systems, on a ring or partially unsaturated ring having aromatic character It is possible for a hetero atom to be located, and the heteroaryl group may or may not be substituted with one or more of the same or different groups as previously defined for the substituents of the heterocycloalkyl group.
    Pharmaceutically acceptable acids include hydrochloric acid, boric acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, glutaric acid, succinic acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, Oxalic acid, methanesulfonic acid, camphoric acid, and the like.
    Pharmaceutically acceptable bases include, but are not limited to, sodium hydroxide, potassium hydroxide, triethylamine, tertiary butylamine, and the like.
    Heterocycloalkyls include, but are not limited to, piperidine, pyreazine and morpholine.
    Heteroaryls include pyridine, pyrimidine, quinoline, isoquinoline, 1,3-dihydro-2H-pyrrolopyridin-2-one, 3H-imidazolpyridine, 1H-pyrrolopyridine, 1,2,3,4- Tetrahydronaphthopyridine and 2,3-dihydro-1H-pyrrolopyridine.
    Preferred compounds of the invention are compounds wherein X is a sulfur atom or an NR 3 group, wherein R 3 is as defined in formula (I).
    Preferred compounds of the present invention are compounds wherein Y is an oxygen atom.
    Preferred according to the invention R 1 is a group selected from phenyl unsubstituted or substituted with a group as defined in formula (I), substituted or unsubstituted quinolyl and substituted or unsubstituted pyridyl.
    Preferred according to the invention R 2 is a group selected from aryl and heteroaryl, each of which is substituted or unsubstituted. In a preferred embodiment, the preferred R 2 substituent is a pyridyl group.
    Preferred U 1 -V 1 -U 2 -V 2 substituents (which is replaced by the oxygen atom one of the carbon atoms), a linear U 1 (C 1 -C 4) alkylene chain in accordance with the present invention, V 1 is an aryl group And U 2 is a single bond and V 2 is a substituent in which the aryl group is unsubstituted or substituted with one of the groups defined in formula (I).
    Particularly preferred U 1 -V 1 -U 2 -V 2 substituents are [1,1′-biphenyl] -4-ylmethoxy groups.
    According to a preferred embodiment of the invention, preferred compounds are compounds in which one of Ra, Rb or Rc is a group of the formula U 1 -V 1 -U 2 -V 2 as defined in formula (I).
    According to a preferred embodiment of the invention, preferred compounds are compounds wherein X is a sulfur atom and Y is an oxygen atom.
    According to a preferred embodiment of the invention, the preferred compound is
    X is a sulfur atom,
    Y is an oxygen atom,
    R 1 is a substituted or unsubstituted phenyl group or a substituted or unsubstituted pyridyl group,
    When T is a carbon atom or a CH group, A is a compound which is a single bond.
    According to a preferred embodiment of the invention, the preferred compound is
    X is a sulfur atom,
    Y is an oxygen atom,
    R 1 is a phenyl group substituted or unsubstituted with a group as defined in formula (I),
    - when T is a nitrogen atom A is an alkyl group (linear or branched (C 1 -C 6) alkyl group, an aryl group, or the alkyl portion is a linear or branched form aryl - (C 1 -C 6) alkyl substituted with Or unsubstituted) or an arylene group.
    According to a fourth preferred embodiment of the invention, the preferred compounds of the invention are compounds of the formula (I bis):
    In the above formula,
    X is a sulfur atom,
    Y is an oxygen atom,
    R 1 is a substituted or unsubstituted phenyl group or a substituted or unsubstituted pyridyl group,
    A is a single bond,
    T is a carbon atom,
    Ra and Rc are each hydrogen atoms,
    U 1 is a (C 1 -C 4 ) alkylene chain,
    V 1 is an arylene group,
    U 2 is a single bond,
    V 2 is an aryl group,
    R b is a U 1 -V 1 -U 2 -V 2 group as defined above,
    R 2 is a heteroaryl group,
    W is a group as defined in formula (I).
    In a very useful form, preferred compounds of the invention are compounds of formula (I bis), wherein the groups of Rb and U 1 -V 1 -U 2 -V 2 are each a [1,1′-biphenyl] -4-ylmethoxy group to be.
    In another very useful form, preferred compounds of the invention are compounds of formula (I bis), wherein R 2 is a pyridyl group.
    In a third very useful form, preferred compounds of the invention are those wherein R 1 is
    - a halogen, linear or branched (C 1 -C 6) alkyl, heteroaryl, heterocyclic alkoxy moiety is a linear or branched form aryl - (C 1 -C 6) alkoxy, linear or branched (C 1 -C 6 ) Or a phenyl group unsubstituted or substituted with one to three groups selected from alkoxy, amino and linear or branched amino- (C 1 -C 6 ) alkoxy (wherein the amino moiety is one or two of each of the two groups) It is possible to be substituted with the same or different linear or branched (C 1 -C 6 ) alkyl groups),
    -A compound of formula (I bis) which is a heteroaryl group selected from pyridyl and quinolyl substituted or unsubstituted with halogen atoms or linear or branched (C 1 -C 6 ) alkyl groups.
    Preferred compounds according to the invention are as follows:
    (E) -3- [5,6-bis ([1,1'-biphenyl] -4-ylmethoxy) -3- (4-chlorophenoxy) benzo [b] thiophen-2-yl] -2- (4-pyridyl) -2-propenoic acid,
    Ethyl (E) -3- [5,6-bis ([1,1'-biphenyl] -4-ylmethoxy) -3- (4-chlorophenoxy) benzo [b] thiophen-2-yl ] -2- (4-pyridyl) -2-propenoate,
    (E) -3- [5,6-bis ([1,1'-biphenyl] -4-ylmethoxy) -3- (3-pyridyloxy) benzo [b] thiophen-2-yl] -2- (4-pyridyl) -2-propenoic acid,
    3- (E)-{5,6-bis ([1,1'-biphenyl] -4-ylmethoxy) -3- [6- (methyl) pyridyl-3-oxy] benzo [b] ti Offen-2-yl} -2- (4-pyridyl) -2-propenoic acid,
    3- (E)-[5,6-bis ([1,1'-biphenyl] -4-ylmethoxy) -3- (6-quinolyloxy) benzo [b] thiophen-2-yl] -2- (4-pyridyl) -2-propenoic acid,
    (E) -3- [5,6-bis ([1,1'-biphenyl] -2-ylmethoxy) -3- (4-chlorophenoxy) benzo [b] thiophen-2-yl] -2- (4-pyridyl) -2-propenoic acid,
    (E) -3- [5,6-bis ([1,1'-biphenyl] -3-ylmethoxy) -3- (4-chlorophenoxy) benzo [b] thiophen-2-yl] -2- (4-pyridyl) -2-propenoic acid,
    (E) -3- [5,6-bis ([1,1'-biphenyl] -4-ylmethoxy) -3- (4-chloro-3-fluorophenoxy) benzo [b] thiophene -2-yl] -2- (4-pyridyl) -2-propenoic acid,
    (E) -3- [5,6-bis ([1,1'-biphenyl] -4-ylmethoxy) -3- (4-chloro-3,5-dimethylphenoxy) benzo [b] ti Offen-2-yl] -2- (4-pyridyl) -2-propenoic acid,
    (E) -3- [5,6-bis ([1,1'-biphenyl] -4-ylmethoxy) -3- (4-chloro-3-methylphenoxy) benzo [b] thiophene- 2-yl] -2- (4-pyridyl) -2-propenoic acid,
    (E) -3- {5,6-bis ([1,1'-biphenyl] -4-ylmethoxy) -3- [4- (4-pyridyloxy) phenoxy] benzo [b] ti Offen-2-yl} -2- (4-pyridyl) -2-propenoic acid,
    (E) -3- {5,6-bis ([1,1'-biphenyl] -4-ylmethoxy) -3- [4- (1H-imidazol-1-yl) phenoxy] benzo [ b] thiophen-2-yl} -2- (4-pyridyl) -2-propenoic acid,
    (E) -3- [5,6-bis ([1,1'-biphenyl] -4-ylmethoxy) -3-phenoxybenzo [b] thiophen-2-yl] -2- (4 Pyridyl) -2-propenoic acid,
    (E) -3- [5,6-bis ([1,1'-biphenyl] -4-ylmethoxy) -3- (3-fluorophenoxy) benzo [b] thiophen-2-yl ] -2- (4-pyridyl) -2-propenoic acid,
    (E) -3- [5,6-bis ([1,1'-biphenyl] -4-ylmethoxy) -3- (3,4-difluorophenoxy) benzo [b] thiophene- 2-yl] -2- (4-pyridyl) -2-propenoic acid,
    (E) -3- {5,6-bis ([1,1'-biphenyl] -4-ylmethoxy) -3-[(6-chloro-3-pyridyl) oxy] benzo [b] ti Offen-2-yl} -2- (4-pyridyl) -2-propenoic acid.
    Addition salts of the preferred compounds with the isomers and pharmaceutically acceptable acids or bases form part of the present invention.
    The present invention also relates to a process for preparing a compound of formula (I), wherein the method uses a compound of formula (II) as starting material, wherein the compound of formula (II)
    When Q of formula (II) is a halogen atom, the compound is reacted with a compound of formula (III) to give a compound of formula (IV / a), or by reacting with a compound of formula (V) Obtaining the compound of IV / a), or
    When Q in formula (II) is a hydroxy group, the compound is reacted with a compound of formula (VI) to give a compound of formula (IV / c), wherein (IV / a), (IV / b) and The compound of (IV / c) constitutes a compound of formula (IV)
    ◆ a compound of formula (IV) is condensed with a compound of formula (VII) in the presence of acetic anhydride to give a compound of formula (VIII), wherein the hydroxy functional group of the compound of formula (VIII) After deprotection under organic synthesis conditions, the compound is reacted with a compound of formula (IX) under basic medium to give a compound of formula (I / a), which is a specific case of the compound of formula (I), If desired, compounds of formula (I / a)
    Catalytic hydrogenation in the presence of palladium to give a compound of formula (I / b), which is a specific case of a compound of formula (I), or
    Hydrolysis in the presence of a basic medium to give a compound of formula (I / c), which is a specific case of a compound of formula (I), wherein the double bond of a compound of formula (I / c) Is reduced by catalytic hydrogenation to give a compound of formula (I / d), which is a specific case of a compound of formula (I), or
    ◆ Treatment of a compound of formula (IV) with a phosphide of formula (X) affords a compound of formula (XI), wherein the hydroxy functional groups of the compound of formula (XI) After deprotection, the compound is reacted with a compound of formula (IX) under basic medium to give a compound of formula (I / e), which is a specific case of the compound of formula (I), Compound of formula (I / e)
    Hydrolysis under basic conditions to give a compound of formula (I / f), which is a specific case of a compound of formula (I), or
    Catalytic hydrogenation to afford a compound of formula (I / g), which is a specific case of a compound of formula (I), and treatment of a compound of formula (I / g) under basic hydrolysis conditions To obtain a compound of formula (I / h), which is a specific case of a compound of formula (I), or
    ◆ The hydroxy functional group of the compound of formula (IV) is deprotected under conventional organic synthesis conditions and then reacted with a compound of formula (IX) under basic medium to give a compound of formula (XII) The aldehyde functional group of the compound of formula (XII) is reduced with a primary alcohol to give a compound of formula (XIII), the terminal hydroxy group of which is replaced by a halogen atom under conventional conditions to give a compound of formula (XIV) ,
    In a compound of formula (XIV), a halogen atom is replaced by an aminated compound of formula (XV) under basic conditions, whereby the compound of formula (I) Is a specific case) and the terminal carbonyl group of the compound of formula (I / i) is hydrolyzed under basic conditions to give a compound of formula (I / j), which is a specific case of the compound of formula (I) ), Or
    ★ A compound of formula (XIV) is first treated with sodium azide to reduce the resulting azide to a primary amine under catalytic hydrogenation conditions to yield a compound of formula (XVI), which is subjected to basic conditions By condensation with a chlorosulfonyl compound of formula (XVII) to afford a compound of formula (I / k), which is a specific case of the compound of formula (I), and, if desired, k)
    Hydrolysis under basic conditions to give a compound of formula (I / l), which is a specific case of a compound of formula (I), or
    Condensation under the basic medium to the formula (XVIII) to afford the compound of formula (I / m), which is a specific case of the compound of formula (I), the compound of formula (I / m) Is treated under hydrolysis conditions in a basic medium to give a compound of formula (I / n), which is a specific case of a compound of formula (I),
    Compounds of formulas (I / c), (I / d), (I / f), (I / h), (I / j), (I / l) and (I / n) are represented by the formula ) And reacting a compound of formula (I ') with an O-substituted hydroxylamine, followed by deprotection of the hydroxylamine functional group to give a compound of formula (I / o) Is a specific case of the compound of I)),
    Compounds of formulas (I / a) to (I / o) constituting the compounds of the invention are purified, if necessary, according to conventional purification techniques, if desired, separated into their different isomers according to conventional separation techniques, Where appropriate, they are converted to addition salts with these pharmaceutically acceptable acids or bases:
    (Wherein Ra, Rb, Rc and X are as defined in formula (I), G is a hydroxy group protected by a protecting group commonly used in organic synthesis, Q is a halogen atom or a hydroxy group, preferably X Q is a halogen atom if it is a sulfur atom or NR 3 (wherein R 3 is as defined in formula (I)) and Q is a hydroxy group when X is an oxygen atom)
    (Wherein R 1 is as defined in formula (I) and Y 1 is an oxygen atom, a sulfur atom or NR 3 (wherein R 3 is as defined in formula (I)))
    (Wherein Ra, Rb, Rc, G, R 1 , X and Y 1 are as defined above)
    (Wherein Ra, Rb, Rc, G and R 1 are as defined above and X 1 is NR 3 (wherein R 3 is heteroaryl- (C 1 -C 6) wherein the alkyl moiety is in linear or branched form. Is an alkyl group)
    (Wherein Ra, Rb, Rc, G, X and R 1 are as defined above)
    (Wherein Ra, Rb, Rc, G, R 1 , X and Y 1 are as defined in formula (I))
    Wherein R 1 is as defined in formula (I)
    Wherein R ′ 2 is as defined for R 2 in Formula (I), R ′ 2 may not be a hydrogen atom, and W 1 is linear or branched (C 1 -C 6 ) alkoxy, aryloxy , arylalkoxy part is a linear or branched form - (C 1 -C 6) alkoxy, cycloalkyloxy, heteroaryl, cycloalkoxy, heteroaryloxy and an amino group (itself a linear or branched (C 1 -C 6) alkyl , Aryl, aryl- (C 1 -C 6 ) alkyl in which the alkyl moiety is in linear or branched form, and cycloalkyl, each substituted or unsubstituted with one or two identical or different groups)
    (Wherein Ra, Rb, Rc, G, R 1 , R ' 2 , X, Y and W 1 are as defined above)
    Wherein U 1 , V 1 , U 2 , and V 2 are as defined in formula (I), and Hal represents a halogen atom.
    Wherein R ′ is a linear or branched (C 1 -C 6 ) alkyl group or a phenyl group, R 2 is as defined in formula (I), W 1 is as defined above, A 1 is a single bond, Alkylene groups selected from linear or branched (C 1 -C 6 ) alkyl, aryl, aryl- (C 1 -C 6 ) alkyl, cycloalkyl, heterocycloalkyl and heteroaryl, in which the alkyl moiety is in linear or branched form Unsubstituted or substituted with one or more groups), an arylene group, a cycloalkylene group, a heterocycloalkylene group, or a heteroarylene group)
    (Wherein Ra, Rb, Rc, G, R 1 , R 2 , X, Y, A 1 and W 1 are as defined above)
    (Wherein Ra, Rb, Rc, U 1 , V 1 , U 2 , V 2 , R 1 , X and Y are as defined above)
    (Wherein Ra, Rb, Rc, U 1 , V 1 , U 2 , V 2 , R 1 , X and Y are as defined above)
    (Wherein Ra, Rb, Rc, U 1 , V 1 , U 2 , V 2 , R 1 , X and Y are as defined above)
    (Wherein R 2 is as defined in formula (I) and A 1 and W 1 are as defined above)
    (Wherein Ra, Rb, Rc, U 1 , V 1 , U 2 , V 2 , R 1 , X and Y are as defined above)
    (Wherein R 4 is as defined in formula (I) and W 1 is as defined above)
    (Wherein Hal is a halogen atom such as iodine and R ' 2 is as defined above)
    (Wherein Ra, Rb, Rc, U 1 , V 1 , U 2 , V 2 , G, R 1 , R ' 2 , X, Y and W 1 are as defined above)
    (Wherein Ra, Rb, Rc, U 1 , V 1 , U 2 , V 2 , G, R 1 , R ' 2 , X, Y and W 1 are as defined above)
    (Wherein Ra, Rb, Rc, U 1 , V 1 , U 2 , V 2 , G, R 1 , R ' 2 , X and Y are as defined above)
    (Wherein Ra, Rb, Rc, U 1 , V 1 , U 2 , V 2 , G, R 1 , R ' 2 , X and Y are as defined above)
    (Wherein Ra, Rb, Rc, U 1 , V 1 , U 2 , V 2 , G, R 1 , R 2 , A 1 , X, Y and W 1 are as defined above)
    (Wherein Ra, Rb, Rc, U 1 , V 1 , U 2 , V 2 , R 1 , R 2 , A 1 , X and Y are as defined above)
    (Wherein Ra, Rb, Rc, U 1 , V 1 , U 2 , V 2 , R 1 , R 2 , A 1 , X, Y and W 1 are as defined above)
    (Wherein Ra, Rb, Rc, U 1 , V 1 , U 2 , V 2 , R 1 , R 2 , A 1 , X and Y are as defined above)
    (Wherein Ra, Rb, Rc, U 1 , V 1 , U 2 , V 2 , R 1 , R 2 , X, Y, A 1 and W 1 are as defined above)
    (Wherein Ra, Rb, Rc, U 1 , V 1 , U 2 , V 2 , R 1 , R 2 , X, Y and A 1 are as defined above)
    (Wherein Ra, Rb, Rc, U 1 , V 1 , U 2 , V 2 , R 1 , R 4 , X, Y and W 1 are as defined above)
    (Wherein Ra, Rb, Rc, U 1 , V 1 , U 2 , V 2 , R 1 , R 4 , X and Y are as defined above)
    (Wherein Ra, Rb, Rc, U 1 , V 1 , U 2 , V 2 , R 1 , R ' 2 , R 4 , X, Y and W 1 are as defined above)
    (Wherein Ra, Rb, Rc, U 1 , V 1 , U 2 , V 2 , R 1 , R ' 2 , R 4 , X and Y are as defined above)
    (Wherein Ra, Rb, Rc, U 1 , V 1 , U 2 , V 2 , R 1 , R 2 , X, Y, Z and A are as defined above)
    (Wherein Ra, Rb, Rc, U 1 , V 1 , U 2 , V 2 , R 1 , R 2 , X, Y, Z and A are as defined above).
    Compounds of formula (II) are obtained according to conventional organic synthesis methods. In particular, a compound of formula (II) wherein X is an oxygen atom and Q is a hydroxy group is obtained starting from a compound of formula (II / A), the synthesis scheme of which is described in J. Med. Chem., 1992, 35, 958-965, wherein the hydroxy functional groups are protected under trialkylsilyl groups under basic conditions, after which the ester functional groups are reduced to primary alcohol functionalities, for example by the action of LiAlH 4 . It is oxidized to an aldehyde functional group, and the alcohol functional group is deprotected under the action of n-Bu 4 NF, allowing to obtain certain compounds of formula (II) wherein X is an oxygen atom and Q is a hydroxy group:
    Wherein R a, R b, R c and G are as defined above and R ′ is a linear or branched (C 1 -C 6 ) alkyl group.
    Certain compounds of formula (II) wherein X is NR 3 are obtained starting from compounds of formula (II / B), the synthesis scheme of which is described in Heterocycles, 1992, 34 (12), 2349-62 and Synthesis, 1994, 862-865, wherein the ester functional group is reduced to a primary alcohol functional group and then oxidized to an aldehyde functional group under the action of manganese dioxide so that X is an NR 3 group and Q is a halogen atom. Obtain the compound:
    Wherein R a, R b, R c, G and R 3 are as defined above and R ′ is a linear or branched (C 1 -C 6 ) alkyl group.
    Certain compounds of formula (II) wherein X is a sulfur atom are obtained starting from compounds of formula (II / C), the synthesis scheme of which is described in J. Heterocyclic. Chem., 1971, 8, 711-714, wherein the carboxylic acid functional group is reduced to a primary alcohol functional group and then oxidized to an aldehyde functional group such that X is a sulfur atom and Q is a halogen atom. Obtain the compound of II):
    Wherein R a, R b, R c and G are as defined above.
    Formulas (III), (V), (VI), (VII), (IX), (X), (XV), (XVII) and (XVIII) are commercially available products or obtained according to conventional organic synthesis methods. .
    The present invention provides one or more pharmaceutically acceptable excipients which alone or inactive and non-toxic as an active ingredient, alone or inactive with one or more compounds of formula (I), their optical isomers or their addition with pharmaceutically acceptable acids or bases. Or to a pharmaceutical composition comprising with a carrier.
    Pharmaceutical compositions according to the invention include those suitable for oral, parenteral (intravenous, intramuscular or subcutaneous administration), transdermal, nasal, rectal, sublingual, ocular or respiratory administration, in particular tablets or dragees, sublingual tablets ( sublingual tablets, sachets, gelatin capsules, lozenges, suppositories, creams, ointments, skin gels, injectable or drinkable preparations, aerosols, eye drops, nasal drops, and the like.
    The dosage used depends on the age and body weight of the patient, the route of administration, the nature of the disease, the severity of the disease and the treatment taken in relation to it and ranges from 0.1 to 1 g at least once a day.
    The following examples are intended to illustrate the invention and in no way limit the invention.
    The starting materials used are known products or prepared according to known procedures.
    Various synthetic steps yield synthetic intermediates useful for preparing the compounds of the present invention.
    The structure of the compounds described in the synthesis steps and examples was determined according to conventional spectroscopic techniques (infrared, NMR, mass spectrometry, etc.).
    Example 1: ethyl (E) -3- [5,6-bis ([1,1'-biphenyl] -4-ylmethoxy) -3- (4-chlorophenoxy) benzo [b] thiophene- 2-yl] -2- (4-pyridyl) -2-propenoate
    Step A: 3-Chloro-5,6- (methylenedioxy) -benzo [b] thiophene-2-carbonyl chloride
    0.026 mol of pyridine and 1.33 mol of SOCl 2 were added dropwise to the suspension of 0.26 ml of 3,4- (methylenedioxy) cinnamic acid in 365 ml of chlorobenzene successively dropwise at ambient temperature. Thereafter, the reaction mixture was refluxed for 2 days. After recovering to ambient temperature, a precipitate formed. After filtration, rinsing with hexanes and drying gave 51.2 g of the expected compound.
    Step B: 3-Chloro-5,6- (methylenedioxy) -benzo [b] thiophene-2-carboxylic acid
    40 ml of water were added to a solution of 70 mmol of the compound of Step A in 250 ml of dioxane. After refluxing for 20 hours, it was returned to ambient temperature to form a precipitate. After filtration and washing with water until neutral, the precipitate was dried over P 2 O 5 under reduced pressure to separate the expected product.
    Step C: (3-Chloro-5,6- (methylenedioxy) -benzo [b] thiophen-2-yl) methanol
    0.14 mol of the compound obtained in step B was added to a solution of 0.15 mol of LiAlH 4 in 450 ml of tetrahydrofuran at 5 ° C. under inert atmosphere. After 2 hours of reaction at ambient temperature, 85 ml of isopropanol and 31 ml of saturated sodium chloride solution were added to hydrolyze the reaction mixture. After stirring for 12 hours at ambient temperature, the reaction product was filtered through celite. The organic phase is then concentrated under reduced pressure, taken up in dichloromethane, washed with water and then saturated NaCl. After drying the organic phase with calcium sulfate, the solution was concentrated under reduced pressure to afford the expected compound.
    Step D: 3-Chloro-5,6- (methylenedioxy) -benzo [b] thiophene-2-carbaldehyde
    3.5 equivalents of MnO 2 was added to a suspension of 0.12 mol of the compound obtained in step C in 925 ml of dioxane anhydride under inert atmosphere at ambient temperature. After reacting at reflux for 3.5 hours, the reaction mixture was filtered through celite to high temperature and washed with dioxane, and then the filtrate was concentrated under reduced pressure. The residue obtained was taken up in 100 ml of ethyl acetate and the solution obtained was refluxed and then returned to ambient temperature. After the precipitate had formed, it was filtered, washed with ethyl acetate and then with water and pentane, and finally dried under vacuum to separate the expected product.
    Step E: 3- (4-Chlorophenoxy) -5,6- (methylenedioxy) -benzo [b] thiophene-2-carbaldehyde
    One equivalent of sodium hydride and then 0.094 mol of the product obtained in step D were added to a solution of 0.10 mol of 4-chlorophenol in 250 ml of dimethylformamide at ambient temperature under inert atmosphere. After reacting at 80 ° C. for 12 hours, the reaction mixture was concentrated under reduced pressure. The residue was then diluted with ethyl acetate and washed with water then an aqueous solution of NaOH and then an aqueous solution of NaCl, dried over calcium sulphate, filtered and concentrated under reduced pressure. Purification by chromatography on silica gel (dichloromethane / ethyl acetate: 98/2) separated the expected compound.
    Step F: Ethyl (E) -3- [3- (4-chlorophenoxy) -5,6- (methylenedioxy) -benzo [b] thiophene-2- (4-pyridyl) -2-prop Phenoate
    A solution containing 85 mmol of the product obtained in step E, 127 mmol of ethyl 4-pyridylacetate and 75 ml of acetic anhydride was heated to 100 ° C. for 18 hours. After recovering to ambient temperature, the reaction mixture was hydrolyzed with saturated NaHCO 3 solution and extracted with ethyl acetate. The organic phase was then washed with water and then with NaCl solution, dried over calcium sulfate, filtered and concentrated under reduced pressure. Purification by chromatography on silica gel (dichloromethane / ethyl acetate: 98/2) separated the expected compound.
    Step G: Ethyl (E) -3- [3- (4-chlorophenoxy) -5,6- (dihydroxy) -benzo [b] thiophene-2- (4-pyridyl) -2-prop Phenoate
    0.1 mol of BBr 3 as a 1 M solution in dichloromethane was added dropwise to a solution of 0.025 mol of product obtained in step F in 170 ml of anhydrous dichloromethane at 5 ° C. and under argon. After stirring for 2 hours, 125 ml of alcohol was added dropwise to the reaction mixture, which was then concentrated under reduced pressure. The residue was taken up in ethyl acetate and stirred for 30 minutes. The precipitate formed was filtered off, washed with ethyl acetate and dried in vacuo to separate the expected compound.
    Step H: ethyl (E) -3-[(5,6-bis ([1,1'-biphenyl] -4-ylmethoxy) -3- (4-chlorophenoxy) -benzo [b] thiophene -2-yl] -2- (4-pyridyl) -2-propenoate
    7.5 mmol of K 2 CO 3 was added to a solution of 4.6 mmol of 4- (chloromethyl) -1,1′-biphenyl and 30 mmol of the product obtained in step G in 30 ml of anhydrous dimethylformamide. After reacting at 80 ° C. for 12 hours, the reaction mixture was returned to ambient temperature and 30 ml of water was added to allow a precipitate to form. The precipitate formed was filtered off, washed with water and dried under vacuum. Purification by chromatography on silica gel (dichloromethane / ethyl acetate: 95/5) separated the expected compound.
    Melting Point: 212 ℃
    Elemental Microanalysis:
    Example 2: (E) -3-[(5,6-bis ([1,1'-biphenyl] -4-ylmethoxy) -3- (4-chlorophenoxy) -benzo [b] thiophene -2-yl] -2- (4-pyridyl) -2-propenoic acid
    A solution containing 1.5 mmol of the product of Example 1, 3 ml of 1N aqueous sodium hydroxide solution and 30 ml of ethanol was refluxed for 12 hours. After recovering to ambient temperature, the reaction mixture was concentrated under reduced pressure and the residue was diluted with water and then taken up in ethyl ether. The organic phase was then acidified by adding 6 ml of 1N HCl solution. The precipitate formed was filtered off, washed with water and dried under reduced pressure to separate the expected compound.
    Elemental Microanalysis:
    Example 3: Sodium (E) -3-[(5,6-bis ([1,1'-biphenyl] -4-ylmethoxy) -3- (4-chlorophenoxy) -benzo [b] thi Offen-2-yl] -2- (4-pyridyl) -2-propenoate
    To a suspension of 1 g of the product of Example 2 in 2.5 ml of 1N sodium hydroxide solution was added until water was completely diluted. Lyophilization separated the expected compound.
    Example 4: (E) -3-[(5,6-bis ([1,1'-biphenyl] -4-ylmethoxy) -3- (4-chlorophenoxy) -benzo [b] thiophene -2-yl] -2- (4-pyridyl) -2-propenoic acid
    The same process as in steps A to H of Example 1 was carried out, and in step F, phenylethanoic acid was used as the reagent.
    Example 5: Ethyl (E) -3-[(5,6-bis ([1,1'-biphenyl] -4-ylmethoxy) -3- (4-chlorophenoxy) -benzo [b] thi Offen-2-yl] -2- (4-pyridyl) -2-propenoate
    20 ml of a 1M tertiary potassium butylated solution in tetrahydrofuran was added dropwise to a suspension of 0.02 mol of (ethoxycarbonylmethyl) triphenylphosphonium bromide in 90 ml of tetrahydrofuran under inert atmosphere at 0 ° C. After the addition was completed, the mixture was returned to ambient temperature and 0.01 mol of the compound obtained in step E of Example 1 diluted with 30 ml of tetrahydrofuran was added. After 12 hours, the reaction mixture was hydrolyzed by the addition of 100 ml of 1N HCl solution and then extracted with ethyl acetate and the combined organic phases were washed with water and then with saturated NaCl solution, dried over sodium sulfate, filtered and under reduced pressure. Concentrated. Purification by chromatography on silica gel (pentane / ethyl acetate: 90/10) separated the expected compound.
    Example 6: ethyl 2-({[(5,6-bis ([1,1'-biphenyl] -4-ylmethoxy) -3- (4-chlorophenoxy) -benzo [b] thiophene- 2-yl] methyl} anilino) acetate
    Step 1: [5,6- (methylenedioxy) -3- (4-chlorophenoxy) -benzo [b] thiophen-2-yl] methanol
    26 mmol of NaBH 4 were added to a solution of 24 mmol of the compound obtained in step E of Example 1 in 100 ml of methanol at ambient temperature. After reacting for 2 hours, 1 equivalent of NaBH 4 was added to the reaction mixture. After reacting for 12 hours, the solution was concentrated, then diluted with ethyl acetate, washed with 1N HCl solution and then with water and then saturated NaCl solution, then dried over calcium sulfate, filtered and concentrated under reduced pressure. Purification by chromatography on silica gel (dichloromethane / ethyl acetate: 95/5) separated the expected compound.
    Step 2: [2-Chloromethyl-3- (4-chlorophenoxy) -5,6- (methylenedioxy)]-benzo [b] thiophene
    0.63 ml of SOCl 2 was added dropwise to 4 mmol of the compound of step 1 diluted to 10 ml of dichloromethane at 0 ° C. After recovering to ambient temperature, the reaction was heated to reflux temperature of dichloromethane for 6 hours and the reaction concentrated under reduced pressure to afford the expected compound.
    Step 3: ethyl 2-({[3- (4-chlorophenoxy) -5,6- (methylenedioxy) benzo [b] thiophen-2-yl] methyl} anilino) acetate
    A solution containing 6.5 mmol of the compound obtained in step 2, 16 equivalents of N-phenylglycine ethyl ester and 1.5 equivalents of K 2 CO 3 in 16 ml of dichloroformamide was heated at 80 ° C. for 18 hours. After evaporation of the solvent, the residue was diluted with ethyl acetate and the organic phase was washed with water and then with saturated NaCl solution, dried over calcium sulfate, filtered and evaporated under reduced pressure. Purification by chromatography on silica gel (toluene / ethyl acetate: 98/2) separated 2.56 g of the expected compound in oil form.
    Step 4: ethyl 2-({[5,6-bis-([1,1'-biphenyl] -4-ylmethoxy) -3- (4-chlorophenoxy) -benzo [b] thiophene-2 -Yl] methyl} anilino) acetate
    The same process as in steps G to H of Example 1 was carried out, and the product obtained in step 3 above was used as the substrate.
    Example 7: ethyl 2-({[5,6-bis ([1,1'-biphenyl] -4-ylmethoxy) -3- (4-chlorophenoxy) -benzo [b] thiophene-2 -Yl] methyl} amino) benzoate
    The same process as in Example 6 was carried out, and ethyl anthranilate was used as a reagent in step 3.
    Example 8: Methyl 2-[({[5,6-bis ([1,1'-biphenyl] -4-ylmethoxy) -3- (4-chlorophenoxy) -benzo [b] thiophene- 2-yl] methyl} amino) sulfonyl] benzoate
    Step 1: [2-azidomethyl-3- (4-chlorophenoxy) -5,6- (methylenedioxy)]-benzo [b] thiophene
    A solution containing 41 mmol of the compound obtained in step 2 of Example 6 and 78 mmol of sodium azide in 80 ml of dimethylformamide was stirred at ambient temperature for 48 hours. Thereafter, the reaction medium was concentrated under reduced pressure. The residue was diluted with ethyl acetate and washed with water then saturated NaCl solution. The organic phase was dried over calcium sulfate, filtered and evaporated to afford the expected compound.
    Step 2: [2-Aminomethyl-3- (4-chlorophenoxy) -5,6- (methylenedioxy)]-benzo [b] thiophene
    A solution containing 1 g of Pd / C in 6.5 ml of anhydrous methanol and 6.5 ml of chloroform and 41 mmol of the compound obtained in step 1 was left under hydrogen atmosphere at ambient temperature. After 12 hours, the reaction mixture was filtered and concentrated under reduced pressure to afford the expected compound.
    Step 3: Methyl 2-[({[3- (4-chlorophenoxy) -5,6- (methylenedioxy)]-benzo [b] thiophen-2-yl] -methyl} amino) sulfonyl] Benzoate
    A solution containing 6.5 mmol of the compound obtained in step 2, 6.5 mmol of methyl 2- (chlorosulfonyl) benzoate and 15.7 mmol of N-methylmorpholine in 50 ml of dichloromethane was stirred at ambient temperature. After 12 hours, the reaction mixture was washed with water and then saturated NaCl solution, dried over sodium sulfate and concentrated under reduced pressure. Purification by chromatography on silica gel (dichloromethane / ethyl acetate: 98/2) separated the expected product.
    Step 4: Methyl 2-[({[5,6-bis ([1,1'-biphenyl] -4-ylmethoxy) -3- (4-chlorophenoxy) -benzo [b] thiophene-2 -Yl] methyl} amino) sulfonyl] benzoate
    The same process as in steps G to H of Example 1 was carried out, and the product obtained in step 3 above was used as the substrate.
    Example 9: 2-[({[5,6-bis ([1,1'-biphenyl] -4-ylmethoxy) -3- (4-chlorophenoxy) -benzo [b] thiophene-2 -Yl] methyl} amino) sulfonyl] benzoic acid
    The same process as in Example 2 was carried out, and the product obtained in Step 4 of Example 8 was used as the substrate.
    Example 10: (E) 3- [5,6-bis ([1,1'-biphenyl] -4-ylmethoxy) -3- (3-pyridyloxy) -benzo [b] thiophene-2 -Yl] -2- (4-pyridyl) -2-propenoic acid
    The same procedure as in Example 1 was carried out using 3-hydroxypyridine as reagent in Step E, followed by the protocol described in Example 2.
    Melting Point: 237 ℃
    Elemental Microanalysis:
    Example 11: (E) 3- [5,6-bis ([1,1'-biphenyl] -4-ylmethoxy) -3- (4-chlorophenoxy) -1H-2-indolyl]- 2- (4-pyridyl) -2-propenoic acid
    In step E, following the same process as in step E to step H of Example 1 using 3-bromo-5,6-dimethoxy-1H-2-indolecarbaldehyde as described in Example 2, Protocol was performed.
    Example 12: (E) 3- [5,6-bis ([1,1'-biphenyl] -4-ylmethoxy) -3-[(methoxyphenyl-sulfanyl] -benzo [b] thiophene -2-yl] -2- (4-pyridyl) -2-propenoic acid
    Following the same process as in Example 1 using 4-methoxybenzenethiol as the reagent in Step E, the protocol described in Example 2 was followed.
    Example 13: 3- (E)-{3- [4- (2- (dimethylamino) ethoxy) -phenoxy] -5,6-bis ([1,1'-biphenyl] -4-ylme Methoxy) -benzo [b] thiophen-2-yl} -2-phenyl-2-propenoic acid
    The same procedure as in Example 1 was carried out using 2- (dimethylamino) ethoxyphenol as the reagent in Step E and phenylethanoic acid as the reagent in Step F, followed by the protocol described in Example 2.
    Example 14 (E) -3- [5,6-bis ([1,1'-biphenyl] -4-ylmethoxy) -3- (3,4-dichlorophenoxy) -benzo [b] ti Offen-2-yl] -2- (4-pyridyl) -2-propenoic acid
    Following the same process as in Example 1 using 3,4-dichlorophenol as reagent in Step E, the protocol described in Example 2 was followed.
    Example 15 3- (E)-[5,6-bis ([1,1'-biphenyl] -4-ylmethoxy) -3- [6- (methyl) pyridyl-3-oxy) -benzo [b] thiophen-2-yl] -2- (4-pyridyl) -2-propenoic acid
    The same procedure as in Example 1 was carried out using 2-methyl-5-hydroxypyridine as reagent in Step E, followed by the protocol described in Example 2.
    Elemental Microanalysis:
    Example 16: 3- (E)-[5,6-bis ([1,1'-biphenyl] -4-ylmethoxy) -3- (6-quinolyloxy) -benzo [b] thiophene- 2-yl] -2- (4-pyridyl) -2-propenoic acid
    The same procedure as in Example 1 was carried out using 6-hydroxyquinoline as reagent in Step E, followed by the protocol described in Example 2.
    Elemental Microanalysis:
    Example 17 3- (E)-[5,6-bis ([1,1'-biphenyl] -2-ylmethoxy) -3- (4-chlorophenoxy) -benzo [b] thiophene- 2-yl] -2- (4-pyridyl) -2-propenoic acid
    In step H, the same procedure as in Example 1 was carried out using 2- (bromomethyl) -1,1'-biphenyl as the reagent, followed by the protocol described in Example 2.
    Elemental Microanalysis:
    Example 18: 3- (E)-[5,6-bis (4-phenoxyphenoxy) -3- (4-chlorophenoxy) -benzo [b] thiophen-2-yl] -2- ( 4-pyridyl) -2-propenoic acid
    The same procedure as in Example 1 was carried out using 1-bromo-4-phenoxybenzene as the reagent in step H, followed by the protocol described in Example 2.
    Example 19: (E) -3- {3- (4-chlorophenoxy) -5,6-bis- [4- (4-pyridylmethyl) phenoxy] -benzo [b] thiophene-2- I} -2- (4-pyridyl) -2-propenoic acid
    The same procedure as in Example 1 was carried out using 4- (4-chlorobenzyl) pyridine as reagent in step H, followed by the protocol described in Example 2.
    Example 20: (E) -3- [5,6-bis ([1,1'-biphenyl] -3-ylmethoxy) -3- (4-chlorophenoxy) -benzo [b] thiophene- 2-yl] -2- (4-pyridyl) -2-propenoic acid
    The same procedure as in Example 1 was carried out using 3- (bromomethyl) -1,1'-biphenyl as the reagent in Step H, followed by the protocol described in Example 2.
    Melting point: 205-210 ℃
    Example 21: (E) -3- [5,6-bis ([1,1'-biphenyl] -4-ylmethoxy) -3- (4-chloro-3-fluorophenoxy) -benzo [ b] thiophen-2-yl] -2- (4-pyridyl) -2-propenoic acid
    Following the same process as in Example 1 using 4-chloro-3-fluorophenol as reagent in Step E, the protocol described in Example 2 was followed.
    Elemental Microanalysis:
    Example 22: (E) -3- [5,6-bis ([1,1'-biphenyl] -4-ylmethoxy) -3- (4-chloro-3,5-dimethylphenoxy) -benzo [b] thiophen-2-yl] -2- (4-pyridyl) -2-propenoic acid
    Following the same process as in Example 1 using 4-chloro-3,5-dimethylphenol as reagent in Step E, the protocol described in Example 2 was followed.
    Elemental Microanalysis:
    Example 23: (E) -3- [5,6-bis ([1,1'-biphenyl] -4-ylmethoxy) -3- (4-chloro-3-methylphenoxy) -benzo [b ] Thiophen-2-yl] -2- (4-pyridyl) -2-propenoic acid
    Following the same process as in Example 1 using 4-chloro-3-methylphenol as reagent in Step E, the protocol described in Example 2 was followed.
    Elemental Microanalysis:
    Example 24: (E) -3- [5,6-bis ([1,1'-biphenyl] -4-ylmethoxy) -3- [4- (4-pyridyloxy) -phenoxy)- Benzo [b] thiophen-2-yl} -2- (4-pyridyl) -2-propenoic acid
    Following the same process as in Example 1 using 4-pyridyloxyphenol as reagent in Step E, the protocol described in Example 2 was followed.
    Elemental Microanalysis:
    Example 25: (E) -3- {5,6-bis ([1,1'-biphenyl] -4-ylmethoxy) -3- [4- (1H-imidazol-1-yl) -phenoxy -Benzo [b] thiophen-2-yl} -2- (4-pyridyl) -2-propenoic acid
    In step E, the same procedure as in Example 1 was carried out using 4- (1H-imidazol-1-yl) -phenol as the reagent, followed by the protocol described in Example 2.
    Elemental Microanalysis:
    Example 26: (E) -3- [5,6-bis ([1,1'-biphenyl] -4-ylmethoxy) -3-phenoxy-benzo [b] thiophen-2-yl]- 2- (4-pyridyl) -2-propenoic acid
    Following the same process as Example 1 using phenol as reagent in Step E, the protocol described in Example 2 was followed.
    Elemental Microanalysis:
    Example 27: (E) -3- [5,6-bis ([1,1'-biphenyl] -4-ylmethoxy) -3- (3-fluorophenoxy) -benzo [b] thiophene -2-yl] -2- (4-pyridyl) -2-propenoic acid
    Following the same process as in Example 1 using 3-fluorophenol as reagent in Step E, the protocol described in Example 2 was followed.
    Elemental Microanalysis:
    Example 28: (E) -3- [5,6-bis ([1,1'-biphenyl] -4-ylmethoxy) -3- (3,4-difluorophenoxy) -benzo [b ] Thiophen-2-yl] -2- (4-pyridyl) -2-propenoic acid
    The same procedure as in Example 1 was carried out using 3,4-difluorophenol as the reagent in step E, followed by the protocol described in Example 2.
    Elemental Microanalysis:
    Example 29: (E) -3- [5,6-bis ([1,1'-biphenyl] -4-ylmethoxy) -3-[(6-chloro3-pyridyl) oxy) -benzo [ b] thiophen-2-yl] -2- (4-pyridyl) -2-propenoic acid
    The same procedure as in Example 1 was carried out using 2-chloro-5-hydroxypyridine as reagent in Step E, followed by the protocol described in Example 2.
    Elemental Microanalysis:
    Example 30: (E) -3- {3- (4-chlorophenoxy) -5,6-bis [(4'-methoxy [1,1'-biphenyl] -4-yl) methoxy] -Benzo [b] thiophen-2-yl] -2- (4-pyridyl) -2-propenoic acid
    In step H, the same procedure as in Example 1 was carried out using 4- (bromomethyl) -4'-methoxy-1,1'-biphenyl as the reagent, followed by the protocol described in Example 2. .
    Melting Point: 235 ℃
    Elemental Microanalysis:
    Example 31: (E) -3- [5,6-bis ([1,1'-biphenyl] -4-ylmethoxy) -3- (4-chlorophenoxy) -benzo [b] thiophene- 2-yl] -2- (4-pyridyl) -2-propenoic acid
    In step H, the same procedure as in Example 1 was carried out using 4- (2-bromoethyl) -1,1'-biphenyl as the reagent, followed by the protocol described in Example 2.
    Example 32: (E) -3- [5,6-bis [(4-benzylbenzyl) oxy] -3-4-chlorophenoxy) -benzo [b] thiophen-2-yl] -2- ( 4-pyridyl) -2-propenoic acid
    The same procedure as in Example 1 was carried out using 1-benzyl-4- (bromomethyl) benzene as the reagent in step H, followed by the protocol described in Example 2.
    Example 33: (E) -3- {3- (4-chlorophenoxy) -5,6-bis [(4-phenoxybenzyl) oxy] -benzo [b] thiophen-2-yl] -2 -(4-pyridyl) -2-propenoic acid
    The same procedure as in Example 1 was carried out using 1- (bromomethyl) -4-phenoxybenzene as the reagent in step H, followed by the protocol described in Example 2.
    Example 34: (E) -3- (3- (4-chlorophenoxy) -5,6-bis {[4- (phenylsulfanyl) benzyl] oxy} -benzo [b] thiophen-2-yl ] -2- (4-pyridyl) -2-propenoic acid
    In step H, the same procedure as in Example 1 was carried out using 1- (bromomethyl) -4- (phenylsulfanyl) benzene as the reagent, followed by the protocol described in Example 2.
    Example 35: (E) -3- (3- (4-chlorophenoxy) -5,6-bis {[4- (phenylsulfonyl) benzyl] oxy} -benzo [b] thiophen-2-yl ] -2- (4-pyridyl) -2-propenoic acid
    In step H, the same procedure as in Example 1 was carried out using 1- (bromomethyl) -4- (phenylsulfonyl) benzene as the reagent, followed by the protocol described in Example 2.
    Example 36: (E) -3- [3- (4-chlorophenoxy) -5,6-bis ({4-[(4-phenoxyphenyl) sulfonyl] -benzyl} oxy) -benzo [b ] Thiophen-2-yl] -2- (4-pyridyl) -2-propenoic acid
    Following the same process as in Example 1 using 1- (bromomethyl) -4-[(4-phenoxyphenyl) sulfonyl] -benzene in Step H, the protocol described in Example 2 was followed. Was performed.
    Example 37: (E) -3- [6- (benzyloxy) -5-([1,1'-biphenyl] -4-ylmethoxy) -3- (4-chlorophenoxy) -benzo [b ] Thiophen-2-yl] -2- (4-pyridyl) -2-propenoic acid
    Step 1: (E) -3- [6- (benzyloxy) -3- (4-chlorophenoxy) -5-hydroxy-benzo [b] thiophen-2-yl] -2- (4-pyri Dill) -2-propenoic acid
    The same process as Steps A to H of Example 1 was carried out using chloromethylphenyl.
    Step 2: (E) -3- [6- (benzyloxy) -5-([1,1'-biphenyl] -4-ylmethoxy) -3- (4-chlorophenoxy) -benzo [b] Thiophen-2-yl] -2- (4-pyridyl) -2-propenoic acid
    After performing the same process as Step H of Example 1, the process described in Example 2 was performed.
    Elemental Microanalysis:
    Example 38: (E) -3- [6-([1,1'-biphenyl] -4-ylmethoxy) -3- (4-chlorophenoxy) -5-phenoxy-benzo [b] thi Offen-2-yl] -2- (4-pyridyl) -2-propenoic acid
    The same process as in Step H of Example 1 was carried out using 4-chloromethyl (1,1′-biphenyl) and chloromethylphenyl as reagent in Step H.
    Example 39: 3- [6-([1,1'-biphenyl] -4-ylmethoxy) -5-([1,1'-biphenyl] -4-yloxy) -3- (4- Chlorophenoxy) -benzo [b] thiophen-2-yl] -2-phenylpropanoic acid
    In step F, a process similar to steps A to F of Example 1 was carried out using phenylethanoic acid instead of ethyl 4-pyridyl acetate as a reagent, followed by steps G to H of Example 1. . The product thus obtained was then treated with hydrogen in the presence of 10% Pd / C in methanol for 24 hours. At the end of the reaction, filtration through celite was followed by purification on chromatography over silica gel to separate the expected product.
    Example 40: 2-({[6-([1,1'-biphenyl] -4-ylmethoxy) -5-([1,1'-biphenyl] -4-yloxy) -3- ( 4-Chlorophenoxy) -benzo [b] thiophen-2-yl] methyl} amino) benzoic acid
    The same process as in Example 2 was carried out using the compound obtained in Example 7 as starting material.
    Pharmacological Study of Compounds of the Invention
    Example 41 Inhibition of PAI-1 Activity
    Inhibition of the activity of PAI-1 was done ex vivo in microplate wells where the formation of fibrin mass followed by disruption was continuously monitored by measuring turbidity using a spectrophotometer. To do this, 50 μl of inhibitor in the presence of 50 μl of a 2 nM solution of recombinant active human PAI-1 for 5 min at ambient temperature, using 50 mM phosphate buffer (pH 7.4) containing 0.05% bovine serum albumin as diluent. Placed. Then, 50 µl of 0.42 nM solution of tissue plasminogen activator, 50 µl of 800 nM solution of human plasminogen and 50 µl of 2 g / L solution of fibrinogen were added, and 50 µl of 14 nM purified human thrombin was added to fibrin. Was formed. In the presence of the product, the inhibition of destruction was measured as the absorbance of the mass for 2 hours after the start of fibrin formation and showed 100% PAI-1 activity. In the absence of product and PAI-1, the degree of destruction was measured by absorbance of the broken mass and indicated as 0% PAI-1 activity. The concentration of product that inhibits PAI-1 activity by 50% was determined by measuring the absorbance of the mass for 2 hours after fibrin formation in the presence of PAI-1 and increasing concentrations of product. For example, the IC 50 of the compounds of Examples 2, 10 and 26 were 0.13 μM and 0.53 μM alc 0.06 μM, respectively. The result demonstrates the very good fibrinolytic activity of the compounds of the present invention compared to the control product XR 5082 with an IC 50 of 190 μM.
    Example 42 Pharmaceutical Composition
    Formulations for the preparation of 1000 tablets each containing 10 mg of active ingredient
    Compound of Example 210 g Hydroxypropyl cellulose2 g Polyvinylpyrrolidone2 g Wheat starch10 g Lactose100 g Magnesium stearate3 g
    The novel benzothiophene, benzofuran and indole compounds according to the present invention have the property of inhibiting the activity of PAI-1, and thus are useful therapeutically in the field of fibrin degradation and thrombosis.
    权利要求:
    Claims (22)
    [1" claim-type="Currently amended] Compounds of formula (I), their isomers, and addition salts thereof with pharmaceutically acceptable acids or bases:

    In the above formula,
    X is an oxygen atom, a sulfur atom or an NR 3 group, where R 3 is a hydrogen atom, a linear or branched (C 1 -C 6 ) alkyl group, a linear or branched (C 1 -C 6 ) acyl group, an acyl group , Aryl- (C 1 -C 6 ) alkyl group, wherein the alkyl moiety is in linear or branched form, or heteroaryl- (C 1 -C 6 ) alkyl group, wherein the alkyl moiety is in linear or branched form Is);
    Y is an oxygen atom, a sulfur atom or an NR 3 group, wherein R 3 is as defined above, or X is NR ' 3 (wherein R' 3 is a heteroaryl wherein the alkyl moiety is in linear or branched form) A (C 1 -C 6 ) alkyl group) can be a single bond;
    T is a nitrogen atom bonded to neighboring carbon atoms to form a single bond (-), or a single bond (-) or double bond (bonded to neighboring carbon atoms) Is a carbon atom or a CH group depending on whether
    A represents a single bond or (C 1 -C 6) alkylene group (the one or more linear or branched (C 1 -C 6) alkyl group, an aryl group, an aryl, alkyl moiety is linear or branched form - (C 1 -C 6 Substituted or unsubstituted with an alkyl group, a cycloalkyl group, a heterocycloalkyl group, or a heteroaryl group), arylene, cycloacylene, heterocycloalkylene, heteroarylene, and -SO 2 -R 4 groups, where SO 2 Moiety is bonded to T, and R 4 is linear or branched (C 1 -C 6 ) alkylene, arylene, aryl- (C 1 -C 6 ) alkylene, cyclo wherein the alkylene moiety is in linear or branched form A group selected from alkylene, heterocycloalkylene and heteroarylene);
    W is hydroxy, linear or branched (C 1 -C 6 ) alkoxy, aryloxy, aryl (C 1 -C 6 ) alkoxy, cycloalkyloxy, heterocycloalkyloxy, hetero, wherein the alkoxy moiety is in linear or branched form aryloxy, amino (itself a linear or branched (C 1 -C 6) alkyl, aryl, alkyl moiety is linear or branched in the form of aryl, each is (C 1 -C 6) selected from alkyl, and cycloalkyl May be substituted with one or two identical or different groups) and hydroxyamino;
    U 1 is an oxygen atom, a sulfur atom or a linear or branched (C 1 -C 6 ) alkylene chain, wherein one or more carbon atoms are unsubstituted or substituted by one or more atoms selected from oxygen, nitrogen and sulfur And alkylene may be unsubstituted or substituted by one or more identical or different groups selected from halogen, hydroxy, linear or branched (C 1 -C 6 ) alkyl and linear or branched (C 1 -C 6 ) alkoxy. Can be);
    V 1 is an arylene, heteroarylene or heterocycloalkylene group;
    U 2 is a single bond, oxygen atom, nitrogen atom, sulfur atom or a linear or branched (C 1 -C 6 ) alkylene chain, wherein at least one carbon atom is oxygen, sulfur or nitrogen atom (nitrogen atom is hydrogen and And may be unsubstituted or substituted by one or more identical or different groups selected from linear or branched (substituted with a group selected from (C 1 -C 6 ) alkyl)) and a SO 2 group;
    V 2 is an aryl, heteroaryl or heterocycloalkyl group;
    Ra, Rb and Rc are the same or different and each individually
    Hydrogen, halogen,
    Hydroxy, cyano, nitro,
    Linear or branched (C 1 -C 6 ) alkyl, linear or branched (C 1 -C 6 ) alkoxy, linear or branched (C 1 -C 6 ) acyl, carboxy, linear or (C 1 -C 6) Alkoxycarbonyl, linear or branched (C 1 -C 6 ) trihaloalkyl,
    -Amino (linear or branched (C 1 -C 6) alkyl, aryl, and the alkyl moiety is linear or branched in the form of aryl - (C 1 -C 6), each one individually selected from alkyl or two of the same or different Unsubstituted or substituted with a group),
    Aryloxy, aryl- (C 1 -C 6 ) alkoxy in which the alkoxy moiety is in linear or branched form, heteroaryloxy, heteroaryloxy- (C 1 -C 6 ) alkoxy in which the alkoxy moiety is in linear or branched form, And
    Or a group selected from the formula -U 1 -V 1 -U 2 -V 2 , wherein U 1 , U 2 , V 1 and V 2 are as defined above, or
    Two of them together are methylenedioxy or ethylenedioxy groups (each of which one or two linear or branched (C 1 -C 6 ) alkyl groups, aryl groups or alkyl moieties in linear or branched form; C 1 -C 6 ) alkyl group unsubstituted or substituted;
    R 1 is
    Halogen, hydroxy, cyano, nitro, carboxy, linear or branched (C 1 -C 6 ) alkyl, linear or branched (C 1 -C 6 ) alkoxy, linear or branched (C 1 -C 6 ) Acyl, linear or branched (C 1 -C 6 ) alkoxycarbonyl, linear or branched (C 1 -C 6 ) trihaloalkyl (with or without a substituted hydroxy group), linear or branched (C 1 -C 6 ) trihaloalkoxy, amino (substituted or unsubstituted with one or two linear or branched (C 1 -C 6 ) alkyl groups, of which alkyl groups are amino, linear or branched (C 1 -C 6 ) Alkylamino and alkyl moieties may or may not be substituted with groups selected from di- (C 1 -C 6 ) alkylamino in linear or branched form, respectively, and amino- (C 1 -C 6 ) alkoxy (alkoxy moieties In linear or branched form, the amino moiety being one or two identical or different linear or branched (C 1 -C 6 ) alkyl groups (C 1 -C 6 ) alkoxycarbonyl (C 1 -C 6 ) alkyl, linear or branched (C 1 -C 6 ), wherein the alkoxy and alkyl moieties are each substituted or unsubstituted ) alkylcarbonylamino, in which the alkyl portion is a linear or branched form aryl - (C 1 -C 6) alkyl, aryloxy, aryl-alkoxy part of the linear or branched form - (C 1 -C 6) alkoxy, aryl amino, the alkyl moiety is a linear or branched form aryl - (C 1 -C 6) alkylamino, aryl-isoquinoline, wherein the aryl alkyl moiety a linear or branched form - (C 1 -C 6) alkyl sulfanyl, heterocycloalkyl Aryl, heteroaryl- (C 1 -C 6 ) alkyl in which the alkyl moiety is in linear or branched form, heteroaryl- (C 1 -C 6 ) alkoxy, heteroaryl in which the alkoxy moiety is in linear or branched form Amino, heteroaryl- (C 1 -C 6 ) alkylamino, heteroarylsulfanyl, alkyl moiety linear or branched Or heteroaryl- (C 1 -C 6 ) alkylsulfanyl in branched form,
    A 1,3-dihydro-2H-indol-2-one, 3,4-dihydro-2 (1H) -quinolinone or 1-hydroxy-2 (1H) -pyridinone group, or
    -A substituted or unsubstituted heteroaryl group;
    R 2 is a hydrogen atom, a linear or branched (C 1 -C 6 ) alkyl group, an aryl group, an aryl- (C 1 -C 6 ) alkyl, group, cycloalkyl group, heterocycloalkyl group in which the alkyl moiety is in linear or branched form , a heterocycloalkyl of the alkyl moiety a linear or branched alkyl form - (C 1 -C 6) alkyl group, heteroaryl group, heteroalkyl portion are the linear or branched form aryl - (C 1 -C 6) alkyl group selected from Is;
    In the above,
    Aryl group means a phenyl, biphenyl, naphthyl, tetrahydronaphthyl or dihydronaphthyl group, each of which is halogen, hydroxy, cyano, nitro, linear or branched (C 1 -C 6 ) alkyl group ( Hydroxy, amino and alkyl moieties are each substituted or unsubstituted with one or more groups selected from mono- or di- (C 1 -C 6 ) alkylamino in linear or branched form), linear or branched (C 1- C 6 ) trihaloalkyl, linear or branched (C 1 -C 6 ) alkoxy, aryloxy, linear or branched (C 1 -C 6 ) acyl, carboxy, linear or branched (C 1 -C 6 ) May be unsubstituted or substituted with one or more identical or different groups selected from alkoxycarbonyl and amino (amino is substituted or unsubstituted with one or two identical or different linear or branched (C 1 -C 6 ) alkyl groups) ;
    -Cycloalkyl group means a single or bicyclic group of (C 3 -C 8 );
    Heterocycloalkyl group means a saturated or unsaturated non-aromatic single or double cyclic having 5 to 12 elements in one ring and containing one to three identical or different heteroatoms selected from oxygen, nitrogen or sulfur; Halogen, hydroxy, linear or branched (C 1 -C 6 ) alkyl, linear or branched (C 1 -C 6 ) trihaloalkyl, linear or branched (C 1 -C 6 ) alkoxy, aryl Oxy, alkoxy moiety is linear or branched aryl- (C 1 -C 6 ) alkoxy, amino (substituted or substituted with one or more linear or branched (C 1 -C 6 ) alkyl groups), linear or branched ( May be substituted or unsubstituted with one or more identical or different groups selected from C 1 -C 6 ) acyl, linear or branched (C 1 -C 6 ) alkoxycarbonyl, nitro and oxo,
    Heteroaryl group means a single or bicyclic heterocycloalkyl, as defined above, having aromatic character in at least one ring, and in the case of bicyclic systems, on a ring or partially unsaturated ring having aromatic character It is possible for a hetero atom to be located, and the heteroaryl group may or may not be substituted with one or more of the same or different groups as previously defined for the substituents of the heterocycloalkyl group.
    [2" claim-type="Currently amended] 2. Compounds, isomers thereof and their pharmaceutically acceptable acids or bases according to claim 1, characterized in that X is a sulfur atom or an NR 3 group wherein R 3 is as defined in formula (I). Addition salt with.
    [3" claim-type="Currently amended] 2. Compounds, isomers thereof, and addition salts thereof with pharmaceutically acceptable acids or bases according to claim 1, wherein Y is an oxygen atom.
    [4" claim-type="Currently amended] A compound according to claim 1, wherein R 1 is a group selected from phenyl unsubstituted or substituted with a group as defined in formula (I), substituted or unsubstituted quinolyl and substituted or unsubstituted pyridyl, Isomers thereof and addition salts thereof with pharmaceutically acceptable acids or bases.
    [5" claim-type="Currently amended] A compound according to claim 1, wherein R 2 is a group selected from aryl and heteroaryl, each of which is substituted or unsubstituted, isomers thereof and additions thereof with pharmaceutically acceptable acids or bases. salt.
    [6" claim-type="Currently amended] A compound according to claim 1 or 5, wherein R 2 is a pyridyl group, isomers thereof, and addition salts thereof with pharmaceutically acceptable acids or bases.
    [7" claim-type="Currently amended] The compound of claim 1, wherein U 1 is a linear (C 1 -C 4 ) alkylene chain (one of the carbon atoms is replaced by an oxygen atom), V 1 is an arylene group, U 2 is a single bond, and V 2 is Compounds, isomers thereof, and addition salts thereof with pharmaceutically acceptable acids or bases, characterized in that they are aryl groups substituted or unsubstituted with one of the groups defined in formula (I).
    [8" claim-type="Currently amended] 8. Compounds according to claim 1 or 7, wherein isomers thereof and isomers thereof and characterized in that the U 1 -V 1 -U 2 -V 2 substituents are [1,1'-biphenyl] -4-ylmethoxy groups; Addition salts with pharmaceutically acceptable acids or bases.
    [9" claim-type="Currently amended] 2. Compounds, isomers thereof and pharmaceuticals thereof according to claim 1, characterized in that at least one of Ra, Rb or Rc is a compound of the formula U 1 -V 1 -U 2 -V 2 as defined in formula (I). Addition salts with acids or bases that are acceptable.
    [10" claim-type="Currently amended] 4. Compounds, isomers thereof and addition salts thereof with pharmaceutically acceptable acids or bases according to any of claims 1 to 3, wherein X is a sulfur atom and Y is an oxygen atom.
    [11" claim-type="Currently amended] 2. A compound according to claim 1, wherein X is a sulfur atom, Y is an oxygen atom, R 1 is a substituted or unsubstituted phenyl group or a substituted or unsubstituted pyridyl group, and when T is a carbon atom or a CH group, it is a single bond. Compounds, isomers thereof, and addition salts thereof with pharmaceutically acceptable acids or bases.
    [12" claim-type="Currently amended] 2. A compound according to claim 1, wherein X is a sulfur atom, Y is an oxygen atom, R 1 is a phenyl group unsubstituted or substituted with a group defined by formula (I) or a substituted or unsubstituted pyridyl group, and T is a nitrogen atom a is an alkylene group (a linear or branched (C 1 -C 6) alkyl group, form an aryl group, or a linear or branched alkyl portion of the aryl - (C 1 -C 6) substituted with an alkyl group or not substituted), or aryl Compounds characterized in that they are ren groups, isomers thereof, and addition salts thereof with pharmaceutically acceptable acids or bases.
    [13" claim-type="Currently amended] 2. Compounds according to claim 1, represented by the formula (I bis), isomers thereof and addition salts thereof with pharmaceutically acceptable acids or bases:

    In the above formula,
    X is a sulfur atom,
    Y is an oxygen atom,
    R 1 is a heteroaryl group selected from a substituted or unsubstituted phenyl group or a substituted or unsubstituted pyridyl group and a substituted or unsubstituted quinolyl group,
    A is a single bond,
    T is a carbon atom,
    Ra and Rc are each hydrogen atoms,
    U 1 is a (C 1 -C 4 ) alkylene chain,
    V 1 is an arylene group,
    U 2 is a single bond,
    V 2 is an aryl group,
    R b is a U 1 -V 1 -U 2 -V 2 group as defined above,
    R 2 is a heteroaryl group,
    W is a group as defined in formula (I).
    [14" claim-type="Currently amended] 14. A compound according to claim 13, wherein the groups of Rb and U 1 -V 1 -U 2 -V 2 represent formula (I bis), each of which is a [1,1'-biphenyl] -4-ylmethoxy group. , Isomers thereof and addition salts thereof with pharmaceutically acceptable acids or bases.
    [15" claim-type="Currently amended] 14. Compounds, isomers thereof and addition salts thereof with pharmaceutically acceptable acids or bases according to claim 13, characterized in that R 2 represents a pyridyl group.
    [16" claim-type="Currently amended] The compound of claim 13, wherein R 1 is
    - a halogen, linear or branched (C 1 -C 6) alkyl, heteroaryl, heterocyclic alkoxy moiety is a linear or branched form aryl - (C 1 -C 6) alkoxy, linear or branched (C 1 -C 6 ) Or a phenyl group unsubstituted or substituted with one to three groups selected from alkoxy, amino and linear or branched amino- (C 1 -C 6 ) alkoxy (wherein the amino moiety is one or two of each of the two groups) It is possible to be substituted with the same or different linear or branched (C 1 -C 6 ) alkyl groups),
    Compounds represented by formula (I bis) which are heteroaryl groups selected from pyridyl and quinolyl, optionally substituted with halogen atoms or with linear or branched (C 1 -C 6 ) alkyl groups, isomers thereof and their And addition salts with pharmaceutically acceptable acids or bases.
    [17" claim-type="Currently amended] The compound according to claim 1, wherein (E) -3- [5,6-bis ([1,1'-biphenyl] -4-ylmethoxy) -3- (4-chlorophenoxy) benzo [b] thiophene -2-yl] -2- (4-pyridyl) -2-propenoic acid, isomers thereof, and addition salts thereof with pharmaceutically acceptable acids or bases.
    [18" claim-type="Currently amended] The method of claim 1,
    Ethyl (E) -3- [5,6-bis ([1,1'-biphenyl] -4-ylmethoxy) -3- (4-chlorophenoxy) benzo [b] thiophen-2-yl ] -2- (4-pyridyl) -2-propenoate,
    (E) -3- [5,6-bis ([1,1'-biphenyl] -4-ylmethoxy) -3- (3-pyridyloxy) benzo [b] thiophen-2-yl] -2- (4-pyridyl) -2-propenoic acid,
    3- (E)-{5,6-bis ([1,1'-biphenyl] -4-ylmethoxy) -3- [6- (methyl) pyridyl-3-oxy] benzo [b] ti Offen-2-yl} -2- (4-pyridyl) -2-propenoic acid,
    3- (E)-[5,6-bis ([1,1'-biphenyl] -4-ylmethoxy) -3- (6-quinolyloxy) benzo [b] thiophen-2-yl] -2- (4-pyridyl) -2-propenoic acid,
    (E) -3- [5,6-bis ([1,1'-biphenyl] -2-ylmethoxy) -3- (4-chlorophenoxy) -benzo [b] thiophen-2-yl ] -2- (4-pyridyl) -2-propenoic acid,
    (E) -3- [5,6-bis ([1,1'-biphenyl] -3-ylmethoxy) -3- (4-chlorophenoxy) -benzo [b] thiophen-2-yl ] -2- (4-pyridyl) -2-propenoic acid,
    (E) -3- [5,6-bis ([1,1'-biphenyl] -4-ylmethoxy) -3- (4-chloro-3-fluorophenoxy) -benzo [b] thi Offen-2-yl] -2- (4-pyridyl) -2-propenoic acid,
    (E) -3- [5,6-bis ([1,1'-biphenyl] -4-ylmethoxy) -3- (4-chloro-3,5-dimethylphenoxy) -benzo [b] Thiophen-2-yl] -2- (4-pyridyl) -2-propenoic acid,
    (E) -3- [5,6-bis ([1,1'-biphenyl] -4-ylmethoxy) -3- (4-chloro-3-methylphenoxy) -benzo [b] thiophene -2-yl] -2- (4-pyridyl) -2-propenoic acid,
    (E) -3- {5,6-bis ([1,1'-biphenyl] -4-ylmethoxy) -3- [4- (4-pyridyloxy) phenoxy] -benzo [b] Thiophen-2-yl} -2- (4-pyridyl) -2-propenoic acid,
    (E) -3- {5,6-bis ([1,1'-biphenyl] -4-ylmethoxy) -3- [4- (1H-imidazol-1-yl) phenoxy] -benzo [b] thiophen-2-yl} -2- (4-pyridyl) -2-propenoic acid,
    (E) -3- [5,6-bis ([1,1'-biphenyl] -4-ylmethoxy) -3-phenoxy-benzo [b] thiophen-2-yl] -2- ( 4-pyridyl) -2-propenoic acid,
    (E) -3- [5,6-bis ([1,1'-biphenyl] -4-ylmethoxy) -3- (3-fluorophenoxy) -benzo [b] thiophene-2- Il] -2- (4-pyridyl) -2-propenoic acid,
    (E) -3- [5,6-bis ([1,1'-biphenyl] -4-ylmethoxy) -3- (3,4-difluorophenoxy) -benzo [b] thiophene -2-yl] -2- (4-pyridyl) -2-propenoic acid,
    (E) -3- {5,6-bis ([1,1'-biphenyl] -4-ylmethoxy) -3-[(6-chloro-3-pyridyl) oxy] -benzo [b] Thiophen-2-yl} -2- (4-pyridyl) -2-propenoic acid, isomers thereof and addition salts thereof with pharmaceutically acceptable acids or bases.
    [19" claim-type="Currently amended] A process for preparing a compound of formula (I), wherein the compound of formula (II) is used under basic conditions, using a compound of formula (II) as starting material,
    When Q of formula (II) is a halogen atom, the compound is reacted with a compound of formula (III) to give a compound of formula (IV / a), or by reacting with a compound of formula (V) Obtaining the compound of IV / a), or
    When Q in formula (II) is a hydroxy group, the compound is reacted with a compound of formula (VI) to give a compound of formula (IV / c), wherein (IV / a), (IV / b) and The compound of (IV / c) constitutes a compound of formula (IV)
    ◆ a compound of formula (IV) is condensed with a compound of formula (VII) in the presence of acetic anhydride to give a compound of formula (VIII), wherein the hydroxy functional group of the compound of formula (VIII) After deprotection under organic synthesis conditions, the compound is reacted with a compound of formula (IX) under basic medium to give a compound of formula (I / a), which is a specific case of the compound of formula (I), If desired, compounds of formula (I / a)
    Catalytic hydrogenation in the presence of palladium to give a compound of formula (I / b), which is a specific case of a compound of formula (I), or
    Hydrolysis in the presence of a basic medium to give a compound of formula (I / c), which is a specific case of a compound of formula (I), wherein the double bond of a compound of formula (I / c) Is reduced by catalytic hydrogenation to give a compound of formula (I / d), which is a specific case of a compound of formula (I), or
    ◆ Treatment of a compound of formula (IV) with a phosphide of formula (X) affords a compound of formula (XI), wherein the hydroxy functional groups of the compound of formula (XI) After deprotection, the compound is reacted with a compound of formula (IX) under basic medium to give a compound of formula (I / e), which is a specific case of the compound of formula (I), Compound of formula (I / e)
    Hydrolysis under basic conditions to give a compound of formula (I / f), which is a specific case of a compound of formula (I), or
    Catalytic hydrogenation to afford a compound of formula (I / g), which is a specific case of a compound of formula (I), and treatment of a compound of formula (I / g) under basic hydrolysis conditions To obtain a compound of formula (I / h), which is a specific case of a compound of formula (I), or
    ◆ The hydroxy functional group of the compound of formula (IV) is deprotected under conventional organic synthesis conditions and then reacted with a compound of formula (IX) under basic medium to give a compound of formula (XII) The aldehyde functional group of the compound of formula (XII) is reduced with a primary alcohol to give a compound of formula (XIII), the terminal hydroxy group of which is replaced by a halogen atom under conventional conditions to give a compound of formula (XIV) ,
    In a compound of formula (XIV), a halogen atom is replaced by an aminated compound of formula (XV) under basic conditions, whereby the compound of formula (I) Is a specific case) and the terminal carbonyl group of the compound of formula (I / i) is hydrolyzed under basic conditions to give a compound of formula (I / j), which is a specific case of the compound of formula (I) ), Or
    ★ A compound of formula (XIV) is first treated with sodium azide to reduce the resulting azide to a primary amine under catalytic hydrogenation conditions to yield a compound of formula (XVI), which is subjected to basic conditions By condensation with a chlorosulfonyl compound of formula (XVII) to afford a compound of formula (I / k), which is a specific case of the compound of formula (I), and, if desired, k)
    Hydrolysis under basic conditions to give a compound of formula (I / l), which is a specific case of a compound of formula (I), or
    Condensation under the basic medium to the formula (XVIII) to afford the compound of formula (I / m), which is a specific case of the compound of formula (I), the compound of formula (I / m) Is treated under hydrolysis conditions in a basic medium to give a compound of formula (I / n), which is a specific case of a compound of formula (I),
    Compounds of formulas (I / c), (I / d), (I / f), (I / h), (I / j), (I / l) and (I / n) are represented by the formula ) And reacting a compound of formula (I ') with an O-substituted hydroxylamine, followed by deprotection of the hydroxylamine functional group to give a compound of formula (I / o) Is a specific case of the compound of I)),
    Compounds of formulas (I / a) to (I / o) constituting the compounds of the invention are purified, if necessary, according to conventional purification techniques, if desired, separated into their different isomers according to conventional separation techniques, Where appropriate, conversion of these to addition salts with pharmaceutically acceptable acids or bases:

    (Wherein Ra, Rb, Rc and X are as defined in formula (I), G is a hydroxy group protected by a protecting group commonly used in organic synthesis, Q is a halogen atom or a hydroxy group, preferably X Q is a halogen atom if it is a sulfur atom or NR 3 (wherein R 3 is as defined in formula (I)) and Q is a hydroxy group when X is an oxygen atom)

    (Wherein R 1 is as defined in formula (I) and Y 1 is an oxygen atom, a sulfur atom or NR 3 (wherein R 3 is as defined in formula (I)))

    (Wherein Ra, Rb, Rc, G, R 1 , X and Y 1 are as defined above)

    (Wherein Ra, Rb, Rc, G and R 1 are as defined above and X 1 is NR 3 (wherein R 3 is heteroaryl- (C 1 -C 6) wherein the alkyl moiety is in linear or branched form. Is an alkyl group)

    (Wherein Ra, Rb, Rc, G, X and R 1 are as defined above)

    (Wherein Ra, Rb, Rc, G, R 1 , X and Y 1 are as defined in formula (I))

    Wherein R 1 is as defined in formula (I)

    Wherein R ′ 2 is as defined for R 2 in Formula (I), R ′ 2 may not be a hydrogen atom, and W 1 is linear or branched (C 1 -C 6 ) alkoxy, aryloxy , arylalkoxy part is a linear or branched form - (C 1 -C 6) alkoxy, cycloalkyloxy, heteroaryl, cycloalkoxy, heteroaryloxy and an amino group (itself a linear or branched (C 1 -C 6) alkyl , Aryl, aryl- (C 1 -C 6 ) alkyl in which the alkyl moiety is in linear or branched form, and cycloalkyl, each substituted or unsubstituted with one or two identical or different groups)

    (Wherein Ra, Rb, Rc, G, R 1 , R ' 2 , X, Y and W 1 are as defined above)

    Wherein U 1 , V 1 , U 2 , and V 2 are as defined in formula (I), and Hal represents a halogen atom.

    Wherein R ′ is a linear or branched (C 1 -C 6 ) alkyl group or a phenyl group, R 2 is as defined in formula (I), W 1 is as defined above, A 1 is a single bond, Alkylene groups selected from linear or branched (C 1 -C 6 ) alkyl, aryl, aryl- (C 1 -C 6 ) alkyl, cycloalkyl, heterocycloalkyl and heteroaryl, in which the alkyl moiety is in linear or branched form Unsubstituted or substituted with one or more groups), an arylene group, a cycloalkylene group, a heterocycloalkylene group, or a heteroarylene group)

    (Wherein Ra, Rb, Rc, G, R 1 , R 2 , X, Y, A 1 and W 1 are as defined above)

    (Wherein Ra, Rb, Rc, U 1 , V 1 , U 2 , V 2 , R 1 , X and Y are as defined above)

    (Wherein Ra, Rb, Rc, U 1 , V 1 , U 2 , V 2 , R 1 , X and Y are as defined above)

    (Wherein Ra, Rb, Rc, U 1 , V 1 , U 2 , V 2 , R 1 , X and Y are as defined above)

    (Wherein R 2 is as defined in formula (I) and A 1 and W 1 are as defined above)

    (Wherein Ra, Rb, Rc, U 1 , V 1 , U 2 , V 2 , R 1 , X and Y are as defined above)

    (Wherein R 4 is as defined in formula (I) and W 1 is as defined above)

    (Wherein Hal is a halogen atom such as iodine and R ' 2 is as defined above)

    (Wherein Ra, Rb, Rc, U 1 , V 1 , U 2 , V 2 , G, R 1 , R ' 2 , X, Y and W 1 are as defined above)

    (Wherein Ra, Rb, Rc, U 1 , V 1 , U 2 , V 2 , G, R 1 , R ' 2 , X, Y and W 1 are as defined above)

    (Wherein Ra, Rb, Rc, U 1 , V 1 , U 2 , V 2 , G, R 1 , R ' 2 , X and Y are as defined above)

    (Wherein Ra, Rb, Rc, U 1 , V 1 , U 2 , V 2 , G, R 1 , R ' 2 , X and Y are as defined above)

    (Wherein Ra, Rb, Rc, U 1 , V 1 , U 2 , V 2 , G, R 1 , R 2 , A 1 , X, Y and W 1 are as defined above)

    (Wherein Ra, Rb, Rc, U 1 , V 1 , U 2 , V 2 , R 1 , R 2 , A 1 , X and Y are as defined above)

    (Wherein Ra, Rb, Rc, U 1 , V 1 , U 2 , V 2 , R 1 , R 2 , A 1 , X, Y and W 1 are as defined above)

    (Wherein Ra, Rb, Rc, U 1 , V 1 , U 2 , V 2 , R 1 , R 2 , A 1 , X and Y are as defined above)

    (Wherein Ra, Rb, Rc, U 1 , V 1 , U 2 , V 2 , R 1 , R 2 , X, Y, A 1 and W 1 are as defined above)

    (Wherein Ra, Rb, Rc, U 1 , V 1 , U 2 , V 2 , R 1 , R 2 , X, Y and A 1 are as defined above)

    (Wherein Ra, Rb, Rc, U 1 , V 1 , U 2 , V 2 , R 1 , R 4 , X, Y and W 1 are as defined above)

    (Wherein Ra, Rb, Rc, U 1 , V 1 , U 2 , V 2 , R 1 , R 4 , X and Y are as defined above)

    (Wherein Ra, Rb, Rc, U 1 , V 1 , U 2 , V 2 , R 1 , R ' 2 , R 4 , X, Y and W 1 are as defined above)

    (Wherein Ra, Rb, Rc, U 1 , V 1 , U 2 , V 2 , R 1 , R ' 2 , R 4 , X and Y are as defined above)

    (Wherein Ra, Rb, Rc, U 1 , V 1 , U 2 , V 2 , R 1 , R 2 , X, Y, Z and A are as defined above)

    (Wherein Ra, Rb, Rc, U 1 , V 1 , U 2 , V 2 , R 1 , R 2 , X, Y, Z and A are as defined above).
    [20" claim-type="Currently amended] A pharmaceutical composition comprising as an active ingredient one or more compounds of formula (I) according to any one of claims 1 to 18 alone or in combination with one or more pharmaceutically acceptable excipients or carriers which are inert and nontoxic.
    [21" claim-type="Currently amended] A pharmaceutical composition according to claim 20 used as an inhibitor of PAI-1.
    [22" claim-type="Currently amended] 21. A pharmaceutical composition according to claim 20 for use in the treatment of thrombosis, diseases of which thrombosis is of origin and diseases which increase the risk of thrombosis.
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1999-10-15|Priority to FR9912899A
    1999-10-15|Priority to FR99.12899
    2000-10-13|Application filed by 오딜 오스터만, 아디르 에 꽁빠니
    2001-06-25|Publication of KR20010051018A
    2005-03-08|Application granted
    2005-03-08|Publication of KR100474753B1
    优先权:
    申请号 | 申请日 | 专利标题
    FR9912899A|FR2799756B1|1999-10-15|1999-10-15|Novel benzothiophenic, benzofuranic and indolic derivatives, process for their preparation and the pharmaceutical compositions containing them|
    FR99.12899|1999-10-15|
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