Benzamidine derivatives as factor XA inhibitors

Details Benzamidine derivatives as factor XA inhibitors Benzamidine derivatives as factor XA inhibitors

2000-03-31

2002-12-10

Bernhardt, Emily (Department: 1642)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S252130, C514S254030, C514S253060, C514S254040, C514S254050, C514S253130, C514S254110, C514S255010, C514S255030, C544S363000, C544S365000, C544S367000, C544S371000, C544S375000, C544S376000, C544S377000, C544S379000, C544S383000, C544S386000, C544S387000, C544S388000, C544S392000

Reexamination Certificate

active

06492368

ABSTRACT:

The invention relates to compounds of the formula I
in which
R
1
is —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,
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)
n
A or S(O)
n
Ar,
R
3
is A, cycloalkyl, —[C(R
6
)
2
]
n
Ar, —[C(R
6
)
2
]
n
—O—Ar, —[C(R
6
)
2
]
n
Het or —C(R
6
)
2
═C(R
6
)
2
—Ar,
R
6
is H, A or benzyl,
X is absent, —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
}—O— or —C(COOR
6
)R
6
—O(R
6
)
2
—CO—,
Y is —C(R
6
)
2
—, —SO
2
—, —CO—, —CO— or —CONR
6
—,
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 naphthyl or phenyl which is unsubstituted or mono-, di- or trisubstituted by 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′, COR
6
, COAr′, S(O)
n
A or S(O)
n
Ar,
Ar′ is naphthyl or phenyl 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,
Het is a mono- or bicyclic saturated or unsaturated heterocyclic ring system which contains one, two, three or four identical or different hetero atoms such as nitrogen, oxygen and sulphur and which is unsubstituted or mono- or polysubstituted by Hal, A, Ar′, COOR
6
, CN, N(R
6
)
2
, NO
2
, Ar—CONH—OH
2
and/or carbonyl oxygen,
Hal is F, Cl, Br or I,
n is 0, 1 or 2,
and salts thereof.
The invention also provides the optically active forms, the racemates, the diastereomers and the hydrates and solvates of these compounds.
The invention was based on the object of discovering novel compounds having valuable properties, in particular those which can be used for preparing medicaments.
It has been found that the compounds of the formula I and their salts have very useful pharmacological properties, coupled with good tolerability. In particular, they have factor Xa-inhibiting properties and can therefore be employed for combating and preventing thromboembolic disorders such as thrombosis, myocardial infarction, arteriosclerosis, inflammations, apoplexy, angina pectoris, restenosis after angioplasty and claudicatio intermittens.
Aromatic amidine derivatives having antithrombotic action are known, for example, from 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-inhibiting activity are known, for example, from WO 96/10022.
The antithrombotic and anticoagulant effect of the compounds according to the invention is attributed to the inhibiting action on the activated coagulation protease, known under the name factor Xa. Factor Xa is one of the proteases which is involved in the complex process of blood coagulation. Factor Xa catalyses the conversion of prothrombin into thrombin which in turn contributes to thrombus formation. An activation of thrombin can result in the occurrence of thromboembolic disorders. Inhibition of factor Xa can thus prevent thrombin formation. The compounds of the formula I according to the invention and their salts intervene in the blood coagulation process by inhibiting factor Xa and thus inhibit the formation of thrombi.
The inhibition of factor Xa by the compounds according to the invention and the measurement of the anti-coagulating and antithrombotic activity can be determined by customary in vitro or in vivo methods. A suitable method is described, for example, by J. Hauptmann et al. in
Thrombosis and Haemostasis
63, 220-223 (1990).
The inhibition of factor Xa can be determined, for example, by the method of T. Hara et al. in
Thromb. Haemoscas.
71, 314-319 (1994).
The compounds of the formula I can be employed as medicaments in human and veterinary medicine, in particular for combating and preventing thromboembolic disorders such as thrombosis, myoca-dial infarction, arteriosclerosis, inflammations, apoplexy, angina pectoris, restenosis after angioplasty and claudicatio intermittens.
The invention provides the compounds of the formula I and their salts, and also a process for preparing 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 treatment 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 treatment with a solvolysing or hydrogenolysing agent with hydrogen or liberating an amino group which is protected by a conventional protective group, or
b) that for preparing compounds of the formula I
in which
R
1
is
X is —CO— or —C(R )
2
—CO—,
and R
2
, R
3
and Y are as defined in Claim 1,
 a compound of the formula II
in which
R
3
, R
4
, R
5
, W and Y are as defined in Claim 1,
 is reacted with a compound of the formula III
in which
R
1
is
X is —CO— or —C(R
6
)
2
—CO—,
R
2
is as defined in Claim 1,
and L is Cl, Br, I or a free or a reactive functionally derivatized OH group, or
c) that for preparing compounds of the formula I
in which
R
1
is
Y is —SO
2
—, —CO—, —CO— or —C(R
6
)
2
—,
and R
2
and X are as defined in Claim 1,
 a compound of the formula IV
L—Y—R
3
  IV
in which
Y is —SO
2
—, —CO——CO— or —C(R
6
)
2
—,
R
3
is as defined in Claim 1, and L is Cl, Br, I or a free or a reactive functionally derivatized OH group,
 is reacted with a compound of the formula V
in which
R
1
is
and R
2
and X are as defined in Claim 1, or
d) that for preparing compounds of the formula I
in which
R
1
is
Y is —CONH—,
and R
2
and X are as defined in Claim 1,
 a compound of the formula VI
R
3—N=C=O
  VI
in which
R
3
is as defined in Claim 1,
 is reacted with a compound of the formula V
in which
R
1
is
and R
2
and X are as defined in Claim 1, or
e) that for preparing compounds of the formula I
in which
R
1
is —C(═NH)—NH
2
,
a cyano group is converted into an amidino group,
f) and/or that in a compound of the formula I, one or more radicals R
1
, R
2
and/or R
3
are converted into one or more radicals R
1
, R
2
and/or R
3
by, for example,
i) hydrolysing an ester group to give a carboxyl group,
ii) reducing a nitro group,
iii) acylating an amino group,
g) and/or converting a base or acid of the formula I into one of its salts.
For all the radicals which occur several times, such as, for example, R
6
, the meanings thereof are independent of one another.
Hereinabove and hereinbelow, the radicals or parameters L, X, Y, R
1
, R
2
and R
3
have the meanings given for the formulae I to VI, unless expressly stated otherwise.
In the above formulae, A is alkyl 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. Alkyl is furthermore, for example, trifluoromethyl, pentafluoroethyl, allyl or crotyl.
Cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Cycloalkyl is in particular the radical of a bicyclic terpene, such as, for example, 3-menthyl; very particular preference is given to the camphor-10-yl radical.
COR
6
is acyl and is preferably formyl, acetyl, propionyl, furthermore also butyryl, pentanoyl or hexanoyl.
Hal is preferably F, Cl or Br, but al

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