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    • 专利摘要:
    The present invention relates to novel compounds of formula (I) which are inhibitors of coagulation factor Xa and which can be used for the treatment of thromboembolic diseases: [Formula I] [Where X, Y, R 1 , R 2 and R 3 have the same meaning as in claim 1].
    公开号:KR20010024386A
    申请号:KR1020007003536
    申请日:1998-09-16
    公开日:2001-03-26
    发明作者:도르쉬디이터；유라스지크호르스트；부르찌거한스；자비네 베르노타트-다니엘오스키；멜쩨르기도
    申请人:플레믹 크리스티안；메르크 파텐트 게엠베하；
    IPC主号:
    专利说明:

    BENZAMIDINE DERIVATIVES AS FACTOR XA INHIBITORS}
    The present invention relates to compounds of formula (I) and salts thereof:
    [here,
    R 1 is —C (═NH) —NH, which may be mono-substituted by —COA—, —CO— [C (R 6 ) 2 ] n-Ar, —COOA, —OH, or by conventional amino protecting groups 2 ,
    ego
    R 2 is H, A, OR 6 , N (R 6 ) 2 , NO 2 , CN, Hal, NHCOA, NHCOAr, NHSO 2 A, NHSO 2 Ar, COOR 6 , CON (R 6 ) 2 , CONHAr, COR 6 , COAr, S (O) nA or S (O) nAr,
    R 3 is A, cycloalkyl,-[C (R 6 ) 2 ] nAr,-[C (R 6 ) 2 ] nO-Ar,-[C (R 6 ) 2 ] nHet or -C (R 6 ) 2 = C (R 6 ) 2 -Ar,
    R 6 is H, A or benzyl,
    X is absent or -CO-, -C (R 6 ) 2- , -C (R 6 ) 2 -C (R 6 ) 2- , -C (R 6 ) 2 -CO-, -C (R 6 ) 2 -C (R 6 ) 2 -CO-, -C (R 6 ) = C (R 6 ) -CO-, -NR 6 CO-, -N {[C (R 6 ) 2 ] n-COOR 6 } -CO- or -C (COOR 6 ) R 6 -C (R 6 ) 2 -CO-,
    Y is -C (R 6 ) 2- , -SO 2- , -CO-, -COO- or -CONR 6- ,
    A has 1 to 20 carbon atoms in which 1 or 2 CH 2 groups can be substituted by O or S atoms, or by -CR 6 = CR 6 -groups, and / or 1 to 7 H atoms can be substituted by F Is alkyl,
    Ar is A, Ar ', OR 6 , N (R 6 ) 2 , NO 2 , CN, Hal, NHCOA, NHCOAr', NHSO 2 A, NHSO 2 Ar ', COOR 6 , CON (R 6 ) 2 , CONHAr Naphthyl or phenyl which is mono, di or trisubstituted or unsubstituted by ', COR 6 , COAr', S (O) nA or S (O) nAr,
    Ar 'is one, two or three by A, OR 6 , N (R 6 ) 2 , NO 2 , CN, Hal, NHCOA, COOR 6 , CON (R 6 ) 2 , COR 6 or S (O) nA. Substituted or unsubstituted naphthyl or phenyl,
    Het contains 1, 2, 3 or 4 identical or different hetero atoms such as nitrogen, oxygen and sulfur, and He, A, Ar ', COOR 6 , CN, N (R 6 ) 2 , NO 2 , A monocyclic or bicyclic saturated or unsaturated heterocyclic ring system, mono- or polysubstituted or unsubstituted by Ar-CONH-CH 2 and / or carbonyl oxygen,
    Hal is F, Cl, Br or I,
    n is 0, 1 or 2;
    The invention also provides optically active forms of these compounds, racemates, diastereomers and hydrates and solvates.
    The present invention is based on the object of finding novel compounds with valuable properties, in particular compounds which can be used in the preparation of a medicament.
    It has been found that the compounds of formula (I) and salts thereof have very useful pharmacological properties with good resistance. In particular, they have the property of inhibiting factor Xa, thus treating and preventing thromboembolic diseases such as thrombosis, myocardial infarction, atherosclerosis, inflammation, stroke, angina pectoris, recurrent stenosis and claudicatio intermittens after angioplasty. Can be used for
    Aromatic amidine derivatives with antithrombotic action are known, for example, from EP 0 540 051 B1. Cyclic guanidines for the treatment of thromboembolic diseases are described, for example, in WO 97/08165. Aromatic heterocyclics having a function of inhibiting factor Xa are known, for example, from WO 96/10022.
    The antithrombotic and anticoagulant effects of the compounds according to the invention are due to their inhibitory action on activated coagulation proteases known as factor Xa. Factor Xa is one of the proteases involved in the complex process of blood coagulation. Factor Xa catalyzes the conversion of prothrombin to thrombin, which then contributes to thrombus formation. Activation of thrombin can lead to thromboembolic diseases. Therefore, inhibition of factor Xa can prevent the formation of thrombin. The compounds of formula (I) and their salts according to the invention interfere with the blood coagulation process by inhibiting factor Xa and thus inhibit the formation of thrombi.
    Inhibition of factor Xa by the compounds according to the invention, and determination of anticoagulant antithrombotic activity can be routinely determined in vitro and in vivo methods. Suitable methods are described, for example, in [J. Hauptmann et al., Thrombosis and Haemostasis 63, 220-223 (1990). Inhibition of factor Xa is described, for example, in T. Hara et al. [Thromb. Haemostas. 71, 314-319 (1994).
    The compounds of formula (I) can be used as medicaments in human medicine and veterinary medicine, in particular for the treatment and prevention of thromboembolic diseases such as thrombosis, myocardial infarction, atherosclerosis, inflammation, stroke, angina, recurrent stenosis after angioplasty and intermittent claudication have.
    The present invention provides a compound of formula (I) and salts thereof, and a process for preparing the compound of formula (I) and salts thereof according to claim 1, characterized by the following procedure:
    a) releasing a compound of formula (I) according to claim 1 and salts thereof from one of their functional derivatives by the following steps by treatment with a solubilizer or a hydrogenolytic agent:
    i) liberating an amidino group from its oxadiazole derivative by hydrogenolysis,
    ii) treating a conventional amino protecting group with a solubilizer or a hydrogenolysis agent to replace hydrogen or liberating an amino group protected by a conventional protecting group;
    or
    b) R 1 is ego,
    To prepare a compound of formula (I) wherein X is -CO- or -C (R 6 ) 2 -CO- and R 2 , R 3 and Y are as defined in claim 1, a compound of formula (II) Reacts with compounds:
    Where R 3 , R 4 , R 5 , W and Y are the same as in claim 1,
    [Where R 1 is ego,
    X is -CO- or -C (R 6 ) 2 -CO-,
    R 2 is the same as in claim 1,
    L is Cl, Br, I or an OH group induced with a free or reactive functional group;
    or
    c) R 1 is ego,
    Y is -SO 2- , -CO-, -COO- or -C (R 6 ) 2- ,
    Reacting a compound of formula IV with a compound of formula V to prepare a compound of formula I wherein R 2 and X are as in claim 1:
    LYR 3
    [Where Y is -SO 2- , -CO-, -COO- or -C (R 6 ) 2- ,
    R 3 is the same as in claim 1,
    L is Cl, Br, I or an OH group induced with a free or reactive functional group],
    Where R 1 is ego,
    R 2 and X are the same as in claim 1;
    or
    d) R 1 is ego,
    Reacting a compound of formula VI with a compound of formula V to produce a compound of formula I wherein Y is -CONH- and R 2 and X are as in claim 1:
    R 3 -N = C = O
    (Wherein R 3 is the same as in claim 1),
    [Formula V]
    Where R 1 is ego,
    R 2 and X are the same as in claim 1;
    or
    e) converting the cyano group to an amidino group to prepare a compound of formula I wherein R 1 is -C (= NH) -NH 2 ;
    And / or
    f) Sikkim transition from a compound of formula I, with one or more radicals R 1, R 2 and / or R 3 by, for example, one or more of the radicals by the steps R 1, R 2 and / or R 3:
    i) hydrolyzing the ester group to produce a carboxyl group,
    ii) reducing the nitro group,
    iii) acylating amino groups;
    And / or
    g) converting the base or acid of formula (I) to one of its salts.
    For all radicals which appear several times, for example R 6 , their meanings are independent of each other.
    Before and after, the radicals or parameters L, X, Y, R 1 , R 2 and R 3 have the same meanings as given for the formulas I to IV, unless stated otherwise.
    In the formula, A is alkyl and has 1 to 20 carbon atoms, preferably 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12. A is preferably methyl and ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2 Or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2 -Trimethylpropyl, heptyl, octyl, nonyl or decyl. Alkyl is also for example trifluoromethyl, pentafluoroethyl, allyl or crotyl.
    Cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Cycloalkyls are in particular radicals of bicyclic terpenes such as, for example, 3-mentyl; Very particular preference is given to camphor-10-yl radicals.
    COR 6 is acyl, preferably formyl, acetyl, propionyl, butyryl, pentanoyl or hexanoyl.
    Hal is preferably F, Cl or Br and is also I.
    R 2 is preferably H, fluorine, chlorine, bromine, iodine, hydroxyl, methoxy, ethoxy, propoxy, nitro, amino, methylamino, dimethylamino, ethylamino, diethylamino, acetamido, sulfone Amido, methylsulfonamido, phenylsulfonamido, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl, phenylsulfinyl, phenylsulfonyl, cyano, carboxyl, methi Oxycarbonyl, ethoxycarbonyl, and also acyl or benzoyl.
    R 3 is preferably, for example, A, cycloalkyl, Ar, CH 2 Ar, CH 2 OAr, CH 2 CH 2 Ar, CH 2 Het, CH 2 CH 2 Het or CH═CH—Ar.
    R 6 is H, A or benzyl, but is preferably H.
    X is preferably absent, for example, or absent, -CO-, -CH 2- , -CH 2 -CH 2- , -CH 2 -CO-, -CH 2 -CH 2 -CO-, -CH = CH—CO—, —NR 6 CO—, —N {[CH 2 ] n —COOR 6 } —CO— or —CH (COOR 6 ) —CH 2 —CO—.
    Y is preferably, for example, -SO 2 -or -CO-, and also -COO-, -CONH- or -CH 2- .
    Ar is preferably unsubstituted phenyl or naphthyl, more preferably A, fluorine, chlorine, bromine, iodine, hydroxyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hex Siloxy, benzyloxy, phenethyloxy, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl, phenylsulfinyl, phenylsulfonyl, nitro, amino, methylamino, ethylamino, Dimethylamino, diethylamino, formamido, acetamido, propionylamino, butyrylamino, methylsulfonamido, ethylsulfonamido, propylsulfonamido, butylsulfonamido, phenylsulfonamido, (4 -Methylphenyl) sulfonamido, carboxymethoxy, carboxyethoxy, methoxycarbonylmethoxy, methoxycarbonylethoxy, hydroxymethoxy, hydroxyethoxy, methoxyethoxy, carbonyl, methoxycar Carbonyl, ethoxycarbonyl, cyano, phenylaminocarbonyl, A room or benzoyl, also one by-biphenyl, or a tri-substituted naphthyl or phenyl.
    Ar is therefore preferably, for example, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p- Isopropylphenyl, o-, m- or p-tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-nitrophenyl, o-, m- or p-aminophenyl , o-, m- or p- (N-methylamino) phenyl, o-, m- or p-acetamidophenyl, o-, m- or p-methoxyphenyl, o-, m- or p- Ethoxyphenyl, o-, m- or p-carboxyphenyl, o-, m- or p-methoxycarbonylphenyl, o-, m- or p- (N, N-dimethylamino) phenyl, o-, m- or p- (N-ethylamino) phenyl, o-, m- or p- (N, N-diethylamino) phenyl, o-, m- or p-acetylphenyl, o-, m- or p -Formylphenyl, o-, m- or p-fluorophenyl, o-, m- or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- or p-methylsulphate Phenylphenyl, o-, m- or p- (phenylsulfonamido) phenyl, o-, m- or p- (methylsulfonamido) phenyl, o-, m- or p-methylthiophenyl, more preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2 , 4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- Or 3,5-dibromophenyl, 2,4- or 2,5-dinitrophenyl, 2,5- or 3,4-dimethoxyphenyl, 3-nitro-4-chlorophenyl, 3-amino-4 -Chloro-, 2-amino-3-chloro-, 2-amino-4-chloro-, 2-amino-5-chloro-, or 2-amino-6-chlorophenyl, 2-nitro-4-N, N -Dimethylamino- or 3-nitro-4-N, N-dimethylaminophenyl, 2,3-diaminophenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2, 4,6- or 3,4,5-trichlorophenyl, 2,4,6-trimethoxyphenyl, 2-hydroxy-3,5-dichlorophenyl, p-iodophenyl, 3,6-dichloro- 4-aminophenyl, 4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl, 2,5-difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl , 3-chloro-6-methoxyphenyl, 3-chloro-4-acetamidophenyl, 3-fluoro 4-methoxy-phenyl, 3-amino-6-methylphenyl, 3-chloro-4-acetamido-phenyl, or 2,5-dimethyl-4-chlorophenyl.
    Ar is very particularly preferably unsubstituted phenyl or naphthyl, more preferably phenyl or naphthyl which is mono, di or trisubstituted, for example by A, chlorine, methoxy, amino or dimethylamino, or Biphenyl.
    Ar 'is, for example, phenyl or naphthyl, more preferably, for example o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p- Propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p-tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-nitrophenyl , o-, m- or p-aminophenyl, o-, m- or p- (N-methylamino) phenyl, o-, m- or p-acetamidophenyl, o-, m- or p-meth Oxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p-carboxyphenyl, o-, m- or p-methoxycarbonylphenyl, o-, m- or p- (N , N-dimethylamino) phenyl, o-, m- or p- (N-ethylamino) phenyl, o-, m- or p- (N, N-diethylamino) phenyl, o-, m- or p -Acetylphenyl, o-, m- or p-formylphenyl, o-, m- or p-fluorophenyl, o-, m- or p-bromophenyl, o-, m- or p-chlorophenyl Or o-, m- or p-methylsulfonylphenyl.
    Het is preferably, for example, 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3- , 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, more preferably 1,2,3-triazole-1 -, -4- or -5-yl, 1,2,4-triazol-1-, -3- or -5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazole- 4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4- Thiadiazole-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3- , 4-, 5-, 6- or 7-indolyl, 4- or 5-isoindolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5 -, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzi Sazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or 7 -Benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6- , 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazoli Nyl, 5- or 6-quinoxalinyl, 2-, 3-, 5-, 6-, 7- or 8-2H-benzo [1,4] oxazinyl, more preferably 1,3-benzodioxol -5-yl, 1,4-benzodioxan-6-yl, 2,1,3-benzothiadiazol-4- or -5-yl, 2,1,3-benzoxadiazol-5-yl Or dibenzofuranyl.
    Heterocyclic radicals may also be partially or wholly hydrogenated.
    Het is also, for example, 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or -5 -Furyl, tetrahydro-2- or -3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-l, -2- , -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3 -Pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl, Tetrahydro-1-,-3- or -4-pyrazolyl, 1,4-dihydro-1-, -2-, -3- or -4-pyridyl, 1,2,3,4-tetrahydro -1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-mor Polyyl, tetrahydro-2-,-3- or -4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-,-4- or -5-yl, hexahydro-1 -, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1,2, 3,4-tetrahydrate Rho-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-quinolyl, 1,2,3,4-tetrahydro-1-,- 2-,-3-,-4-, -5-, -6-, -7- or -8-isoquinolyl, 2-, 3-, 5-, 6-, 7- or 8-3,4 -Dihydro-2H-benzo [1,4] oxazinyl, more preferably 2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl, 2,3-ethylenedioxyphenyl, 3,4- Ethylenedioxyphenyl, 3,4- (difluoromethylenedioxy) phenyl, 2,3-dihydrobenzofuran-5- or -6-yl, 2,3- (2-oxomethylenedioxy) phenyl, Or alternatively 3,4-dihydro-2H-1,5-benzodioxepin-6- or -7-yl, more preferably 2,3-dihydrobenzofuranyl or 2,3-dihydro-2 Oxofuranyl.
    Het is mono or polysubstituted or unsubstituted by Hal, A, Ar ', COOR 6 , CN, N (R 6 ) 2 , NO 2 , Ar-CONH-CH 2 . "Plurality" means two, three, four or five;
    Compounds of formula (I) may have one or more chiral centers and, therefore, may exist in various stereoisomeric forms. Formula I encompasses all these forms.
    Accordingly, the present invention provides, in particular, compounds of formula (I) in which one or more of the aforementioned radicals have one of the preferred meanings given above. Some preferred groups of compounds may be represented by the following parts Ia to If corresponding to formula I, wherein radicals not defined in more detail have the same meanings as given for formula I,
    In Ia
    R 1 is —C (═NH) —NH, which may be mono-substituted by —COA—, —CO— [C (R 6 ) 2 ] n-Ar, —COOA, —OH, or by conventional amino protecting groups 2 ,
    ego,
    R 2 is H, A, OR 6 , N (R 6 ) 2 , NO 2 , CN, Hal, NHCOA, NHCOAr, NHSO 2 A, NHSO 2 Ar, COOR 6 , CON (R 6 ) 2 , CONHAr, COR 6 , COAr, S (O) nA or S (O) nAr,
    R 3 is A, cycloalkyl, Ar, CH 2 Ar, CH 2 OAr, CH 2 CH 2 Ar, CH 2 Het, CH 2 CH 2 Het or CH = CH-Ar,
    R 6 is H or A,
    X is absent or -CO-, -CH 2 -CO-, -CH 2 -CH 2 -CO-, -CH 2- , -CH 2 -CH 2- , -CH = CH-CO-, -NHCO -, -N (CH 2 COOR 6 ) -CO- or -CH (COOR 6 ) -CH 2 -CO-,
    Y is -SO 2- , -CO-, -COO-, -CO-NH- or -CH 2- ,
    A has 1 to 20 carbon atoms in which 1 or 2 CH 2 groups can be substituted by O or S atoms, or by -CR 6 = CR 6 -groups, and / or 1 to 7 H atoms can be substituted by F Is alkyl,
    Ar is A, Ar ', OR 6 , N (R 6 ) 2 , NO 2 , CN, Hal, NHCOA, NHCOAr', NHSO 2 A, NHSO 2 Ar ', COOR 6 , CON (R 6 ) 2 , CONHAr Naphthyl or phenyl which is mono, di or trisubstituted or unsubstituted by ', COR 6 , COAr', S (O) nA or S (O) nAr,
    Ar 'is one, two or three by A, OR 6 , N (R 6 ) 2 , NO 2 , CN, Hal, NHCOA, COOR 6 , CON (R 6 ) 2 , COR 6 or S (O) nA. Substituted or unsubstituted naphthyl or phenyl,
    Het contains 1, 2, 3 or 4 identical or different hetero atoms such as nitrogen, oxygen and sulfur, and He, A, Ar ', COOR 6 , CN, N (R 6 ) 2 , NO 2 , A monocyclic or bicyclic saturated or unsaturated heterocyclic ring system, mono- or polysubstituted or unsubstituted by Ar-CONH-CH 2 and / or carbonyl oxygen,
    Hal is F, Cl, Br or I,
    n is 0, 1 or 2;
    In Ib
    R 1 is —C (═NH) —NH, which may be mono-substituted by —COA—, —CO— [C (R 6 ) 2 ] n-Ar, —COOA, —OH, or by conventional amino protecting groups 2 ,
    ego,
    R 2 is H,
    R 3 is A, cycloalkyl, Ar, -CH 2 Ar, -CH 2 OAr, -CH 2 CH 2 Ar, -CH 2 Het, -CH 2 CH 2 Het or -CH = CH-Ar,
    R 6 is H or A,
    X is absent or -CO-, -CH 2 -CO-, -CH 2 -CH 2 -CO-, -CH 2- , -CH 2 -CH 2- , -CH = CH-CO-, -NHCO -, -N (CH 2 COOR 6 ) -CO- or -CH (COOR 6 ) -CH 2 -CO-,
    Y is -SO 2- , -CO-, -COO-, -CO-NH- or -CH 2- ,
    A has 1 to 20 carbon atoms in which 1 or 2 CH 2 groups can be substituted by O or S atoms, or by -CR 6 = CR 6 -groups, and / or 1 to 7 H atoms can be substituted by F Is alkyl,
    Ar is A, Ar ', OR 6 , NH 2 , NO 2 , CN, Hal, NHCOA, NHCOAr', NHSO 2 A, NHSO 2 Ar ', COOR 6 , CON (R 6 ) 2 , CONHAr', COR 6 , Naphthyl or phenyl which is mono, di or trisubstituted or unsubstituted by COAr ', S (O) nA or S (O) nAr,
    Ar 'is one, two or three by A, OR 6 , N (R 6 ) 2 , NO 2 , CN, Hal, NHCOA, COOR 6 , CON (R 6 ) 2 , COR 6 or S (O) nA. Substituted or unsubstituted naphthyl or phenyl,
    Het contains 1, 2, 3 or 4 identical or different hetero atoms such as nitrogen, oxygen and sulfur, and He, A, Ar ', COOR 6 , CN, N (R 6 ) 2 , NO 2 , A monocyclic or bicyclic saturated or unsaturated heterocyclic ring system, mono- or polysubstituted or unsubstituted by Ar-CONH-CH 2 and / or carbonyl oxygen,
    Hal is F, Cl, Br or I,
    n is 0, 1 or 2;
    In Ic
    R 1 is —C (═NH) —NH, which may be mono-substituted by —COA—, —CO— [C (R 6 ) 2 ] n-Ar, —COOA, —OH, or by conventional amino protecting groups 2 ,
    ego,
    R 2 is H,
    R 3 is A, cycloalkyl, Ar, -CH 2 Ar, -CH 2 OAr, -CH 2 CH 2 Ar, -CH 2 Het, -CH 2 CH 2 Het or -CH = CH-Ar,
    R 6 is H or A,
    X is absent or -CO-, -CH 2 -CO-, -CH 2 -CH 2 -CO-, -CH 2- , -CH 2 -CH 2- , -CH = CH-CO-, -NHCO -, -N {CH 2 -COOR 6 } -CO- or -CH (COOR 6 ) -CH 2 -CO-,
    Y is -SO 2- , -CO-, -COO-, -CO-NH- or -CH 2- ,
    A has 1 to 20 carbon atoms in which 1 or 2 CH 2 groups can be substituted by O or S atoms, or by -CR 6 = CR 6 -groups, and / or 1 to 7 H atoms can be substituted by F Is alkyl,
    Ar is A, Ar ', OR 6 , N (R 6 ) 2 , NO 2 , CN, Hal, NHCOA, NHCOAr', NHSO 2 A, NHSO 2 Ar ', COOR 6 , CON (R 6 ) 2 , CONHAr Naphthyl or phenyl which is mono, di or trisubstituted or unsubstituted by ', COR 6 , COAr', S (O) nA or S (O) nAr,
    Ar 'is one, two or three by A, OR 6 , N (R 6 ) 2 , NO 2 , CN, Hal, NHCOA, COOR 6 , CON (R 6 ) 2 , COR 6 or S (O) nA. Substituted or unsubstituted naphthyl or phenyl,
    Het is carbonyl oxygen and / or Hal, A, Ar ', COOR 6 , CN, selected from the group consisting of thiophene, tetrahydroquinoline, chroman, pyrazole, isoxazole, pyridine, benzodioxol or benzothiophene A monocyclic or bicyclic heterocyclic ring system which is mono- or polysubstituted or unsubstituted by N (R 6 ) 2 , NO 2 , Ar-CONH-CH 2 ,
    Hal is F, Cl, Br or I,
    n is 0, 1 or 2;
    In Id
    R 1 is —C (═NH) —NH, which may be mono-substituted by —COA—, —CO— [C (R 6 ) 2 ] n-Ar, —COOA, —OH, or by conventional amino protecting groups 2 ,
    ego,
    R 2 is H,
    R 3 is A, cycloalkyl, Ar, -CH 2 Ar, -CH 2 OAr, -CH 2 CH 2 Ar, -CH 2 Het, -CH 2 CH 2 Het or -CH = CH-Ar,
    R 6 is H or A,
    X is absent or -CO-, -CH 2 -CO-, -CH 2 -CH 2 -CO-, -CH 2- , -CH 2 -CH 2- , -CH = CH-CO-, -NHCO -, -N {CH 2 -COOR 6 } -CO- or -CH (COOR 6 ) -CH 2 -CO-,
    Y is -SO 2- , -CO-, -COO-, -CO-NH- or -CH 2- ,
    A has 1 to 20 carbon atoms in which 1 or 2 CH 2 groups can be substituted by O or S atoms, or by -CR 6 = CR 6 -groups, and / or 1 to 7 H atoms can be substituted by F Is alkyl,
    Ar is A, Ar ', OR 6 , N (R 6 ) 2 , NO 2 , CN, Hal, NHCOA, NHCOAr', NHSO 2 A, NHSO 2 Ar ', COOR 6 , CON (R 6 ) 2 , CONHAr Naphthyl or phenyl which is mono, di or trisubstituted or unsubstituted by ', COR 6 , COAr', S (O) nA or S (O) nAr,
    Ar 'is phenyl,
    Het is carbonyl oxygen and / or Hal, A, Ar ', COOR selected from the group consisting of thiophene, tetrahydroquinoline, chroman, pyrazole, isoxazole, pyridine, benzodioxol, benzothiophene or dibenzofuran 6 , CN, N (R 6 ) 2 , NO 2 , monocyclic or bicyclic heterocyclic ring system which is mono- or polysubstituted or unsubstituted by Ar-CONH-CH 2 ,
    Hal is F, Cl, Br or I,
    n is 0, 1 or 2;
    In Ie
    R 1 is —C (═NH) —NH, which may be mono-substituted by —COA—, —CO— [C (R 6 ) 2 ] n-Ar, —COOA, —OH, or by conventional amino protecting groups 2 ,
    ego,
    R 2 is H,
    R 3 is A, cycloalkyl, Ar, CH 2 Ar, CH 2 OAr, CH 2 CH 2 Ar, CH 2 Het, CH 2 CH 2 Het or CH = CH-Ar,
    R 6 is H or A,
    X is absent or -CO-, -CH 2 -CO-, -CH 2 -CH 2 -CO-, -CH 2- , -CH 2 -CH 2- , -NHCO-, -N {CH 2- COOR 6 } —CO— or —CH (COOR 6 ) —CH 2 —CO—,
    Y is -SO 2- , -CO- or -CH 2- ,
    A has 1 to 20 carbon atoms in which 1 or 2 CH 2 groups can be substituted by O or S atoms, or by -CR 6 = CR 6 -groups, and / or 1 to 7 H atoms can be substituted by F Is alkyl,
    Ar is A, Ar ', OR 6 , N (R 6 ) 2 , NO 2 , CN, Hal, NHCOA, NHCOAr', NHSO 2 A, NHSO 2 Ar ', COOR 6 , CON (R 6 ) 2 , CONHAr Naphthyl or phenyl which is mono, di or trisubstituted or unsubstituted by ', COR 6 , COAr', S (O) nA or S (O) nAr,
    Ar 'is phenyl,
    Het is carbonyl oxygen and / or Hal, A, Ar ', COOR selected from the group consisting of thiophene, tetrahydroquinoline, chroman, pyrazole, isoxazole, pyridine, benzodioxol, benzothiophene or dibenzofuran 6 , CN, N (R 6 ) 2 , NO 2 , monocyclic or bicyclic heterocyclic ring system which is mono- or polysubstituted or unsubstituted by Ar-CONH-CH 2 ,
    Hal is F, Cl, Br or I,
    n is 0, 1 or 2;
    If In
    R 1 is —C (═NH) —NH 2 , which may be monosubstituted by —COOA-,
    ego,
    R 2 is H,
    R 3 is A, cycloalkyl, Ar, -CH 2 Ar, -CH 2 OAr, -CH 2 CH 2 Ar, -CH 2 Het, -CH 2 CH 2 Het or -CH = CH-Ar,
    R 6 is H or A,
    X is absent or -CO-, -CH 2 -CO-, -CH 2 -CH 2 -CO-, -CH 2- , -CH 2 -CH 2- , -NHCO-, -N {CH 2- COOR 6 } —CO— or —CH (COOR 6 ) —CH 2 —CO—,
    Y is -SO 2- , -CO- or -CH 2- ,
    A has 1 to 20 carbon atoms in which 1 or 2 CH 2 groups can be substituted by O or S atoms, or by -CR 6 = CR 6 -groups, and / or 1 to 7 H atoms can be substituted by F Is alkyl,
    Ar is A, Ar ', OR 6 , N (R 6 ) 2 , NO 2 , CN, Hal, NHCOA, NHCOAr', NHSO 2 A, NHSO 2 Ar ', COOR 6 , CON (R 6 ) 2 , CONHAr Naphthyl or phenyl which is mono, di or trisubstituted or unsubstituted by ', COR 6 , COAr', S (O) nA or S (O) nAr,
    Ar 'is phenyl,
    Het is carbonyl oxygen and / or Hal, A, Ar ', COOR selected from the group consisting of thiophene, tetrahydroquinoline, chroman, pyrazole, isoxazole, pyridine, benzodioxol, benzothiophene or dibenzofuran 6 , CN, N (R 6 ) 2 , NO 2 , monocyclic or bicyclic heterocyclic ring system which is mono- or polysubstituted or unsubstituted by Ar-CONH-CH 2 ,
    Hal is F, Cl, Br or I,
    n is 0, 1 or 2.
    Alternatively, the compounds of formula (I) and starting materials for their preparation may also be themselves, such as those described in Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart). By a method known in the art, in particular under the reaction conditions suitable and known for the abovementioned reactions. In this reaction, variations which are known per se and are not mentioned in detail in the present invention may also be utilized.
    If desired, the starting material is shaped in situ so that it is further reacted immediately without separation from the reaction mixture to give the compound of formula (I).
    The compounds of formula (I) can preferably be obtained by treating the compounds of formula (I) with their solubilizers or hydrogenolytic agents to liberate from their functional derivatives.
    Preferred starting materials for solvolysis or hydrogenolysis are those which contain protected amino and / or hydroxyl groups which, in another way, correspond to formula I but instead of one or more free amino and / or hydroxyl groups, Preferably those carrying amino protecting groups instead of H atoms bonded to N atoms, in particular those containing R'-N groups in which R 'is an amino protecting group instead of HN groups, and / or H atoms of hydroxyl groups Those containing hydroxyl protecting groups, such as those corresponding to formula I, but with -COOR '' in which R '' is a hydroxyl protecting group instead of the -COOH group.
    Preferred starting materials also include oxadiazole derivatives which can be converted to the corresponding amidino compounds.
    Introduction of the oxadiazole group is carried out, for example, by reacting a cyano compound with hydroxylamine and reacting with phosgene, dialkyl carbonate, chloroformic ester, N, N'-carbonyldiimidazole or acetic anhydride do.
    It is also possible for several identical or different, protected amino and / or hydroxyl groups to be present in the molecule of the starting material. If the protecting groups present are different from one another, in many cases they may be selectively cleaved off.
    The term "amino protecting group" is generally known and refers to a group which is suitable for protecting (blocking) amino groups from chemical reactions but which can be easily removed at other positions of the molecule after the desired chemical reaction has been carried out. Typical such groups are, in particular, unsubstituted or substituted acyl, aryl, aralkyloxy or aralkyl groups. Since amino protecting groups are removed after the desired reaction (or reaction sequence), their nature and size are usually not critical, but those having 1 to 20 carbon atoms, especially 1 to 8 carbon atoms, are preferred. The term "acyl group" is to be interpreted in a broad sense with respect to the method. This includes acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids, in particular alkoxycarbonyl, aryloxycarbonyl and above all aralkyloxycarbonyl groups. Examples of such acyl groups include alkanoyl such as acetyl, propionyl or butynyl; Arkanoyl such as phenylacetyl; Aroyl such as benzoyl or toluyl; Aryloxyalkanoyl such as POA; Alkoxycarbonyls such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC (tert-butyloxycarbonyl), 2-iodoethoxycarbonyl; Aralkyloxycarbonyls such as CBZ (“carbenzoxy”), 4-methoxybenzyloxycarbonyl, FMOC; Arylsulfonyl such as Mtr. Preferred amino protecting groups are BOC and Mtr and CBZ, Fmoc, benzyl and acetyl.
    The term "hydroxyl protecting group" is also generally known and refers to a group suitable for protecting hydroxyl groups from chemical reactions but which can be easily removed at other positions of the molecule after the desired chemical reaction has been carried out. Typical such groups are the aforementioned unsubstituted or substituted aryl, aralkyl or acyl groups, and alkyl groups. Since hydroxyl protecting groups are removed after the desired chemical reaction or reaction sequence, their nature and size are not critical and groups having 1 to 20 carbon atoms, especially 1 to 10 carbon atoms, are preferred. Examples of hydroxyl protecting groups are in particular benzyl, p-nitrobenzoyl, p-toluenesulfonyl, tert-butyl and acetyl, with benzyl and tert-butyl being particularly preferred.
    The liberalization of the compounds of formula (I) from their functional derivatives depends, for example, on the protecting groups used, for example strong acids, advantageously TFA or perchloric acid, and other strong inorganic acids such as hydrochloric acid or sulfuric acid, strong organic carboxylic acids such as Trichloroacetic acid, or sulfonic acids such as benzene- or p-toluenesulfonic acid. Additional inert solvents may be present but are not always necessary. Suitable inert solvents are preferably organic solvents, for example carboxylic acids such as acetic acid, ethers such as tetrahydrofuran or dioxane, amides such as DMF, halogenated hydrocarbons such as dichloromethane, or alcohols such as methanol, ethanol Or isopropanol, and water. Mixtures of the foregoing solvents are also possible. TFA can preferably be used in excess without additional solvent addition, and perchloric acid is used in the form of a 9: 1 ratio mixture of acetic acid and 70% perchloric acid. The reaction temperature for cleavage is advantageously from about 0 to about 50 ° and the reaction is preferably carried out at 15 to 30 ° (room temperature).
    The BOC, OBut and Mtr groups can preferably be cleaved off with about 3 to 5 N HCl in TFA or dioxane in dichloromethane at 15 to 30 °, for example, and the FMOC group is dimethylamine in DMF at 15 to 30 °. , Diethylamine or piperidine with about 5-50% solution.
    Protecting groups that can be removed by hydrogenolysis (eg free radicals of amidino groups from CBZ, benzyl, or oxadiazole derivatives thereof) are for example catalysts (eg noble metal catalysts such as palladium, glass Preferably in the presence of a support such as carbon). Suitable solvents for this reaction are those described above, in particular for example alcohols such as methanol or ethanol, or amides such as DMF. Hydrolysis is generally carried out at a temperature of about 0 to 100 ° and at about 1 to 200 bar, preferably at 20 to 30 ° and 1 to 10 bar. Hydrolysis of the CBZ groups is effected immediately with ammonium formate (instead of oxygen), for example on Pd / C of 5 to 10% in methanol at 20-30 ° or on Pd / C in methanol / DMF.
    R 1 is And wherein X is -CO- or -C (R 6 ) 2 -CO-, and R 2 , R 3 and Y are the same as in claim 1, the compounds of formula (I) are preferably compounds of formula (II) Obtained by reaction with a compound.
    In the compounds of formula III, L is preferably Cl, Br, I or a reactively modified OH group such as an activated ester, imidazolide or alkylsulfonyloxy having 1 to 6 carbon atoms (preferably methylsul Phonyloxy) or arylsulfonyloxy (preferably phenyl- or p-tolylsulfonyloxy) having 6 to 10 carbon atoms.
    The reaction is generally an acid binder, preferably an alkali metal hydroxide, carbonate or bicarbonate or alkaline earth metal hydroxide, carbonate or bicarbonate, or other salt of a weak acid of alkali or alkaline earth metal, preferably Is carried out in an inert solvent in the presence of salts of potassium, sodium, calcium or cerium. Organic bases such as triethylamine, dimethylaniline, pyridine or quinoline; Or excess amine component of formula II; Or addition of alkylated derivatives of formula III may also be preferred. Depending on the conditions used, the reaction time is from several minutes to 14 days, the reaction temperature is from about 0 ° to 150 °, and typically from 20 ° to 130 °.
    Suitable inert solvents are, for example, hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; Chlorinated hydrocarbons such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; Alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; Glycol ethers such as ethylene glycol monomethyl or monoethyl ether (methylglycol or ethylglycol) or ethylene glycol dimethyl ether (diglyme); Ketones such as acetone or butanone; Amides such as acetamide, dimethylacetamide, N-methylpyrrolidone (NMP) or dimethylformamide (DMF); Nitriles such as acetonitrile; Sulfoxides such as dimethyl sulfoxide (DMSO); Carbon disulfide; Carboxylic acids such as formic acid or acetic acid; Nitro compounds such as nitromethane or nitrobenzene; Ethers such as ethyl acetate, or mixtures of the above solvents.
    Starting materials of the formulas (II) and (III) are generally known. They are novel but can be prepared by methods known per se.
    R 1 is And wherein Y is -SO 2- , -CO- or -COO-, and R 2 and X are the same as in claim 1, the compounds of formula I are preferably obtained by reacting a compound of formula IV with a compound of formula V can do.
    In the compound of formula IV, L is preferably Cl, Br, I or a reactively modified OH group, for example an activated ester, imidazolide or alkylsulfonyloxy having 1 to 6 carbon atoms (preferably methylsul Phonyloxy) or arylsulfonyloxy (preferably phenyl- or p-tolylsulfonyloxy) having 6 to 10 carbon atoms.
    The reaction of the compound of formula IV with the compound of formula V is preferably carried out by addition of a base in an inert solvent at the aforementioned temperatures.
    Starting materials of the formulas (IV) and (V) are generally known. They are novel but can be prepared by methods known per se.
    R 1 is And compounds of formula (I) wherein Y is -CONH and R 2 and X are as in claim 1 are preferably obtained by reacting a compound of formula (VI) with a compound of formula (V).
    The reaction of the compound of formula VI with the compound of formula V is preferably carried out in an inert solvent at the aforementioned temperatures.
    Starting materials of the formula (VI) are generally known. They are novel but can be prepared by methods known per se.
    Compounds of formula I wherein R 1 is -C (= NH) -NH 2 can also be obtained from the corresponding cyano compounds.
    The conversion of the cyano group to an amidino group is carried out by reacting with hydroxylamine, for example, followed by reacting N-hydroxysamidine with hydrogen, for example in the presence of a catalyst such as Pd / C.
    To prepare amidine of formula I (R 1 = -C (= NH) -NH 2 ), ammonia can also be added to the nitrile of formula (R 1 = CN). The addition is preferably carried out in a manner known per se: a) nitrile with H 2 S to thioamide, which is converted with the alkylating agent, for example CH 3 I, to the corresponding S-alkyl-imidothioester Then react with NH 3 to produce amidine, b) converting the nitrile to the corresponding imidoester with alcohol, for example ethanol, in the presence of HCl and treating it with ammonia or c) nitrile to lithium bis (trimethyl The reaction is carried out with silyl) amide, followed by several steps by the procedure of hydrolysis of the product.
    In addition, for example, by reducing the nitro group (eg hydrogenating on Pd / carbon or Raney nickel in an inert solvent such as methanol or ethanol) to an amino group, one or more radicals R 1 , R 2 , R 3 , R 4 and / or R 5 can be converted to one or more radicals R 1 , R 2 , R 3 , R 4 and / or R 5 to convert the compound of formula I to another compound of formula I.
    The ester can be hydrolyzed at a temperature of 0 to 100 °, for example with acetic acid or NaOH or KOH in water, water-THF or water-dioxane.
    Advantageously free amino groups in conventional manner acyl chloride or acid anhydride, in an inert solvent such as dichloromethane or THF and / or at a temperature of -60 to + 30 ° in the presence of a base such as triethylamine or pyridine It is also possible to acylate or alkylate together with unsubstituted or substituted alkyl halides.
    The base of the formula (I) can be converted into an acid addition salt, which is associated with an acid, for example by reaction of an equivalent base and acid in an inert solvent such as ethanol and subsequent evaporation. Acids which produce physiologically acceptable salts are particularly suitable for the present reaction. Inorganic acids such as sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric or hydrobromic acid, phosphoric acid such as orthophosphoric acid, sulfamic acid, or organic acids, in particular aliphatic, cycloaliphatic, araliphatic, aromatic or heterocyclic monovalent Or polybasic carboxylic acids, sulfonic acids or sulfuric acids, for example formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, glutamic acid Cholic acid, ascorbic acid, nicotinic acid, isnicotinic acid, methane- or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene-mono- or -disulfonic acid and lauryl sulfate have. Salts with physiologically acceptable acids, such as picrates, can be used for the isolation and / or purification of the compounds of formula (I).
    On the other hand, the compounds of formula (I) can be converted into the corresponding metals, in particular alkali metal or alkaline earth metal salts, or the corresponding ammonium salts together with bases (eg sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate).
    Due to their molecular structure, the compounds of formula (I) according to the invention can be chiral and therefore can exist in various enantiomeric forms. Therefore they may exist in racemic or optically active forms.
    Since the pharmaceutical activity of the racemates and / or stereoisomers of the compounds according to the invention may be different, it would be preferable to use enantiomers. In this case, the final product or even intermediates may be separated into enantiomers using chemical or physical means known to those skilled in the art, or they may even be used for synthesis as such.
    In the case of racemic amines, diastereomers are formed from the mixture by reaction with an optically active separating agent. Suitable separating agents are, for example, optically active acids such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (eg N-benzoylproline or N-benzenesulfonyl Proline) or R- and S-forms of various optically active camphorsulfonic acids. Chromatographic separation of enantiomers also aids with optically active isolators (e.g., dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chiral derived methacrylate polymers immobilized on silica gel). Can be advantageously performed. Suitable solvents for this purpose are, for example, aqueous or alcoholic solvent mixtures such as hexane / isopropanol / acetonitrile in a ratio of 82: 15: 3.
    The present invention provides the use of compounds of formula (I) and / or physiologically acceptable salts thereof, in particular for the preparation of pharmaceutical formulations by non-chemical routes. For this purpose, they may be formulated in a suitable formulation together with one or more solid, liquid and / or semi-liquid carriers or auxiliaries, if appropriate in combination with one or more further active compounds.
    The invention also provides pharmaceutical formulations containing one or more compounds of formula (I) and / or physiologically acceptable salts thereof.
    Such formulations may be used as medicaments in human medicine or veterinary medicine. Possible carriers are organic or inorganic substances suitable for intra-intestinal (eg oral), transdermal or topical administration and which do not react with the new compounds, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols , Glycerol triacetate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc and petroleum jelly. Tablets, pills, coated tablets, capsules, powders, granules, syrups, juices and drops are especially used for oral administration, suppositories are used for rectal administration, solutions, preferably oily or aqueous solutions, and suspensions, emulsions or Inserts are used for transdermal administration and ointments, creams or powders are used for topical administration. The novel compounds can also be lyophilized and the resulting lyophilisate can be used, for example, in the preparation of injectable formulations. The formulations may be sterilized and / or auxiliary agents such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for affecting osmotic pressure, buffers, pigments, perfumes and / or some additional active compounds, eg For example, it may contain one or more vitamins.
    The compounds of formula (I) and their physiologically acceptable salts can be used to treat and prevent thromboembolic diseases such as thrombosis, myocardial infarction, atherosclerosis, inflammation, stroke, angina, recurrent stenosis after angioplasty and intermittent claudication. .
    To this end, the substances according to the invention are usually administered at a dosage of about 1 to 500 mg, in particular 5 to 100 mg, per dosage unit. The daily dosage is preferably about 0.02 to 10 mg / kg body weight. However, a particular batch for each patient may be affected by the most diverse factors, such as activity, age, weight, general health, sex, food, time and route of administration, and rate of excretion, drug combination and treatment of the specific compound used. It depends on the extent of the particular disease being applied. Oral administration is preferred.
    All temperatures before and after are given in ° C. In the following examples, "normal workup" means: water is added if necessary, the pH is adjusted to a value from 2 to 10 if necessary depending on the structure of the final product, and the mixture is ethyl acetate or di Extract with chloromethane, separate organic phase, dry over sodium sulfate, evaporate and residue is purified by chromatography on silica gel and / or recrystallization.
    Rf value is for silica gel; Mobile phase: ethyl acetate / methanol is 9: 1.
    Mass spectrometer (MS):
    EI (electron impact ionization) M +
    FAB (Fast Atomic Collision) (M + H) +
    Example 1
    46 ml of thionyl chloride and 1 ml of DMF are added to a solution of 10.0 g of 4- (5-methyl-1,2,4-oxadiazol-3-yl) benzoic acid in 150 ml toluene. The solution is heated at reflux for 5 hours. Removal of the solvent gives 4- (5-methyl-1,2,4-oxadiazol-3-yl) benzoyl chloride, EI 222. It is then reacted with 9.3 g of 1-tert-butoxycarbonylpiperazine in 48 ml of triethyleneamine and 150 ml of dichloromethane, followed by tert-butyl 4- [4- (5-methyl [1 , 2,4] oxadiazol-3-yl) benzoyl] piperazine-1-carboxylate, FAB 373.
    The BOC group is cleaved off using 4N HCl in dioxane.
    In 100 mg of the resulting [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl] piperazin-1-ylmethanone ("A '), and 5 ml of dichloromethane 120 mg of 6-chloronaphthalene-2-sulfonyl chloride solution is mixed with 400 mg of 4-dimethylaminopyridine on polystyrene and the mixture is stirred at room temperature for 18 hours, filtered and the solvent is removed, [4- ( 6-chloronaphthalene-2-sulfonyl) piperazin-1-yl] [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl] methanone, FAB 497 is obtained.
    Similarly, with "A"
    4-biphenylyl-2-sulfonyl chloride is reacted to [4- (4-biphenylylsulfonyl) piperazin-1-yl] [4- (5-methyl [1,2,4] oxadiazole- 3-yl) phenyl] methanone;
    2-naphthylsulfonyl chloride was reacted to [4- (2-naphthylsulfonyl) piperazin-1-yl] [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl] Obtaining methanone;
    4-propylphenylsulfonyl chloride is reacted to [4- (4-propylphenylsulfonyl) piperazin-1-yl] [4- (5-methyl [1,2,4] oxadiazol-3-yl) Phenyl] methanone is obtained;
    2-phenylvinylsulfonyl chloride was reacted to [4- (2-phenylvinylsulfonyl) piperazin-1-yl] [4- (5-methyl [1,2,4] oxadiazol-3-yl) Phenyl] methanone is obtained;
    3-nitro-4-chlorophenylsulfonyl chloride was reacted to [4- (3-nitro-4-chlorophenylsulfonyl) piperazin-1-yl] [4- (5-methyl [1,2,4] Oxadiazol-3-yl) phenyl] methanone is obtained;
    2-nitro-4-methoxyphenylsulfonyl chloride was reacted to [4- (2-nitro-4-methoxyphenylsulfonyl) piperazin-1-yl] [4- (5-methyl [1,2, 4] oxadiazol-3-yl) phenyl] methanone;
    p-tolylsulfonyl chloride was reacted to [4- (4-tolylsulfonyl) piperazin-1-yl] [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl] Obtaining methanone;
    Decylsulfonyl chloride is reacted to give [4- (decylsulfonyl) piperazin-1-yl] [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl] methanone and;
    Benzylsulfonyl chloride is reacted to give [4- (benzylsulfonyl) piperazin-1-yl] [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl] methanone and;
    3-nitro-6-methylbenzylsulfonyl chloride was reacted to [4- (3-nitro-6-methylbenzylsulfonyl) piperazin-1-yl] [4- (5-methyl [1,2,4] Oxadiazol-3-yl) phenyl] methanone is obtained;
    2,3-dichlorophenylsulfonyl chloride was reacted to [4- (2,3-dichlorophenylsulfonyl) piperazin-1-yl] [4- (5-methyl [1,2,4] oxadiazole- 3-yl) phenyl] methanone;
    3,4-dichlorophenylsulfonyl chloride is reacted to [4- (3,4-dichlorophenylsulfonyl) piperazin-1-yl] [4- (5-methyl [1,2,4] oxadiazole- 3-yl) phenyl] methanone;
    Phenylsulfonyl chloride is reacted to give [4- (phenylsulfonyl) piperazin-1-yl] [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl] methanone and;
    3-bromophenylsulfonyl chloride was reacted to [4- (3-bromophenylsulfonyl) piperazin-1-yl] [4- (5-methyl [1,2,4] oxadiazole-3- To obtain phenyl] methanone;
    3,4-dimethoxyphenylsulfonyl chloride was reacted to [4- (3,4-dimethoxyphenylsulfonyl) piperazin-1-yl] [4- (5-methyl [1,2,4] oxadia Zol-3-yl) phenyl] methanone;
    4-acetamido-3-chlorophenylsulfonyl chloride was reacted to [4- (4-acetamido-3-chlorophenylsulfonyl) piperazin-1-yl] [4- (5-methyl [1, 2,4] oxadiazol-3-yl) phenyl] methanone;
    4-chloro-2,5-dimethylphenylsulfonyl chloride was reacted to [4- (4-chloro-2,5-dimethylphenylsulfonyl) piperazin-1-yl] [4- (5-methyl [1, 2,4] oxadiazol-3-yl) phenyl] methanone;
    m-tolylsulfonyl chloride was reacted to [4- (3-tolylsulfonyl) piperazin-1-yl] [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl] Obtaining methanone;
    2-methoxy-5-methylphenylsulfonyl chloride was reacted to [4- (2-methoxy-5-methylphenylsulfonyl) piperazin-1-yl] [4- (5-methyl [1,2,4] Oxadiazol-3-yl) phenyl] methanone is obtained;
    3-chlorophenylsulfonyl chloride was reacted to [4- (3-chlorophenylsulfonyl) piperazin-1-yl] [4- (5-methyl [1,2,4] oxadiazol-3-yl) Phenyl] methanone is obtained;
    4-methoxyphenylsulfonyl chloride is reacted to [4- (4-methoxyphenylsulfonyl) piperazin-1-yl] [4- (5-methyl [1,2,4] oxadiazole-3- To obtain phenyl] methanone;
    2-thienylsulfonyl chloride was reacted to [4- (2-thienylsulfonyl) piperazin-1-yl] [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl] Obtaining methanone;
    4-chlorophenylsulfonyl chloride is reacted to [4- (4-chlorophenylsulfonyl) piperazin-1-yl] [4- (5-methyl [1,2,4] oxadiazol-3-yl) Phenyl] methanone is obtained;
    Isopropylsulfonyl chloride was reacted to [4- (isopropylsulfonyl) piperazin-1-yl] [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl] methanone To obtain;
    8-quinolylsulfonyl chloride is reacted to [4- (8-quinolylsulfonyl) piperazin-1-yl] [4- (5-methyl [1,2,4] oxadiazol-3-yl) Phenyl] methanone is obtained;
    4-nitrophenylsulfonyl chloride was reacted to [4- (4-nitrophenylsulfonyl) piperazin-1-yl] [4- (5-methyl [1,2,4] oxadiazol-3-yl) Phenyl] methanone is obtained;
    3-chloro-6-methoxyphenylsulfonyl chloride was reacted to [4- (3-chloro-6-methoxyphenylsulfonyl) piperazin-1-yl] [4- (5-methyl [1,2, 4] oxadiazol-3-yl) phenyl] methanone;
    4-acetamidophenylsulfonyl chloride is reacted to [4- (4-acetamidophenylsulfonyl) piperazin-1-yl] [4- (5-methyl [1,2,4] oxadiazole- 3-yl) phenyl] methanone;
    2,2,5,7,8-pentamethylchroman-6-ylsulfonyl chloride was reacted to [4- (2,2,5,7,8-pentamethylchroman-6-ylsulfonyl) piperazine- 1-yl] [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl] methanone;
    Camphor-10-ylsulfonyl chloride was reacted to [4- (camphor-10-ylsulfonyl) piperazin-1-yl] [4- (5-methyl [1,2,4] oxadiazole-3- To obtain phenyl] methanone;
    5- (1-methyl-5-trifluoromethyl-3-pyrazolyl) -2-thienylsulfonyl chloride was reacted to give {4- [5- (1-methyl-5-trifluoromethyl-3-pyra Zolyl) -2-thienylsulfonyl) piperazin-1-yl} [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl] methanone;
    2,5-dichlorophenylsulfonyl chloride was reacted to [4- (2,5-dichlorophenylsulfonyl) piperazin-1-yl] [4- (5-methyl [1,2,4] oxadiazole- 3-yl) phenyl] methanone;
    2,4,6-trimethylphenylsulfonyl chloride was reacted to [4- (2,4,6-trimethylphenylsulfonyl) piperazin-1-yl] [4- (5-methyl [1,2,4] Oxadiazol-3-yl) phenyl] methanone is obtained;
    2-methylsulfonylphenylsulfonyl chloride is reacted to [4- (2-methylsulfonylphenylsulfonyl) piperazin-1-yl] [4- (5-methyl [1,2,4] oxadiazole- 3-yl) phenyl] methanone;
    5-benzamidomethyl-2-thienylsulfonyl chloride was reacted to [4- (5-benzamidomethyl-2-thienylsulfonyl) piperazin-1-yl] [4- (5-methyl [1, 2,4] oxadiazol-3-yl) phenyl] methanone;
    Reaction of methylsulfonyl chloride yields [4- (methylsulfonyl) piperazin-1-yl] [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl] methanone and;
    1,3-dimethyl-5-chloro-4-pyrazolylsulfonyl chloride was reacted to [4- (1,3-dimethyl-5-chloro-4-pyrazolylsulfonyl) piperazin-1-yl] [4 To obtain-(5-methyl [1,2,4] oxadiazol-3-yl) phenyl] methanone;
    3,5-dimethyl-4-isoxazolylsulfonyl chloride was reacted to [4- (3,5-dimethyl-4-isoxazolylsulfonyl) piperazin-1-yl] [4- (5-methyl [ 1,2,4] oxadiazol-3-yl) phenyl] methanone;
    4-bromo-2-ethylphenylsulfonyl chloride was reacted to [4- (4-bromo-2-ethylphenylsulfonyl) piperazin-1-yl] [4- (5-methyl [1,2, 4] oxadiazol-3-yl) phenyl] methanone;
    1-naphthylsulfonyl chloride was reacted to [4- (1-naphthylsulfonyl) piperazin-1-yl] [4- (5-methyl [1,2,4] oxadiazol-3-yl) phenyl] Obtaining methanone;
    5-dimethylamino-1-naphthylsulfonyl chloride was reacted to [4- (5-dimethylamino-1-naphthylsulfonyl) piperazin-1-yl] (4- (5-methyl [1,2,4] Oxadiazol-3-yl) phenyl] methanone is obtained;
    3,4-difluorophenylsulfonyl chloride was reacted to [4- (3,4-difluorophenylsulfonyl) piperazin-1-yl] [4- (5-methyl [1,2,4] Oxadiazol-3-yl) phenyl] methanone is obtained;
    4-tert-butylphenylsulfonyl chloride is reacted to [4- (4-tert-butylphenylsulfonyl) piperazin-1-yl] [4- (5-methyl [1,2,4] oxadiazole- 3-yl) phenyl] methanone;
    4-ethylphenylsulfonyl chloride was reacted to [4- (4-ethylphenylsulfonyl) piperazin-1-yl] [4- (5-methyl [1,2,4] oxadiazol-3-yl) Phenyl] methanone is obtained;
    4- (1,1-dimethylpropyl) phenylsulfonyl chloride was reacted to [4- (4- (1,1-dimethylpropyl) phenylsulfonyl) piperazin-1-yl] [4- (5-methyl [ 1,2,4] oxadiazol-3-yl) phenyl] methanone;
    4-isopropylphenylsulfonyl chloride was reacted to [4- (4-isopropylphenylsulfonyl) piperazin-1-yl] [4- (5-methyl [1,2,4] oxadiazole-3- To obtain phenyl] methanone;
    4-trifluoromethylphenylsulfonyl chloride is reacted to [4- (4-trifluoromethylphenylsulfonyl) piperazin-1-yl] [4- (5-methyl [1,2,4] oxadiazole- 3-yl) phenyl] methanone;
    3-nitro-4-methylphenylsulfonyl chloride was reacted to [4- (3-nitro-4-methylphenylsulfonyl) piperazin-1-yl] [4- (5-methyl [1,2,4] oxadia Zol-3-yl) phenyl] methanone;
    4-pentylphenylsulfonyl chloride was reacted to [4- (4-pentylphenylsulfonyl) piperazin-1-yl] [4- (5-methyl [1,2,4] oxadiazol-3-yl) Phenyl] methanone is obtained;
    4-butylphenylsulfonyl chloride is reacted to [4- (4-butylphenylsulfonyl) piperazin-1-yl] [4- (5-methyl [1,2,4] oxadiazol-3-yl) Phenyl] methanone is obtained;
    3-chloro-4-methylphenylsulfonyl chloride was reacted to [4- (3-chloro-4-methylphenylsulfonyl) piperazin-1-yl] [4- (5-methyl [1,2,4] oxadia Zol-3-yl) phenyl] methanone is obtained.
    Example 2
    100 mg of [4- (6-chloronaphthalene-2-sulfonyl) piperazin-1-yl] [4- (5-methyl [1,2,4] oxadiazol-3-yl in 5 ml of methanol ) Phenyl] methanone solution is mixed with 100 mg Raney nickel and one drop of acetic acid and hydrogenated to complete the reaction at room temperature and atmospheric pressure. The catalyst and solvent are removed to afford 4- [4- (6-chloronaphthalene-2-sulfonyl) piperazine-1-carbonyl] benzamidine, acetate, FAB 457.
    Similarly, the following compounds are obtained from the metanon derivatives listed in Example 1:
    4- [4- (4-biphenylylsulfonyl) piperazin-1-carbonyl] benzamidine, acetate, FAB 449;
    4- [4- (2-naphthylsulfonyl) piperazin-1-carbonyl] benzamidine, acetate, EI 405 (M + -NH 2 );
    4- [4- (4-propylphenylsulfonyl) piperazine-1-carbonyl] benzamidine, acetate, FAB 415;
    4- [4- (2-phenylvinylsulfonyl) piperazine-1-carbonyl] benzamidine, acetate, FAB 399;
    4- [4- (3-amino-4-chlorophenylsulfonyl) piperazin-1-carbonyl] benzamidine, acetate, FAB 422;
    4- [4- (2-amino-4-methoxyphenylsulfonyl) piperazin-1-carbonyl] benzamidine, acetate, FAB 418;
    4- [4- (4-tolylsulfonyl) piperazine-1-carbonyl] benzamidine, acetate, FAB 387;
    4- [4- (decylsulfonyl) piperazine-1-carbonyl] benzamidine, acetate, FAB 437;
    4- [4- (benzylsulfonyl) piperazine-1-carbonyl] benzamidine, acetate, FAB 387;
    4- [4- (3-amino-6-methylbenzylsulfonyl) piperazin-1-carbonyl] benzamidine, acetate, FAB 402; ,
    4- [4- (2,3-dichlorophenylsulfonyl) piperazin-1-carbonyl] benzamidine, acetate, FAB 441;
    4- [4- (3,4-dichlorophenylsulfonyl) piperazin-1-carbonyl] benzamidine, acetate, FAB 441;
    4- [4- (phenylsulfonyl) piperazine-1-carbonyl] benzamidine, acetate, FAB 373;
    4- [4- (3-bromophenylsulfonyl) piperazine-1-carbonyl] benzamidine, acetate, FAB 451, 453;
    4- [4- (3,4-dimethoxyphenylsulfonyl) piperazin-1-carbonyl] benzamidine, acetate, FAB 433;
    4- [4- (4-acetamido-3-chlorophenylsulfonyl) piperazine-1-carbonyl] benzamidine, acetate, FAB 464;
    4- [4- (4-chloro-2,5-dimethylphenylsulfonyl) piperazine-1-carbonyl] benzamidine, acetate, FAB 435;
    4- [4- (3-tolylsulfonyl) piperazine-1-carbonyl] benzamidine, acetate, FAB 387;
    4- [4- (2-methoxy-5-methylphenylsulfonyl) piperazin-1-carbonyl] benzamidine, acetate, FAB 417;
    4- [4- (3-chlorophenylsulfonyl) piperazine-1-carbonyl] benzamidine, acetate, FAB 407;
    4- [4- (4-methoxyphenylsulfonyl) piperazine-1-carbonyl] benzamidine, acetate, FAB 402;
    4- [4- (2-thienylsulfonyl) piperazine-1-carbonyl] benzamidine, acetate, FAB 379;
    4- [4- (4-chlorophenylsulfonyl) piperazine-1-carbonyl] benzamidine, acetate, FAB 407;
    4- [4- (isopropylsulfonyl) piperazine-1-carbonyl] benzamidine, acetate, FAB 339;
    4- [4- (1,2,3,4-tetrahydroquinoline-8-ylsulfonyl) piperazin-1-carbonyl] benzamidine, acetate, FAB 428;
    4- [4- (4-aminophenylsulfonyl) piperazine-1-carbonyl] benzamidine, acetate, FAB 388;
    4- [4- (3-chloro-6-methoxyphenylsulfonyl) piperazin-1-carbonyl] benzamidine, acetate, FAB 437;
    4- [4- (4-acetamidophenylsulfonyl) piperazin-1-carbonyl] benzamidine, acetate, FAB 437;
    4- [4- (2,2,5,7,8-pentamethylchroman-6-ylsulfonyl) piperazin-1-carbonyl] benzamidine, acetate, FAB 499;
    4- [4- (camphor-10-ylsulfonyl) piperazine-1-carbonyl] benzamidine, acetate, FAB 447;
    4- {4- [5- (1-methyl-5-trifluoromethyl-3-pyrazolyl) -2-thienylsulfonyl] piperazin-1-carbonyl} benzamidine, acetate, FAB 527;
    4- [4- (2,5-dichlorophenylsulfonyl) piperazine-1-carbonyl] benzamidine, acetate, FAB 441;
    4- [4- (2,4,6-trimethylphenylsulfonyl) piperazin-1-carbonyl] benzamidine, acetate, FAB 415;
    4- [4- (2-methylsulfonylphenylsulfonyl) piperazine-1-carbonyl] benzamidine, acetate, FAB 451;
    4- [4- (5-benzamidomethyl-2-thienylsulfonyl) piperazine-1-carbonyl] benzamidine, acetate, FAB 512;
    4- [4- (methylsulfonyl) piperazin-1-carbonyl] benzamidine, acetate, EI 292 (M + -NH 2 );
    4- [4- (1,3-dimethyl-5-chloro-4-pyrazolylsulfonyl) piperazine-1-carbonyl] benzamidine, acetate;
    4- [4- (3,5-dimethyl-4-isoxazolylsulfonyl) piperazine-1-carbonyl] benzamidine, acetate;
    4- [4- (4-bromo-2-ethylphenylsulfonyl) piperazin-1-carbonyl] benzamidine, acetate, EI 461, 463 (M + -NH 2 );
    4- [4- (1-naphthylsulfonyl) piperazin-1-carbonyl] benzamidine, acetate, EI 405 (M + -NH 2 );
    4- [4- (5-dimethylamino-1-naphthylsulfonyl) piperazin-1-carbonyl] benzamidine, acetate, EI 448 (M + -NH 2 );
    4- [4- (3,4-difluorophenylsulfonyl) piperazine-1-carbonyl] benzamidine, acetate;
    4- [4- (4-tert-butylphenylsulfonyl) piperazine-1-carbonyl] benzamidine, acetate, FAB 429;
    4- [4- (4-ethylphenylsulfonyl) piperazine-1-carbonyl] benzamidine, acetate, FAB 401;
    4- [4- (4- (1,1-dimethylpropyl) phenylsulfonyl) piperazine-1-carbonyl] benzamidine, acetate, FAB 442;
    4- [4- (4-isopropylphenylsulfonyl) piperazin-1-carbonyl] benzamidine, acetate, FAB 415;
    4- [4- (4-trifluoromethylphenylsulfonyl) piperazin-1-carbonyl] benzamidine, acetate, FAB 441;
    4- [4- (3-amino-4-methylphenylsulfonyl) piperazine-1-carbonyl] benzamidine, acetate, FAB 402;
    4- [4- (4-pentylphenylsulfonyl) piperazine-1-carbonyl] benzamidine, acetate, FAB 443;
    4- [4- (4-butylphenylsulfonyl) piperazine-1-carbonyl] benzamidine, acetate, FAB 429;
    4- [4- (3-chloro-4-methylphenylsulfonyl) piperazine-1-carbonyl] benzamidine, acetate, FAB 421.
    Example 3
    4- [4- (6-chloronaphthalene-2-sulfonyl) piperazin-1-carbonyl] benzamidine is reacted with an equal molar amount of methyl chloroformate in pyridine and a catalytic amount of dimethylaminopyridine to After work up, the compound methyl {imino- [4- (4- (6-chloronaphthalene-2-sulfonyl) piperazin-1-carbonyl) phenyl] methyl} carbamate is obtained.
    Example 4
    Similar to Example 1, 3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -1-piperazin-1-ylpropan-1-one [3 -[4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -1- (4-tert-butyloxycarbonyl) piperazin-1-ylpropan-1-one Can be obtained by treatment with TFA / CH 2 Cl 2 ] and 6-chloronaphthalene-2-sulfonyl chloride to give compound 1- [4- (6-chloronaphthalene-2-sulfonyl) piperazine-1- Yl] -3- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] propan-1-one and 4- {3-oxo-3- after hydrogenation Obtain [4- (6-chloronaphthalene-2-sulfonyl) piperazin-1-yl] propyl} benzamidine.
    Example 5
    Similar to Examples 1 and 2, [3- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] piperazin-1-ylmethanone and 5-chloronaphthalene-2-sul Phonyyl chloride is reacted and then hydrogenated to give compound 3- [4- (6-chloronaphthalene-2-sulfonyl) piperazine-1-carbonyl] benzamidine, acetate, FAB 457.
    Similarly, [3- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] piperazin-1-ylmethanone is reacted with 4-propylphenylsulfonyl chloride followed by hydrogenation, Compound 3- [4- (4-propylphenylsulfonyl) piperazin-1-carbonyl] benzamidine, acetate, FAB 415 is obtained.
    Example 6
    Similar to Example 1, 2- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -1-piperazin-1-ylethan-1-one (" B ") and 4-propylphenylsulfonyl chloride to react with compound 1- [4- (4-propylphenylsulfonyl) piperazin-1-yl] -2- [4- (5-methyl- [1, 2,4] oxadiazol-3-yl) phenyl] ethan-1-one and 4- {2-oxo-2- [4- (4-propylphenylsulfonyl) piperazin-1- after hydrogenation Il] ethyl} benzamidine, FAB 429 is obtained.
    Similarly, with "B"
    1- [4- (decylsulfonyl) piperazin-1-yl] -2- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) by reacting decylsulfonyl chloride Phenyl] ethan-1-one;
    Phenylsulfonyl chloride is reacted to give 1- [4- (phenylsulfonyl) piperazin-1-yl] -2- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) Phenyl] ethan-1-one;
    3,4-dichlorophenylsulfonyl chloride was reacted to give 1- [4- (3,4-dichlorophenylsulfonyl) piperazin-1-yl] -2- [4- (5-methyl- [1,2, 4] oxadiazol-3-yl) phenyl] ethan-1-one;
    Benzylsulfonyl chloride to react 1- [4- (benzylsulfonyl) piperazin-1-yl] -2- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) Phenyl] ethan-1-one;
    3,4-dimethoxyphenylsulfonyl chloride was reacted to give 1- [4- (3,4-dimethoxyphenylsulfonyl) piperazin-1-yl] -2- [4- (5-methyl- [1, 2,4] oxadiazol-3-yl) phenyl] ethan-1-one;
    1- [4- (isopropylsulfonyl) piperazin-1-yl] -2- [4- (5-methyl- [1,2,4] oxadiazole-3- by reacting isopropylsulfonyl chloride Yl) phenyl] ethan-1-one;
    Camphor-10-ylsulfonyl chloride was reacted to give 1- [4- (camphor-10-ylsulfonyl) piperazin-1-yl] -2- [4- (5-methyl- [1,2,4] Oxadiazol-3-yl) phenyl] ethan-1-one;
    3-methoxy-4-methoxycarbonyl-2-thienylsulfonyl chloride was reacted to give 1- [4- (3-methoxy-4-methoxycarbonyl-2-thienylsulfonyl) piperazine-1- Yl] -2- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] ethan-1-one;
    2,4,6-trimethylphenylsulfonyl chloride was reacted to give 1- [4- (2,4,6-trimethylphenylsulfonyl) piperazin-1-yl] -2- [4- (5-methyl- [ 1,2,4] oxadiazol-3-yl) phenyl] ethan-1-one;
    2-phenylvinylsulfonyl chloride was reacted to give 1- [4- (2-phenylvinylsulfonyl) piperazin-1-yl] -2- [4- (5-methyl- [1,2,4] oxadia Zol-3-yl) phenyl] ethan-1-one;
    Methylsulfonyl chloride is reacted to give 1- [4- (methylsulfonyl) piperazin-1-yl] -2- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) Phenyl] ethan-1-one;
    [2,1,3] benzothiadiazol-4-ylsulfonyl chloride was reacted to produce 1- [4-([2,1,3] benzothiadiazol-4-ylsulfonyl) piperazin-1-yl] 2--2- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] ethan-1-one;
    2,4-dichlorophenylsulfonyl chloride was reacted to give 1- [4- (2,4-dichlorophenylsulfonyl) piperazin-1-yl] -2- [4- (5-methyl- [1,2, 4] oxadiazol-3-yl) phenyl] ethan-1-one;
    1-naphthylsulfonyl chloride is reacted to give 1- [4- (1-naphthylsulfonyl) piperazin-1-yl] -2- [4- (5-methyl- [1,2,4] oxadiazole- 3-yl) phenyl] ethan-1-one;
    2-naphthylsulfonyl chloride is reacted to give 1- [4- (2-naphthylsulfonyl) piperazin-1-yl] -2- [4- (5-methyl- [1,2,4] oxadiazole- 3-yl) phenyl] ethan-1-one;
    5-dimethylamino-1-naphthylsulfonyl chloride was reacted to give 1- [4- (5-dimethylamino-1-naphthylsulfonyl) piperazin-1-yl] -2- [4- (5-methyl- [ 1,2,4] oxadiazol-3-yl) phenyl] ethan-1-one;
    4-methylsulfonylphenylsulfonyl chloride was reacted to give 1- [4- (4-methylsulfonylphenylsulfonyl) piperazin-1-yl] -2- [4- (5-methyl- [1,2, 4] oxadiazol-3-yl) phenyl] ethan-1-one.
    By hydrogenation, the compounds produce the following amidine derivatives:
    4- {2-oxo-2- [4- (decylsulfonyl) piperazin-1-yl] ethyl} benzamidine, acetate, FAB 450;
    4- {2-oxo-2- [4- (phenylsulfonyl) piperazin-1-yl] ethyl} benzamidine, acetate, FAB 387;
    4- {2-oxo-2- [4- (3,4-dichlorophenylsulfonyl) piperazin-1-yl] ethyl} benzamidine, acetate, FAB 454;
    4- {2-oxo-2- [4- (benzylsulfonyl) piperazin-1-yl] ethyl} benzamidine, acetate, FAB 401;
    4- {2-oxo-2- [4- (3,4-dimethoxyphenylsulfonyl) piperazin-1-yl] ethyl} benzamidine, acetate, FAB 447;
    4- {2-oxo-2- [4- (isopropylsulfonyl) piperazin-1-yl] ethyl} benzamidine, acetate, FAB 353;
    4- {2-oxo-2- [4- (camphor-10-ylsulfonyl) piperazin-1-yl] ethyl} benzamidine, acetate, FAB 353;
    4- {2-oxo-2- [4- (3-methoxy-4-methoxycarbonyl-2-thienylsulfonyl) piperazin-1-yl] ethyl} benzamidine, acetate, FAB 481;
    4- {2-oxo-2- [4- (2,4,6-trimethylphenylsulfonyl) piperazin-1-yl] ethyl} benzamidine, acetate, FAB 429;
    4- {2-oxo-2- [4- (2-phenylvinylsulfonyl) piperazin-1-yl] ethyl} benzamidine, acetate, FAB 413;
    4- {2-oxo-2- [4- (methylsulfonyl) piperazin-1-yl] ethyl} benzamidine, acetate, FAB 325;
    4- {2-oxo-2- [4- (2,3-diaminophenylsulfonyl) piperazin-1-yl] ethyl} benzamidine, acetate, FAB 415;
    4- {2-oxo-2- [4- (2,4-dichlorophenylsulfonyl) piperazin-1-yl] ethyl} benzamidine, acetate, FAB 455;
    4- {2-oxo-2- [4- (1-naphthylsulfonyl) piperazin-1-yl] ethyl} benzamidine, acetate, FAB 437;
    4- {2-oxo-2- [4- (2-naphthylsulfonyl) piperazin-1-yl] ethyl} benzamidine, acetate, FAB 437;
    4- {2-oxo-2- [4- (5-dimethylamino-1-naphthylsulfonyl) piperazin-1-yl] ethyl} benzamidine, acetate, FAB 480;
    4- {2-oxo-2- [4- (4-methylsulfonylphenylsulfonyl) piperazin-1-yl] ethyl} benzamidine, acetate, FAB 465.
    Example 7
    Similar to Example 1, "A" and
    4-biphenylylcarbonyl chloride is reacted to [4- (4-phenylbenzoyl) piperazin-1-yl] [4- (5-methyl- [1,2,4] oxadiazol-3-yl) Phenyl] methanone is obtained;
    By reacting cyclopentylcarbonyl chloride [4- (cyclopentylcarbonyl) piperazin-1-yl] [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] meta To obtain rice fields;
    Phenoxyacetyl chloride was reacted to [4- (phenoxyacetyl) piperazin-1-yl] [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] methanone To obtain;
    [4- (1-naphthylcarbonyl) piperazin-1-yl] [4- (5-methyl- [1,2,4] oxadiazol-3-yl by reacting 1-naphthylcarbonyl chloride ) Phenyl] methanone;
    2-naphthylcarbonyl chloride was reacted to [4- (2-naphthylcarbonyl) piperazin-1-yl] [4- (5-methyl- [1,2,4] oxadiazol-3-yl ) Phenyl] methanone;
    Nicotinoyl chloride was reacted to [4- (nicotinoyl) piperazin-1-yl] [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] methanone To obtain;
    3-nitrobenzoyl chloride is reacted to [4- (3-nitrobenzoyl) piperazin-1-yl] [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] meta To obtain rice fields;
    Benzo- [b] thiophene-2-carbonyl chloride was reacted to [4- (benzo- [b] thiophene-2-carbonyl) piperazin-1-yl] [4- (5-methyl- [1 , 2,4] oxadiazol-3-yl) phenyl] methanone;
    4-trifluoromethoxybenzoyl chloride is reacted to [4- (4-trifluoromethoxybenzoyl) piperazin-1-yl] [4- (5-methyl- [1,2,4] oxadiazole-3 -Yl) phenyl] methanone;
    2,5-dimethoxyphenylacetyl chloride was reacted to [4- (2,5-dimethoxyphenylacetyl) piperazin-1-yl] [4- (5-methyl- [1,2,4] oxadiazole -3-yl) phenyl] methanone;
    4-chlorophenylacetyl chloride is reacted to [4- (4-chlorophenylacetyl) piperazin-1-yl] [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl ] Metanon is obtained;
    1,3-benzodioxol-5-carbonyl chloride was reacted to [4- (1,3-benzodioxol-5-carbonyl) piperazin-1-yl] [4- (5-methyl- [1 , 2,4] oxadiazol-3-yl) phenyl] methanone;
    3,4-dichlorobenzoyl chloride was reacted to [4- (3,4-dichlorobenzoyl) piperazin-1-yl] [4- (5-methyl- [1,2,4] oxadiazol-3-yl ) Phenyl] methanone;
    Isobutyl chloroformate is reacted to [4- (isobutyloxycarbonyl) piperazin-1-yl] [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] Obtain metanon.
    By hydrogenation, the compounds produce the following amidine derivatives:
    4- [4- (4-phenylbenzoyl) piperazine-1-carbonyl] benzamidine, acetate, FAB 413;
    4- [4- (cyclopentylcarbonyl) piperazine-1-carbonyl] benzamidine, acetate, FAB 329;
    4- [4- (phenoxyacetyl) piperazin-1-carbonyl] benzamidine, acetate, FAB 367;
    4- [4- (1-naphthylcarbonyl) piperazine-1-carbonyl] benzamidine, acetate, FAB 387;
    4- [4- (2-naphthylcarbonyl) piperazine-1-carbonyl] benzamidine, acetate, FAB 387;
    4- [4- (nicotinoyl) piperazine-1-carbonyl] benzamidine, acetate, FAB 338;
    4- [4- (3-aminobenzoyl) piperazine-1-carbonyl] benzamidine;
    4- [4- (benzo- [b] thiobenzene-2-carbonyl) piperazine-1-carbonyl] benzamidine, acetate, FAB 393;
    4- [4- (4-trifluoromethoxybenzoyl) piperazin-1-carbonyl] benzamidine, acetate, FAB 421;
    4- [4- (2,5-dimethoxyphenylacetyl) piperazine-1-carbonyl] benzamidine, acetate, FAB 411;
    4- [4- (4-chlorophenylacetyl) piperazin-1-carbonyl] benzamidine, acetate, FAB 385;
    4- [4- (1,3-benzodioxol-5-carbonyl) piperazine-1-carbonyl] benzamidine, acetate, FAB 381;
    4- [4- (3,4-dichlorobenzoyl) piperazin-1-carbonyl] benzamidine, acetate, FAB 381;
    4- [4- (isobutyloxycarbonyl) piperazine-1-carbonyl] benzamidine, acetate, FAB 333.
    Example 8
    4- [4- (6-chloronaphthalene-2-sulfonyl) piperazin-1-carbonyl] benzamidine is reacted with an equal molar amount of acetyl chloride in pyridine and a catalytic amount of dimethylaminopyridine to allow for normal work-up. After that, N- {imino-4- [4- (6-chloronaphthalene-2-sulfonyl) piperazine-1-carbonyl] phenylmethyl} acetamide is obtained.
    Example 9
    Equal amounts of 4-cyanobenzyl bromide, BOC-piperazine and triethylamine in dichloromethane are reacted to yield 1- (4-cyanobenzyl) -4- (tert-butyloxycarbonyl) piperazine do. a) reacted with hydroxylamine hydrochloride, triethylamine and acetic anhydride in ethanol to 1- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) benzyl] -4 Obtain-(tert-butyloxycarbonyl) piperazine.
    Similar to Examples 1 and 2, after removing the BOC group with TFA in CH 2 Cl 2 , 1- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) benzyl] pipe Razine is reacted with 6-chloronaphthalene-2-sulfonyl chloride and then hydrogenated and conventional workup to give compound 4-[(6-chloronaphthalene-2-sulfonyl) piperazin-1-ylmethyl] benzamidine To obtain.
    The following compounds are similarly obtained:
    4-[(4-biphenylylsulfonyl) piperazin-1-ylmethyl] benzamidine,
    4-[(2-naphthylsulfonyl) piperazin-1-ylmethyl] benzamidine,
    4-[(4-propylphenylsulfonyl) piperazin-1-ylmethyl] benzamidine and
    4-[(2-phenylvinylsulfonyl) piperazin-1-ylmethyl] benzamidine.
    Example 10
    Equal molar amount of 4- (5-methyl- [1,2,4] oxadiazol-3-yl] benzoic acid, diphenylphosphoryl azide and triethylamine in DMF was reacted to give 4 after normal workup. Obtain-(5-methyl- [1,2,4] oxadiazol-3-yl) benzoyl azide.
    When heated with BOC-piperazine in toluene, 1-BOC-4- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenylcar after normal workup in the rearrangement reaction Barmoyl] piperazine is obtained. 4- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenylcarbamoyl] piperazine ("C") by removing the BOC group with TFA in CH 2 Cl 2 To obtain.
    Similar to Examples 1 and 2, “C” is reacted with 6-chloronaphthalenesulfonyl chloride and then hydrogenated to give compound N- (4-amidinophenyl) -4- (6-chloronaphthalene-2-sulfonyl ) Piperazine-1-carboxamide is obtained.
    The following compounds are similarly obtained:
    N- (4-amidinophenyl) -4- (4-biphenylylsulfonyl) piperazine-1-carboxamide,
    N- (4-amidinophenyl) -4- (2-naphthylsulfonyl) piperazine-1-carboxamide,
    N- (4-amidinophenyl) -4- (4-propylphenylsulfonyl) piperazine-1-carboxamide and
    N- (4-amidinophenyl) -4- (2-phenylvinylsulfonyl) piperazine-1-carboxamide.
    Example 11
    Equal molar amount of 1-BOC-4- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenylcarbamoyl] piperazine, methyl bromoacetate and potassium tert in DMF -Butoxide reacted, after normal workup, compound methyl {(4-BOC-piperazin-1-carbonyl) [4- (5-methyl- [1,2,4] oxadiazol-3-yl ) Phenyl] amino} acetate.
    a) HCl / dioxane and b) NaOH to react the compound methyl {(piperazin-1-carbonyl) [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl ) Amino} acetate is obtained.
    Similar to Example 1, by reacting with 6-chloronaphthalenesulfonyl chloride, the compound methyl {[4- (6-chloronaphthalene-2-sulfonyl) piperazin-1-carbonyl] [4- (5-methyl -[1,2,4] oxadiazol-3-yl) phenyl] amino} acetate.
    This yields methyl {[4- (6-chloronaphthalene-2-sulfonyl) piperazin-1-carbonyl] [4-amidinophenyl] amino} acetate by hydrogenation on Raney nickel.
    Methyl esters are cleaved by treatment with NaOH in methanol / water. Typical workup yields {[4- (6-chloronaphthalene-2-sulfonyl) piperazine-1-carbonyl] [4-amidinophenyl] amino} acetic acid.
    Similarly, the following compounds are obtained:
    {[4- (4-biphenylylsulfonyl) piperazin-1-carbonyl] [4-amidinophenyl] amino} acetic acid,
    {[4- (2-naphthylsulfonyl) piperazine-1-carbonyl] [4-amidinophenyl] amino} acetic acid
    {[4- (4-propylphenylsulfonyl) piperazin-1-carbonyl] [4-amidinophenyl] amino} acetic acid and
    {[4- (2-phenylvinylsulfonyl) piperazine-1-carbonyl] [4-amidinophenyl] amino} acetic acid.
    Example 12
    Equal molar amount of 4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenylacetic acid, methyl iodide and potassium carbonate were reacted to afford methyl 4- (5-methyl- [ 1,2,4] oxadiazol-3-yl) phenylacetate ("D") is obtained.
    Equal amounts of BOC-piperazine and to chloroacetyl chloride in toluene are heated to give 1-BOC-4-chloromethylcarbonylpiperazine ("E") after normal workup. After normal workup by reacting “D” and “E” with NaH in DMF, the compound methyl 4- (4-BOC-piperazin-1-yl) -2- [4- (5-methyl- [1,2 , 4] oxadiazol-3-yl) phenyl] -4-oxobutyrate.
    a) HCl / dioxane and b) NaOH to react the compound methyl 4- (piperazin-1-yl) -2- [4- (5-methyl- [1,2,4] oxadiazole-3- To obtain phenyl] -4-oxobutyrate.
    Similar to Example 1, by reacting with 6-chloronaphthalenesulfonyl chloride, the compound methyl 4- [4- (6-chloronaphthalene-2-sulfonyl) piperazin-1-yl] -2- [4- ( 5-Methyl- [1,2,4] oxadiazol-3-yl) phenyl] -4-oxobutyrate is obtained.
    By hydrogenation similar to Example 2, it is compound methyl 4- [4- (6-chloronaphthalene-2-sulfonyl) piperazin-1-yl] -2- [4-amidinophenyl] -4-oxobutyrate Create
    Methyl esters are cleaved by treatment with NaOH in methanol / water. Typical workup yields 4- [4- (6-chloronaphthalene-2-sulfonyl) piperazin-1-yl] -2- (4-amidinophenyl) -4-oxobutyric acid.
    The following compounds are similarly obtained:
    4- [4- (4-biphenylylsulfonyl) piperazin-1-yl] -2- (4-amidinophenyl) -4-oxobutyric acid,
    4- [4- (2-naphthylsulfonyl) piperazin-1-yl] -2- (4-amidinophenyl) -4-oxobutyric acid,
    4- [4- (4-propylphenylsulfonyl) piperazin-1-yl] -2- (4-amidinophenyl) -4-oxobutyric acid and
    4- [4- (2-phenylvinylsulfonyl) piperazin-1-yl] -2- (4-amidinophenyl) -4-oxobutyric acid.
    Example 13
    Equivalent amount of "A" in dichloromethane and phenyl isocyanate at room temperature are reacted, and after normal workup, compound N-phenyl-4- [4- (5-methyl- [1,2,4] oxadiazole- 3-yl) benzoyl] piperazin-1-carboxamide is obtained.
    Similarly, with "A"
    4-trifluoromethylphenyl isocyanate to react N- (4-trifluoromethylphenyl) -4- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) benzoyl] piperazine To obtain -1-carboxamide;
    Butyl isocyanate is reacted to give N-butyl-4- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) benzoyl] piperazine-1-carboxamide;
    Reacting 1-naphthyl isocyanate to N- (1-naphthyl) -4- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) benzoyl] piperazin-1-car To obtain voxamide;
    4-methoxyphenyl isocyanate to react N- (4-methoxyphenyl) -4- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) benzoyl] piperazine-1 -Carboxamide is obtained;
    4-nitrophenyl isocyanate is reacted to give N- (4-nitrophenyl) -4- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) benzoyl] piperazin-1-car To obtain voxamide;
    Cyclohexyl isocyanate is reacted to obtain N-cyclohexyl-4- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) benzoyl] piperazine-1-carboxamide;
    Reacting 3-ethoxycarbonylphenyl isocyanate N- (3-ethoxycarbonylphenyl) -4- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) benzoyl] Obtain piperazine-1-carboxamide.
    The compounds produce the following amidine derivatives by hydrogenation similar to Example 2:
    N-phenyl-4- (4-amidinobenzoyl) piperazine-1-carboxamide, acetate, FAB 352;
    N-butyl-4- (4-amidinobenzoyl) piperazine-1-carboxamide, acetate, FAB 332;
    N- (1-naphthyl) -4- (4-amidinobenzoyl) piperazine-1-carboxamide, acetate, FAB 402;
    N- (4-methoxyphenyl) -4- (4-amidinobenzoyl) piperazine-1-carboxamide, acetate, FAB 382;
    N- (4-aminophenyl) -4- (4-amidinobenzoyl) piperazine-1-carboxamide, acetate, FAB 367;
    N-cyclohexyl-4- (4-amidinobenzoyl) piperazine-1-carboxamide, acetate, FAB 358;
    N- (3-ethoxycarbonylphenyl) -4- (4-amidinobenzoyl) piperazine-1-carboxamide, acetate, FAB 424.
    Example 14
    Similar to Examples 1 and 2, the following compounds are obtained:
    3- [4- (2-naphthylsulfonyl) piperazine-1-carbonyl] benzamidine, acetate, FAB 423;
    3- [4- (3-chloro-4-methylphenylsulfonyl) piperazine-1-carbonyl] benzamidine, acetate, FAB 421;
    3- [4- (2,4,6-trichlorophenylsulfonyl) piperazin-1-carbonyl] benzamidine, acetate, FAB 475,477;
    3- [4- (3-amino-4-chlorophenylsulfonyl) piperazine-1-carbonyl] benzamidine, acetate, FAB 422;
    3- [4- (4-chlorophenylsulfonyl) piperazine-1-carbonyl] benzamidine, acetate, FAB 407;
    3- [4- (3-trifluoromethylphenylsulfonyl) piperazine-1-carbonyl] benzamidine, acetate, FAB 441;
    3- [4- (4-biphenylylsulfonyl) piperazin-1-carbonyl] benzamidine, acetate, FAB 449;
    4- [4- (3,5-dimethoxyphenylsulfonyl) piperazine-1-carbonyl] benzamidine, acetate, FAB 433;
    4- [4- (dibenzofuran-2-ylsulfonyl) piperazin-1-carbonyl] benzamidine, acetate, FAB 463;
    4- [4- (3-fluoro-4-methoxyphenylsulfonyl) piperazin-1-carbonyl] benzamidine, acetate, FAB 421;
    4- [4- (2,4-dichloro-6-methoxyphenylsulfonyl) piperazine-1-carbonyl] benzamidine, acetate, FAB 471;
    4- (4-benzylpiperazin-1-carbonyl) benzamidine, acetate, FAB 323;
    4- [4- (2-naphthylmethyl) piperazine-1-carbonyl] benzamidine, acetate, FAB 373;
    4- [4- (4-methoxyphenylmethyl) piperazin-1-carbonyl] benzamidine, diacetate, FAB 353;
    4- [4- (4-methoxycarbonylphenylsulfonyl) piperazin-1-carbonyl] benzamidine, acetate, FAB 431;
    4- [4- (4-propylphenylsulfonyl) piperazine-1-carbonyl] -3-methylbenzamidine, acetate, FAB 429;
    4- [4- (2-naphthylsulfonyl) piperazine-1-carbonyl] -3-methylbenzamidine, acetate, FAB 437;
    4- [4- (6-chloro-2-naphthylsulfonyl) piperazin-1-carbonyl] -3-methylbenzamidine, acetate, FAB 471;
    4- [4- (7-methoxy-2-naphthylsulfonyl) piperazine-1-carbonylbenzamidine, acetate, FAB 453;
    4- [4- (3,5-dimethoxyphenylmethyl) piperazine-1-carbonyl] benzamidine, acetate, FAB 383.
    Example 15
    Similar to Example 6, the following compounds are obtained:
    4- {3-oxo-3- [4- (butylsulfonyl) piperazin-1-yl] propyl} benzamidine, acetate, FAB 381;
    4- {3-oxo-3- [4- (4-propylphenylsulfonyl) piperazin-1-yl] propyl} benzamidine, acetate, FAB 443;
    4- {3-oxo-3- [4- (6-chloro-2-naphthylsulfonyl) piperazin-1-yl] propyl} benzamidine, acetate, FAB 485;
    4- {3-oxo-3- [4- (2-naphthylsulfonyl) piperazin-1-yl] propyl} benzamidine, acetate, FAB 451;
    4- {3-oxo-3- [4- (3-chloro-4-methylphenylsulfonyl) piperazin-1-yl] propyl} benzamidine, acetate, FAB 449;
    4- {3-oxo-3- [4- (4-chlorophenylsulfonyl) piperazin-1-yl] propyl} benzamidine, acetate, FAB 435;
    4- {3-oxo-3- [4- (4-biphenylylsulfonyl) piperazin-1-yl] propyl} benzamidine, acetate, FAB 477;
    4- {3-oxo-3- [4- (2,4,6-trimethylphenylsulfonyl) piperazin-1-yl] propyl} benzamidine, acetate, FAB 443;
    3- {3-oxo-3- [4- (butylsulfonyl) piperazin-1-yl] propyl} benzamidine, acetate, FAB 381;
    3- {3-oxo-3- [4- (4-methoxyphenylsulfonyl) piperazin-1-yl] propyl} benzamidine, acetate, FAB 431;
    3- {3-oxo-3- [4- (4-chlorophenylsulfonyl) piperazin-1-yl] propyl} benzamidine, acetate, FAB 435;
    3- {3-oxo-3- [4- (4-isopropylphenylsulfonyl) piperazin-1-yl] propyl} benzamidine, acetate, FAB 443;
    3- {3-oxo-3- [4- (2,4,6-trimethylphenylsulfonyl) piperazin-1-yl] propyl} benzamidine, acetate, FAB 443;
    3- {3-oxo-3- [4- (3-chloro-4-methylphenylsulfonyl) piperazin-1-yl] propyl} benzamidine, acetate, FAB 449;
    3- {3-oxo-3- [4- (6-chloro-2-naphthylsulfonyl) piperazin-1-yl] propyl} benzamidine, acetate, FAB 485;
    3- {3-oxo-3- [4- (2-naphthylsulfonyl) piperazin-1-yl] propyl} benzamidine, acetate, FAB 451;
    3- {3-oxo-3- [4- (4-biphenylylsulfonyl) piperazin-1-yl] propyl} benzamidine, acetate, FAB 477.
    Example 16
    Similar to Example 13, 4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl isocyanate ("F") and
    N- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -4- (2-naphthylsulfonyl by reacting 1- (2-naphthylsulfonyl) piperazine ) Piperazine-1-carboxamide
    N- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -4- (2-phenylvinyl by reacting 1- (2-phenylvinylsulfonyl) piperazine Sulfonyl) piperazine-1-carboxamide;
    N- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -4- (4-propylphenyl by reacting 1- (4-propylphenylsulfonyl) piperazine Sulfonyl) piperazine-1-carboxamide;
    N- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -4- (4-chlorophenyl by reacting 1- (4-chlorophenylsulfonyl) piperazine Sulfonyl) piperazine-1-carboxamide;
    1- (2,4,6-trimethylphenylsulfonyl) piperazine was reacted to give N- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -4- ( 2,4,6-trimethylphenylsulfonyl) piperazine-1-carboxamide;
    N- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -4- (6 by reacting 1- (6-chloro-2-naphthylsulfonyl) piperazine -Chloro-2-naphthylsulfonyl) piperazine-1-carboxamide.
    By hydrogenation similar to Example 2, the compounds yield the following amidine derivatives:
    N- (4-amidinophenyl) -4- (2-naphthylsulfonyl) piperazine-1-carboxamide, acetate, FAB 438;
    N- (4-amidinophenyl) -4- (2-phenylvinylsulfonyl) piperazine-1-carboxamide, acetate, FAB 414;
    N- (4-amidinophenyl) -4- (4-propylphenylsulfonyl) piperazine-1-carboxamide, acetate, FAB 430;
    N- (4-amidinophenyl) -4- (4-chlorophenylsulfonyl) piperazine-1-carboxamide, acetate, FAB 422;
    N- (4-amidinophenyl) -4- (2,4,6-trimethylphenylsulfonyl) piperazine-1-carboxamide, acetate, FAB 430;
    N- (4-amidinophenyl) -4- (6-chloro-2-naphthylsulfonyl) piperazine-1-carboxamide, acetate, FAB 472.
    Example 17
    Similar to Example 1, 1- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) benzyl] piperazine ("G") and
    4-propylphenylsulfonyl chloride was reacted to produce 1- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) benzyl] -4- (4-propylphenylsulfonyl) piperazine To obtain;
    4-methoxyphenylsulfonyl chloride was reacted to give 1- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) benzyl] -4- (4-methoxyphenylsulfonyl) Obtaining piperazine;
    4-biphenylylsulfonyl chloride is reacted to give 1- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) benzyl] -4- (4-biphenylylsulfonyl) piperazine To obtain;
    2-naphthylsulfonyl chloride was reacted to give 1- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) benzyl] -4- (2-naphthylsulfonyl) piperazine and;
    6-chloro-2-naphthylsulfonyl chloride was reacted to give 1- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) benzyl] -4- (6-chloro-2- To obtain naphthylsulfonyl) piperazine;
    7-methoxy-2-naphthylsulfonyl chloride was reacted to give 1- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) benzyl] -4- (7-methoxy- Obtaining 2-naphthylsulfonyl) piperazine;
    Reacting 3,5-dimethoxybenzyl chloride with 1- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) benzyl] -4- (3,5-dimethoxybenzyl) Obtaining piperazine;
    4-isopropylphenylsulfonyl chloride was reacted to give 1- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) benzyl] -4- (4-isopropylphenylsulfonyl) Obtaining piperazine;
    4-biphenylylcarbonyl chloride is reacted to give 1- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) benzyl] -4- (4-biphenylylcarbonyl) Obtaining piperazine;
    2-naphthylcarbonyl chloride was reacted to give 1- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) benzyl] -4- (2-naphthylcarbonyl) piperazine To obtain;
    Reacting 3,5-dimethoxybenzyl chloride with 1- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) benzyl] -4- (3,5-dimethoxybenzyl) Obtaining piperazine;
    2-naphthylmethyl chloride was reacted to give 1- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) benzyl] -4- (2-naphthylmethyl) piperazine do.
    By hydrogenation similar to Example 2, the compounds yield the following amidine derivatives:
    1- (4-amidinobenzyl) -4- (4-propylphenylsulfonyl) piperazine, acetate, FAB 401;
    1- (4-amidinobenzyl) -4- (4-methoxyphenylsulfonyl) piperazine, acetate, FAB 389;
    1- (4-amidinobenzyl) -4- (4-biphenylylsulfonyl) piperazine, acetate, FAB 435;
    1- (4-amidinobenzyl) -4- (2-naphthylsulfonyl) piperazine, acetate, FAB 409;
    1- (4-amidinobenzyl) -4- (6-chloro-2-naphthylsulfonyl) piperazine, acetate, FAB 443;
    1- (4-amidinobenzyl) -4- (7-methoxy-2-naphthylsulfonyl) piperazine, acetate, FAB 439;
    1- (4-amidinobenzyl) -4- (3,5-dimethoxybenzyl) piperazine, acetate, FAB 369;
    1- (4-amidinobenzyl) -4- (4-isopropylphenylsulfonyl) piperazine, acetate, FAB 441;
    1- (4-amidinobenzyl) -4- (4-biphenylylcarbonyl) piperazine, diacetate, FAB 399;
    51- (4-amidinobenzyl) -4- (2-naphthylcarbonyl) piperazine, diacetate, FAB 373;
    1- (4-amidinobenzyl) -4- (3,5-dimethoxybenzyl) piperazine, diacetate, FAB 369;
    1- (4-amidinobenzyl) -4- (2-naphthylmethyl) piperazine, diacetate, FAB 359.
    Example 18
    4- [4- (6-chloro-2-naphthylsulfonyl) piperazin-1-carbonyl] -3-methylbenzamidine is reacted with methyl chloroformate in dichloromethane to give compound methyl after normal workup. (Imino- {4- [4- (6-chloro-2-naphthylsulfonyl) piperazin-1-carbonyl] phenyl} methyl) carbamate is obtained.
    Example 19
    Similar to Example 1. 1- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] piperazine ("H ') and
    4-propylphenylsulfonyl chloride was reacted to give 1- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -4- (4-propylphenylsulfonyl) piperazine To obtain;
    4-butylsulfonyl chloride is reacted to give 1- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -4- (4-butylsulfonyl) piperazine and;
    4-methoxyphenylsulfonyl chloride is reacted to give 1- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -4- (4-methoxyphenylsulfonyl) Obtaining piperazine;
    4-chlorophenylsulfonyl chloride is reacted to give 1- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -4- (4-chlorophenylsulfonyl) piperazine To obtain;
    4-isopropylphenylsulfonyl chloride is reacted to give 1- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -4- (4-isopropylphenylsulfonyl) Obtaining piperazine;
    4-biphenylylsulfonyl chloride is reacted to give 1- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -4- (4-biphenylylphenylsulfonyl) Obtaining piperazine;
    1- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -4- (2,4,6 by reacting 2,4,6-trimethylphenylsulfonyl chloride -Trimethylphenylsulfonyl) piperazine;
    3-chloro-4-methylphenylsulfonyl chloride was reacted to give 1- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -4- (3-chloro-4- Obtaining methylphenylsulfonyl) piperazine;
    2-naphthylsulfonyl chloride was reacted to give 1- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -4- (2-naphthylsulfonyl) piperazine and;
    6-chloro-2-naphthylsulfonyl chloride was reacted to give 1- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) phenyl] -4- (6-chloro-2- Naphthylsulfonyl) piperazine is obtained.
    By hydrogenation similar to Example 2, the compounds yield the following amidine derivatives:
    1- (4-amidinophenyl) -4- (4-propylphenylsulfonyl) piperazine, acetate, FAB 387;
    1- (4-amidinophenyl) -4- (4-butylsulfonyl) piperazine, acetate, FAB 325;
    1- (4-amidinophenyl) -4- (4-methoxyphenylsulfonyl) piperazine, acetate, FAB 375;
    1- (4-amidinophenyl) -4- (4-chlorophenylsulfonyl) piperazine, acetate, FAB 379;
    1- (4-amidinophenyl) -4- (4-isopropylphenylsulfonyl) piperazine, acetate, FAB 387;
    1- (4-amidinophenyl) -4- (4-biphenylylphenylsulfonyl) piperazine, acetate, FAB 421;
    1- (4-amidinophenyl) -4- (2,4,6-trimethylphenylsulfonyl) piperazine, acetate, FAB 387;
    1- (4-amidinophenyl) -4- (3-chloro-4-methylphenylsulfonyl) piperazine, acetate, FAB 393;
    1- (4-amidinophenyl) -4- (2-naphthylsulfonyl) piperazine, acetate, FAB 395;
    1- (4-amidinophenyl) -4- (6-chloro-2-naphthylsulfonyl) piperazine, acetate, FAB 429.
    The following examples relate to pharmaceutical formulations.
    Example A: Injection Vials
    A solution of 5 g disodium hydrogen phosphate and 100 g of the active compound of formula (I) in 3 L of double distilled water was adjusted to pH 6.5 with 2 N hydrochloric acid, then sterile filtered, and the injection vial was filled with the solution, Lyophilized under sterile conditions and sealed under sterile conditions. Each injection vial contains 5 mg of active compound.
    Example B: Suppositories
    A mixture of 20 g of active compound of formula I and 100 g of soy lecithin and 1400 g of cocoa butter is melted, poured into a mold and cooled. Each suppository contains 20 mg of active compound.
    Example C: Solution
    The solution was prepared from 1 g of active compound of formula I, 9.38 g of NaH 2 PO 4 2H 2 O, 28.48 g of Na 2 HPO 4 12H 2 O and 0.1 g of benzalkonium chloride in 940 ml of distilled distilled water. Manufacture. The pH is adjusted to 6.8, filled to 1 l and sterilized by spinning. The solution may be used in the form of eye drops.
    Example D: Ointment
    500 g of the active compound of formula (I) are mixed with 99.5 g of petrolatum under aseptic conditions.
    Example E: Tablets
    1 kg of active compound of formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate are pressed into tablets in a conventional manner, so that each tablet gives 10 mg of active compound. Make it contain.
    Example F: Coated Tablets
    The tablets are pressed similarly to Example E and then coated with a coating of sucrose, potato starch, talc, tragacanth gum and pigment.
    Example G: Capsule
    Hard gelatin capsules are filled with 2 kg of the active compound of formula I in a conventional manner, such that each capsule contains 20 mg of the active compound.
    Example H: Ampule
    A solution of 1 kg of the active compound of formula I in 60 L of double distilled water is sterile filtered, the ampoules are filled with the solution, lyophilized under sterile conditions and sealed under sterile conditions. Each ampoule contains 10 mg of active compound.
    权利要求:
    Claims (9)
    [1" claim-type="Currently amended] Compounds of formula I and salts thereof
    [Formula I]
    [here,
    R 1 is —C (═NH) —NH, which may be mono-substituted by —COA—, —CO— [C (R 6 ) 2 ] n-Ar, —COOA, —OH, or by conventional amino protecting groups 2 ,
    ego
    R 2 is H, A, OR 6 , N (R 6 ) 2 , NO 2 , CN, Hal, NHCOA, NHCOAr, NHSO 2 A, NHSO 2 Ar, COOR 6 , CON (R 6 ) 2 , CONHAr, COR 6 , COAr, S (O) nA or S (O) nAr,
    R 3 is A, cycloalkyl,-[C (R 6 ) 2 ] nAr,-[C (R 6 ) 2 ] nO-Ar,-[C (R 6 ) 2 ] nHet or -C (R 6 ) 2 = C (R 6 ) 2 -Ar,
    R 6 is H, A or benzyl,
    X is absent or -CO-, -C (R 6 ) 2- , -C (R 6 ) 2 -C (R 6 ) 2- , -C (R 6 ) 2 -CO-, -C (R 6 ) 2 -C (R 6 ) 2 -CO-, -C (R 6 ) = C (R 6 ) -CO-, -NR 6 CO-, -N {[C (R 6 ) 2 ] n-COOR 6 } -CO- or -C (COOR 6 ) R 6 -C (R 6 ) 2 -CO-,
    Y is -C (R 6 ) 2- , -SO 2- , -CO-, -COO- or -CONR 6- ,
    A has 1 to 20 carbon atoms in which 1 or 2 CH 2 groups can be substituted by O or S atoms, or by -CR 6 = CR 6 -groups, and / or 1 to 7 H atoms can be substituted by F Is alkyl,
    Ar is A, Ar ', OR 6 , N (R 6 ) 2 , NO 2 , CN, Hal, NHCOA, NHCOAr', NHSO 2 A, NHSO 2 Ar ', COOR 6 , CON (R 6 ) 2 , CONHAr Naphthyl or phenyl which is mono, di or trisubstituted or unsubstituted by ', COR 6 , COAr', S (O) nA or S (O) nAr,
    Ar 'is one, two or three by A, OR 6 , N (R 6 ) 2 , NO 2 , CN, Hal, NHCOA, COOR 6 , CON (R 6 ) 2 , COR 6 or S (O) nA. Substituted or unsubstituted naphthyl or phenyl,
    Het contains 1, 2, 3 or 4 identical or different hetero atoms such as nitrogen, oxygen and sulfur, and He, A, Ar ', COOR 6 , CN, N (R 6 ) 2 , NO 2 , A monocyclic or bicyclic saturated or unsaturated heterocyclic ring system, mono- or polysubstituted or unsubstituted by Ar-CONH-CH 2 and / or carbonyl oxygen,
    Hal is F, Cl, Br or I,
    n is 0, 1 or 2;
    [2" claim-type="Currently amended] A compound according to claim 1, wherein
    a) 4- [4- (4-propylphenylsulfonyl) -1-piperazinylcarbonyl] benzamidine;
    b) 4- [4- (3-amino-4-chlorophenylsulfonyl) -1-piperazinylcarbonyl] benzamidine;
    c) 4- [4- (6-chloronaphthalene-2-sulfonyl) -1-piperazinylcarbonyl] benzamidine;
    d) 4- [4- (2-phenylvinylsulfonyl) -1-piperazinylcarbonyl] benzamidine.
    [3" claim-type="Currently amended] A process for the preparation of compounds of formula (I) and salts thereof according to claim 1 characterized by
    a) releasing a compound of formula (I) according to claim 1 and salts thereof from one of their functional derivatives by the following steps by treatment with a solubilizer or a hydrogenolytic agent:
    i) liberating an amidino group from its oxadiazole derivative by hydrogenolysis,
    ii) treating a conventional amino protecting group with a solubilizer or a hydrogenolysis agent to replace hydrogen or liberating an amino group protected by a conventional protecting group;
    or
    b) R 1 is ego,
    To prepare a compound of formula (I) wherein X is -CO- or -C (R 6 ) 2 -CO- and R 2 , R 3 and Y are as defined in claim 1, a compound of formula (II) Reacts with compounds:
    [Formula II]
    Where R 3 and Y are the same as in claim 1,
    [Formula III]
    [Where R 1 is ego,
    X is -CO- or -C (R 6 ) 2 -CO-,
    R 2 is the same as in claim 1,
    L is Cl, Br, I or an OH group induced with a free or reactive functional group;
    or
    c) R 1 is ego,
    Y is -SO 2- , -CO-, -COO- or -C (R 6 ) 2- ,
    Reacting a compound of formula IV with a compound of formula V to prepare a compound of formula I wherein R 2 and X are as in claim 1:
    [Formula IV] LYR 3
    [Where Y is -SO 2- , -CO-, -COO- or -C (R 6 ) 2- ,
    R 3 is the same as in claim 1,
    L is Cl, Br, I or an OH group induced with a free or reactive functional group],
    [Formula V]
    Where R 1 is ego,
    R 2 and X are the same as in claim 1;
    or
    d) R 1 is ego,
    Reacting a compound of formula VI with a compound of formula V to produce a compound of formula I wherein Y is -CONH- and R 2 and X are as in claim 1:
    [Formula VI] R 3 -N = C = O
    (Wherein R 3 is the same as in claim 1),
    [Formula V]
    Where R 1 is ego,
    R 2 and X are the same as in claim 1;
    or
    e) converting the cyano group to an amidino group to prepare a compound of formula I wherein R 1 is -C (= NH) -NH 2 ;
    And / or
    f) Sikkim transition from a compound of formula I, with one or more radicals R 1, R 2 and / or R 3 by, for example, one or more of the radicals by the steps R 1, R 2 and / or R 3:
    i) hydrolyzing the ester group to produce a carboxyl group,
    ii) reducing the nitro group,
    iii) acylating amino groups;
    And / or
    g) converting the base or acid of formula (I) to one of its salts.
    [4" claim-type="Currently amended] A compound of formula (I) according to claim 1 and / or one of its physiologically acceptable salts is prepared in a suitable dosage form together with one or more solid, liquid or semi-liquid carriers or auxiliaries. Manufacturing method.
    [5" claim-type="Currently amended] A pharmaceutical formulation characterized by the content of one or more compounds of formula (I) according to claim 1 and / or physiologically acceptable salts thereof.
    [6" claim-type="Currently amended] A compound of formula (I) according to claim 1 and a physiologically acceptable salt thereof for the treatment of thrombosis, myocardial infarction, atherosclerosis, inflammation, stroke, angina, recurrent stenosis and claudicatio intermittens after angioplasty.
    [7" claim-type="Currently amended] Pharmaceuticals of formula I according to claim 1 and physiologically acceptable salts thereof, as inhibitors of coagulation factor Xa.
    [8" claim-type="Currently amended] Use of a compound of formula I according to claim 1 and / or a physiologically acceptable salt thereof for the manufacture of a medicament.
    [9" claim-type="Currently amended] Use of a compound of formula (I) and / or a physiologically acceptable salt thereof according to claim 1 for the treatment of thrombosis, myocardial infarction, atherosclerosis, inflammation, stroke, angina, recurrent stenosis and intermittent claudication after angioplasty.
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    同族专利:
    公开号 | 公开日
    EP1025086A1|2000-08-09|
    JP2001518467A|2001-10-16|
    CN1272107A|2000-11-01|
    HU0004306A2|2001-11-28|
    ID24430A|2000-07-20|
    CA2305568A1|1999-04-08|
    RU2194044C2|2002-12-10|
    PL339173A1|2000-12-04|
    ZA9808937B|1999-03-31|
    AU9540798A|1999-04-23|
    EP1025086B1|2003-06-25|
    AU736080B2|2001-07-26|
    AR017164A1|2001-08-22|
    BR9812699A|2000-08-22|
    WO1999016751A1|1999-04-08|
    NO20001687L|2000-03-31|
    SK4472000A3|2000-11-07|
    NO20001687D0|2000-03-31|
    AT243681T|2003-07-15|
    US6492368B1|2002-12-10|
    HU0004306A3|2001-12-28|
    SK282799B6|2002-12-03|
    DE19743435A1|1999-04-08|
    ZA988937B|1999-03-31|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1997-10-01|Priority to DE19743435A
    1997-10-01|Priority to DE19743435.5
    1998-09-16|Application filed by 플레믹 크리스티안, 메르크 파텐트 게엠베하
    1998-09-16|Priority to PCT/EP1998/005898
    2001-03-26|Publication of KR20010024386A
    优先权:
    申请号 | 申请日 | 专利标题
    DE19743435A|DE19743435A1|1997-10-01|1997-10-01|Benzamidine derivatives|
    DE19743435.5|1997-10-01|
    PCT/EP1998/005898|WO1999016751A1|1997-10-01|1998-09-16|Benzamidine derivatives as factor xa inhibitors|
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