Biphenyl derivatives

Details Biphenyl derivatives Biphenyl derivatives

2000-12-29

2002-04-30

Kumar, Shailendra (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Amino nitrogen containing

C514S364000, C514S539000, C514S561000, C514S563000, C514S564000, C514S616000, C514S631000, C514S636000, C514S637000, C548S131000, C548S132000, C560S039000, C562S439000, C562S469000, C564S244000, C564S245000, C564S157000

Reexamination Certificate

active

06380430

ABSTRACT:

This application is a 371 of PCT/EP99/02457, filed Apr. 12, 1999.
The invention relates to compounds of the formula I
in which
R
1
, R
4
in each case independently of one another are —C(═NH)—NH
2
, which can also be monosubstituted by —COA, —CO—[C(R
6
)
2
]
n
—Ar, —COOA, —OH or by a conventional amino protective group, NH—C(═NH)—NH
2
, —CO—N═C(NH
2
)
2
,
R
2
, R
3
, R
5
in each case independently of one another are 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)
n
A, S(O)
n
Ar, —O—[C(R
6
)
2
]
m
—COOR
6
, —[C(R
6
)
2
]
p
—COOR
6
, —O—[C(R
6
)
2
]
m
—CON(R
6
)
2
, —[C(R
6
)
2
]
p
—CON(R
6
)
2
, —O—[C(R
6
)
2
]
m
—CONHAr, or —[C(R
6
)
2
]
p
—CONHAr,
X is —[CR
6
)
2
]
n
—, —CR
6
═CR
6
—, —[C(R
6
)
2
]
n
—O—, —O—[C(R
6
)
2
]
n
—, —COO—, —OOC—, —CONR
6
— or —NR
6
CO—,
R
6
is H, A or benzyl,
A is alkyl having 1-20 C atoms, in which one or two CH
2
groups can be replaced by O or S atoms or by —CR
6
═CR
6
— groups and/or 1-7 H atoms can be replaced by F,
Ar is phenyl or naphthyl, which is unsubstituted or mono-, di- or trisubstituted by A, Ar′, OR
6
, OAr′, N(R
6
)
2
, NO
2
, CN, Hal, NHCOA, NHCCOAr′, NHSO
2
A, NHSO
2
Ar′, COOR
6
, CON(R
6
)
2
, CONHAr′, COR
6
, COAr′, S(O)
n
A or S(O)
n
Ar′,
Ar′ is phenyl or naphthyl, which is unsubstituted or mono-, di- or trisubstituted by A, OR
6
, N(R
6
)
2
, NO
2
, CN, Hal, NHCOA, COOR
6
, CON(R
6
)
2
, COR
6
or S(O)
n
A,
Hal is F, Cl, Br or I,
n is 0, 1 or 2,
m is 1 or 2,
p is 1 or 2,
and their salts.
The invention also relates to the hydrates and solvates of these compounds.
The invention is based on the object of finding novel compounds having valuable properties, in particular those which can be used for the production of medicaments.
It has been found that the compounds of the formula I and their salts have very valuable pharmacological properties together with good tolerability. In particular, they exhibit factor Xa-inhibiting properties and can therefore be employed for the control and prevention of thromboembolic disorders such as thrombosis, myocardial infarct, arteriosclerosis, inflammations, apoplexy, angina pectoris, restenosis after angioplasty and intermittent claudication.
Aromatic amidine derivatives having antithrombotic action are disclosed, for example, in EP 0 540 051 B1. Cyclic guanidines for the treatment of thromboembolic disorders are described, for example, in WO 97/08165. Aromatic heterocycles having factor Xa-inhibitory activity are disclosed, for example, in WO 96/10022.
The antithrombotic and anticoagulating effect of the compounds according to the invention is attributed to the inhibitory action against the activated clotting protease, known under the name factor Xa. Factor. Xa is one of the proteases which is involved in the complex process of blood clotting. Factor Xa catalyzes the conversion of prothrombin into thrombin, which for its part contributes to thrombus formation. Activation of thrombin can lead to the occurrence of thromboembolic disorders.
Inhibition of the factor Xa can thus prevent thrombin being formed.
The compounds of the formula I according to the invention and their salts intervene in the blood clotting process by inhibition of the factor Xa and thus inhibit the formation of thrombi.
The inhibition of the factor Xa by the compounds according to the invention and the measurement of the anticoagulatory and antithrombotic activity can be determined according to customary in vitro or in vivo methods. A suitable procedure is described, for example, by J. Hauptmann et al. in
Thrombosis and Haeemostasis
63, 220-223 (1990).
The measurement of the addition of factor Xa can be carried out, for example, according to the method of T. Hara et al. in
Thromb. Haemostas
. 71, 314-319 (1994).
The compounds of the formula I can be employed as pharmaceutical active compounds in human and veterinary medicine, in particular for the control and prevention of thromboembolic disorders such as thrombosis, myocardial infarct, arteriosclerosis, inflammations, apoplexy, angina pectoris, restenosis after angioplasty and intermittent claudication.
The invention relates to the compounds of the formula I and their salts and to a process for the preparation of compounds of the formula I according to claim
1
and their salts, characterized in that
a) they are liberated from one of their functional derivatives by treating with a solvolysing or hydrogenolysing agent by
i) liberating an amidino group from its oxadiazole derivative by hydrogenolysis,
ii) replacing a conventional amino protective group by hydrogen by treating with a solvolysing or hydrogenolysing agent or liberating an amino group protected by a conventional protective group, or
b) in a compound of the formula I, converting one or more radical(s) Y, R
1
, R
2
, R
3
, R
4
and/or R
5
into one or more radical(s) R
1
, R
2
, R
3
, R
4
and/or R
5
, by for example,
i) hydrolysing an ester group to a carboxyl group,
ii) converting a hydroxylated amidino group to an amidino group,
iii) reducing a nitro group,
iv) acylating an amino group, and/or
c) converting a base or an acid of the formula I into one of its salts.
For all radicals which occur a number of times such as, for example, R
6
, it applies that their meanings are independent of one another.
Hydrates are understood as meaning, for example, the hemi-, mono- or dihydrates and solvates are understood as meaning, for example, alcohol addition compounds such as, for example, with methanol or ethanol.
In the above formulae, A is alkyl, is linear or branched, and has 1 to 20, preferably 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 C atoms. A is preferably methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore 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.
A is furthermore, for example, trifluoromethyl, pentafluoroethyl, allyl or crotyl.
COR
6
is acyl and is preferably formyl, acetyl, propionyl, furthermore also butyryl, pentanoyl or hexanoyl. COOR
6
is preferably methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl or butoxycarbonyl.
Hal is preferably F, Cl or Br, but also I.
R
2
, R
3
and R
5
are, in each case independently of one another, preferably H, fluorine, chlorine, bromine, iodine, hydroxyl, methoxy, ethoxy, propoxy, nitro, amino, methylamino, dimethylamino, ethylamino, diethylamino, acetamido, sulfonamido, methylsulfonamido, phenylsulfonamido, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl, phenylsulfinyl, phenylsulfonyl, cyano, carboxyl, methoxycarbonyl, ethoxycarbonyl, carboxymethoxy, methoxycarbonylmethoxy, carboxymethyl, methoxycarbonylmethyl, aminocarbonylmethoxy, aminocarbonylmethyl, N-phenylaminocarbonylmethoxy or N-phenylaminocarbonylmethyl, furthermore also acyl or benzoyl.
In particular, R
2
, R
5
are H.
R
3
is in particular, for example, H, COOA or —OCH
2
COOR
6
, where R
6
is H or alkyl having 1-4 C atoms.
R
6
is H, A or benzyl, but in particular H or alkyl having 1-4 C atoms.
X is preferably, for example, —CH
2
—, —CH═CH—, —CH
2
O—, —O—CH
2
—, —COO—, —OOC—, —CONH— or —NHCO—; —CH
2
O—, —O—CH
2
— or —CH
2
—CH
2
— is very particularly preferred.
Ar is preferably unsubstituted phenyl or naphthyl, furthermore phenyl or naphthyl, furthermore also biphenyl, which is preferably mono-, di- or trisubstituted, for example, by A, fluorine, chlorine, bromine, iodine, hydroxyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, benzyloxy, phenethyloxy, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl, phenylsulfinyl, phenylsulfonyl, nitro, amino, methylamino, ethylamino, d

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